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WO2025079039A1 - Traitement à base d'anti-pd-1 avant et après chirurgie - Google Patents

Traitement à base d'anti-pd-1 avant et après chirurgie Download PDF

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Publication number
WO2025079039A1
WO2025079039A1 PCT/IB2024/059994 IB2024059994W WO2025079039A1 WO 2025079039 A1 WO2025079039 A1 WO 2025079039A1 IB 2024059994 W IB2024059994 W IB 2024059994W WO 2025079039 A1 WO2025079039 A1 WO 2025079039A1
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antibody
cancer
administered
pct
seq
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Wenjuan ZHENG
Ruihua Wang
Qiuyang ZHANG
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BeiGene Switzerland GmbH
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BeiGene Switzerland GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • a method for the prevention, delay of progression or treatment of solid tumors, such as breast, colon and lung cancer e.g., non-small cell lung cancer
  • administering an antibody that binds to anti-PD-1, or a fragment thereof, as described herein (in particular using the doses and regimes of administration described herein), optionally in combination with a chemotherapy.
  • Immune checkpoint therapies targeting PD-L1, or its receptor, PD-1 have resulted in technological improvements in clinical response in multiple human cancer types (see, e.g., Brahmer et al., N Engl J Med, 366: 2455-2465 (2012); Robert et al., N Engl J Med, 372:320-330 (2015); Topalian et al., N Engl J Med, 366:2443-2454 (2012); Wolchok et al., N Engl J Med, 369:122-133 (2013)).
  • Tislelizumab (also known as BGB A317) is a humanized, immunoglobulin G4 (IgG4)-variant monoclonal antibody against PD-1 that has been developed for the treatment of human malignancies in multiple organs and tissues. Tislelizumab binds to the extracellular domain of human PD-1 with high specificity and affinity, and competitively blocks the binding of both PD-L1 and programmed death ligand-2 (PD-L2). Unlike other PD-1 inhibitors, tislelizumab has been specifically engineered to remove the Fc and hinge regions to minimize Fc ⁇ receptor binding on macrophages, which may abate potentially negative interactions.
  • IgG4 immunoglobulin G4
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, wherein the cancer is a surgically resectable solid cancer, comprising: (i) during a first treatment period parenterally administering to the subject a first dose of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the first dose of the anti- PD-1 antibody is 200 mg (e.g., once every three-weeks); (ii) after (i), surgically resecting the cancer of the subject; and [0009] (iii) during a second treatment period after (ii) parenterally administering to the subject a second dose of the anti-PD-1 antibody, or an antigen-binding fragment thereof, wherein 2 4893-2664-4718.1 Atty.
  • the second dose of the anti-PD-1 antibody is 400 mg (e.g., once every 6 weeks)
  • tumor lesions are measured by CT scan or X-ray before treatment and then after 200 mg at the time of surgery.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a VH CDR1, VH CDR2, and a VH CDR3 comprising amino acid sequences as set forth in SEQ ID Nos: 31, 32 and 33, and a VL CDR1, VL CDR2, and a VL CDR3 comprising amino acid sequences as set forth in SEQ ID Nos: 34, 35 and 36.
  • the cancer is an early-stage cancer. In some aspects, the cancer is a Stage II or Stage IIIA cancer. In some aspects, the cancer is a Stage I cancer. In some aspects, the cancer is a Stage IIA cancer. In some aspects, the cancer is a Stage IIB cancer.
  • the cancer is an mid-stage cancer. In some aspects, the cancer is an advanced stage or metastatic cancer (such as resectable advanced or metastatic cancer). In some aspects, the cancer is breast, colon or a lung cancer. In some aspects, the cancer is non-small cell lung cancer (NSCLC). In some aspects, the cancer is squamous cell carcinoma. In some aspects, the cancer is non-squamous cell carcinoma. In some aspects, the cancer is stage II or IIIA NSCLC. In some aspects, the cancer is not locally advanced or metastatic (e.g., not locally advanced or metastatic NSCLC).
  • NSCLC non-small cell lung cancer
  • the cancer is squamous cell carcinoma. In some aspects, the cancer is non-squamous cell carcinoma. In some aspects, the cancer is stage II or IIIA NSCLC. In some aspects, the cancer is not locally advanced or metastatic (e.g., not locally advanced or metastatic NSCLC).
  • the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO:24
  • the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO:26
  • the anti-PD-1 antibody comprises an IgG constant region comprising an amino acid sequence of SEQ ID NO:88.
  • the anti-PD-1 antibody is administered intravenously, optionally wherein the administration is by IV infusion.
  • the subject has not been previously treated for the cancer or the treatment is a first-line therapy. In some aspects, the subject has not been previously treated with chemotherapy, radiotherapy and/or immunotherapy. In some aspects, the treatment is a second line therapy.
  • the first treatment period comprises 3 or 4 cycles of three-weeks 3 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 each.
  • the second treatment period comprises less than or equal to 8 cycles of six weeks each. In some aspects, the second treatment period comprises at least 8 cycles of six weeks each. In some aspects, the second treatment period starts within 8 weeks of the surgical resecting. [0014] In some aspects, the surgical resecting is followed by radiotherapy before the start of the second treatment period.
  • the radiotherapy is administered 30 to 60 days after the surgical resecting, and the second treatment period starts between 7 and 30 days after the radiotherapy. In some aspects, the surgical resecting is not followed by radiotherapy. In some aspects, the second treatment period starts between 2 and 8 weeks after the surgical resection. [0015] In some aspects, the first treatment period further comprises administering a therapeutically effective amount of one or more chemotherapeutic drugs. In some aspects, the one or more chemotherapeutic drugs comprises a platinum chemotherapy drug. In some aspects, the one or more chemotherapeutic drug is carboplatin or cisplatin.
  • the cisplatin is administered intravenously at about 75 mg/m2 or the carboplatin is administered intravenously at about area under the plasma or serum concentration-time curve 5 (AUC5), optionally wherein the administering is once every three-weeks (Q3W), optionally wherein the administration is by IV infusion.
  • the one or more chemotherapeutic drug further comprises pemetrexed or paclitaxel, optionally wherein the pemetrexed is used when the NSCLC is non- squamous and the paclitaxel is used when NSCLC is squamous.
  • the pemetrexed is administered intravenously at about 500 mg/m2, optionally wherein the administering is once every three-weeks (Q3W), optionally wherein the administration is by IV infusion.
  • the paclitaxel is administered intravenously at about 175 mg/m2, optionally wherein the administering is once every three-weeks (Q3W), optionally wherein the administration is by IV infusion.
  • the treating is clinically effective or the subject is a responder to the treating by at least one measure of response to treatment.
  • the response to treatment is measured by overall survival, progression-free or event-free survival, major 4 4893-2664-4718.1 Atty. Dkt.
  • MPR pathological response
  • pCR pathological complete response
  • a major pathological response is defined as less than 10% residual viable tumor after neoadjuvant therapy.
  • the treating results in the MPR in the subject.
  • the MPR is at least twice that observed in the control group not treated with the anti-PD-1 antibody.
  • the subject has at least 25%, 35%, 40%, 45% or 50% probability of the MPR.
  • the treating is effective as demonstrated by patient population MPR of at least 25%, 35%, 40%, 45% or 50%.
  • the response to treatment is measured by tumor volume, size or diameter, and wherein the treating reduces tumor volume, size or diameter in the subject by at least or more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%.
  • the treating results in the pCR in the subject.
  • the subject has at least 15%, 20%, 25%, 30%, 35%, or 40% probability of the pCR, or the treating is effective as demonstrated by patient population pCR of at least 15%, 20%, 25%, 30%, 35%, or 40%.
  • the subject does not have an EGFR mutation, ROS1 mutation or an ALK gene translocation. In some aspects, the subject is EGFR negative for genomic tumor aberrations. In some aspects, the subject is negative for ALK genomic tumor aberrations. [0019] In some aspects, the subject is a human. In some aspects, the human is an adult. In some aspects, the subject does not have a locally advanced cancer and/or metastatic cancer. In some aspects, the subject has liver, lung, lymph node, bone and/or adrenal gland metastasis, optionally wherein the subject has liver, lung and/or lymph node metastasis.
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, wherein: the cancer is a solid cancer, and the solid cancer is selected from the group consisting of a lung cancer, a breast cancer, and a colon cancer, the method comprises parenterally administering to the subject a dose of an anti-PD-1 antibody, or an antigen-binding fragment thereof, wherein the dose is: (i) about 50 to 800 mg, or (ii) about 2 mg/kg to about 5 mg/kg; and the anti-PD-1 antibody comprises: 5 4893-2664-4718.1 Atty. Dkt.
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, wherein the cancer is a solid cancer, comprising parenterally administering to the subject an anti-PD-1 antibody, or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody is administered: (i) at a dose from about 50 to 800 mg, or (ii) at a dose from about 2 mg/kg to about 5 mg/kg; and the anti-PD-1 antibody comprises: (a) a VH CDR1, VH CDR2, and a VH CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:31, 32 and 33, and (b) a VL CDR1, VL CDR2, and a VL CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:34, 35 and 36; and the method further comprises administering a therapeutically effective amount of chemotherapeutic drugs comprising (i) a platinum chemotherapy drug, or (ii) carboplatin, and
  • the method further comprises administering a therapeutically effective amount of one or more chemotherapeutic drugs.
  • the one or more chemotherapeutic drugs comprises a platinum chemotherapy drug.
  • the one or more chemotherapeutic drugs comprises pemetrexed and a platinum chemotherapy drug.
  • the platinum chemotherapy drug is carboplatin or cisplatin.
  • the one or more chemotherapeutic drugs comprises (a) carboplatin, and (b) paclitaxel or nab-paclitaxel.
  • the cancer is a lung cancer, wherein the lung cancer is locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), wherein the lung cancer is negative for epidermal growth factor receptor (EGFR) aberrations and anaplastic 6 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 lymphoma kinase (ALK) genomic tumor aberrations, and the method further comprises administering pemetrexed and a platinum chemotherapy drug.
  • NSCLC metastatic non-squamous non-small cell lung cancer
  • the cancer is locally advanced or metastatic squamous non- small cell lung cancer (NSCLC), and the method further comprises administering (a) carboplatin, and (b) paclitaxel or nab-paclitaxel.
  • NSCLC metastatic squamous non- small cell lung cancer
  • the method further comprises administering (a) carboplatin, and (b) paclitaxel or nab-paclitaxel.
  • the subject has not been previously treated for the cancer or the treatment is a first-line therapy.
  • the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO:24
  • the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO:26.
  • the anti-PD-1 antibody comprises an IgG constant region comprising an amino acid sequence of SEQ ID NO:88.
  • the anti-PD-1 antibody is administered intravenously, optionally wherein the administration is by IV infusion.
  • the carboplatin is administered intravenously at about area under the plasma or serum concentration-time curve 5 (AUC5), optionally wherein the administering is once every three-weeks (Q3W), optionally wherein the administration is by IV infusion.
  • the pemetrexed is administered intravenously at about 500 mg/m2, optionally wherein the administering is once every three-weeks (Q3W), optionally wherein the administration is by IV infusion.
  • the paclitaxel is administered intravenously at about 175 mg/m2, optionally wherein the administering is once every three-weeks (Q3W), optionally wherein the administration is by IV infusion.
  • the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to 5 mg/kg, optionally wherein the anti-PD-1 antibody is administered at a dose of about 2mg/kg Q3W, 5mg/kg Q3W or 200 mg Q3W, optionally wherein the anti-PD-1 antibody is administered at a dose of about 400 mg, optionally wherein the anti-PD-1 antibody is administered at a dose of about 150 mg Q2W, optionally wherein the anti-PD-1 antibody is administered at a dose of about 300 mg Q4W, and optionally wherein the anti-PD-1 antibody is administered at a dose of about 400 mg Q6W.
  • the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 7 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg.
  • the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, optionally wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks.
  • the PD-1 antibody is administered at a first dose prior to surgical removal of the solid cancer, and wherein the PD-1 antibody is administered at a second dose after surgical removal of the solid cancer.
  • the first dose is: (i) about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, or (ii) about 2 mg/kg to about 5 mg/kg; optionally wherein the first dose is 200 mg once every three-weeks (Q3W); and wherein the second dose is: (i) about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, or (ii) about 2 mg/kg to about 5 mg/kg; optionally wherein the first dose is 400 mg once every six weeks (Q6W).
  • the solid cancer is an early-stage cancer. [0029] In some embodiments, the solid cancer is a Stage II or Stage IIIA cancer. [0030] In some embodiments, the solid cancer is not locally advanced or metastatic. [0031] In some embodiments, the solid cancer is breast, colon or a lung cancer. [0032] In some embodiments, the solid cancer is non-small cell lung cancer (NSCLC). [0033] In some embodiments, the solid cancer is squamous cell carcinoma. [0034] In some embodiments, the solid cancer is non-squamous cell carcinoma. [0035] In some embodiments, the solid cancer is stage II or IIIA. [0036] In some embodiments, the solid cancer is not locally advanced or metastatic.
  • NSCLC non-small cell lung cancer
  • the solid cancer is esophageal squamous cell carcinoma.
  • the anti-PD-1 antibody is formulated in a pharmaceutical composition comprising a histidine buffer, a surfactant, and a stabilizer.
  • the surfactant is a polysorbate.
  • the stabilizer is trehalose.
  • the present disclosure relates to a composition comprising an anti- PD-1 antibody for use in a method disclosed herein.
  • the present disclosure provides an anti- PD-1 antibody for the manufacture of a medicament for use in a method disclosed herein.
  • FIG.1 is a schematic showing clinical trial treatment arms in a randomized, double- blind, placebo-controlled Phase 3 study to compare the efficacy and safety of neoadjuvant treatment with tislelizumab plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab treatment versus neoadjuvant treatment with placebo plus platinum-based doublet chemotherapy followed by placebo in patients with resectable Stage II or IIIA NSCLC.
  • the study consisted of a screening phase, a treatment phase that included a neoadjuvant phase, surgery and an adjuvant phase, a safety follow-up phase, and a survival follow up phase.
  • AE adverse event
  • d Day 1
  • ECOG PS Eastern Cooperative Oncology Group Performance Status
  • IV intravenous(ly)
  • N number of patients
  • NSCLC non-small cell lung cancer
  • Q3W once every 3 weeks
  • Q6W once every 6 weeks
  • Sq Squamous
  • R randomization ratio
  • R0 pathological complete resection of the primary tumor
  • WT wild type.
  • FIG.2 Provides a table showing significant improvements in major pathological response (MPR) and pathological complete response (pCR) rates when comparing the efficacy of tislelizumab (i.e., an anti-PD-1 antibody) + platinum doublet (e.g., cisplatin or carboplatin + 9 4893-2664-4718.1 Atty. Dkt.
  • MPR major pathological response
  • pCR pathological complete response
  • FIG.3 provides a schematic of a study design to evaluate tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant treatment for resectable esophageal squamous cell carcinoma.
  • FIGs.4A-4B show results of the percentage of residual viable tumor in responders (FIG.4A) and non-responders (FIG.4B).
  • FIG.6 is a Kaplan-Meier plot of the ITT population. Kaplan-Meier plot of event-free survival assessed by blinded independent central review (ITT population) (A).
  • FIG.7 shows major pathological response rate and pathological complete response rate.
  • *MPR rate was defined as the proportion of patients with ⁇ 10% residual viable tumour in the resected primary tumour and all resected lymph nodes after completion of neoadjuvant treatment, as assessed by blinded independent pathology review in the ITT population. Patients who did not receive surgical resection, or if a surgical specimen was not available, were considered as non-responders in the analysis.
  • ⁇ pCR rate was defined as the proportion of patients absent of residual viable tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant treatment, as assessed by blinded independent pathology review in 10 4893-2664-4718.1 Atty. Dkt.
  • FIG.8 shows subgroup analysis of pathological complete response.
  • the present application provides the discovery of unexpected clinical benefits of the treatment regimen described herein before and/or after surgical removal of the solid cancer such as lung cancer, which historically has been difficult to treat.
  • a lung cancer such as non-small cell lung cancer
  • an anti-PD-1 antibody or an antigen-binding fragment thereof e.g., tislelizumab or an anti-PD-1 antibody having CDRs of the tislelizumab
  • chemotherapy e.g., tislelizumab or an anti-PD-1 antibody having CDRs of the tislelizumab
  • the chemotherapy is carboplatin and/or cisplatin, and optionally further paclitaxel and/or pemetrexed (e.g., paclitaxel if the cancer is a squamous cell carcinoma, and pemetrexed if the cancer is a non- squamous cell carcinoma).
  • paclitaxel if the cancer is a squamous cell carcinoma, and pemetrexed if the cancer is a non- squamous cell carcinoma.
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, wherein: the cancer is a solid cancer, and the solid cancer is selected from the group consisting of a lung cancer, a breast cancer, and a colon cancer, the method comprises parenterally administering to the subject a dose of an anti-PD-1 antibody, or an antigen-binding fragment thereof, wherein the dose is: (i) about 50 to 800 mg, or (ii) about 2 mg/kg to about 5 mg/kg; and the anti-PD-1 antibody comprises: (a) a VH CDR1, VH CDR2, and a VH CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:31, 32 and 33, and (b) a VL CDR1, VL CDR2, and a VL CDR3 comprising amino acid sequences as set forth
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, wherein the cancer is a solid cancer, comprising parenterally administering to the subject an anti-PD-1 antibody, or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody is administered: (i) at a dose from about 50 to 800 mg, or (ii) at a dose from about 2 mg/kg to about 5 mg/kg; and the anti-PD-1 antibody comprises: (a) a VH CDR1, VH CDR2, and a VH CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:31, 32 and 33, and (b) a VL CDR1, VL CDR2, and a VL CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:34, 35 and 36; and the method further comprises administering a therapeutically effective amount of chemotherapeutic drugs comprising (i) a platinum chemotherapy drug, or (ii) carboplatin, and
  • the method further comprises administering a therapeutically effective amount of one or more chemotherapeutic drugs.
  • a resectable solid cancer e.g. a lung cancer, such as non-small cell lung cancer
  • a subject e.g., human
  • PCT/CN2023/135545 and PCT/CN2023/124264 thereof e.g., tislelizumab or an anti-PD-1 antibody having CDRs of the tislelizumab
  • chemotherapy carboplatin, cisplatin, paclitaxel and/or pemetrexed
  • methods of treatment or delay or progression of a resectable solid cancer e.g.
  • a lung cancer such as non-small cell lung cancer
  • a subject e.g., human
  • a first dose of an anti-PD-1 antibody or an antigen- binding fragment thereof e.g., tislelizumab or an anti-PD-1 antibody having CDRs of the tislelizumab
  • chemotherapy carboplatin, cisplatin, paclitaxel and/or pemetrexed
  • a second dose of the anti-PD-1 antibody or an antigen-binding fragment thereof is administered to a second dose of the anti-PD-1 antibody or an antigen-binding fragment thereof.
  • the first dose of the anti-PD-1 antibody or fragment thereof is 200 mg
  • the second dose of the anti-PD-1 antibody or fragment thereof is 400 mg.
  • the first dose is administered every 3 weeks (e.g., for 2, 3, or 4 cycles).
  • the second dose is administered every 6 weeks (e.g., for 6, 7, 8, 9 or 10 cycles or more).
  • the solid cancer treated in accordance with the methods described herein is early- to mid-stage solid cancer, for example lung cancer (e.g., non-small cell lung cancer).
  • the solid cancer is a squamous cell carcinoma.
  • the solid cancer is a non-squamous cell carcinoma.
  • the non-small cell lung cancer is a squamous cell carcinoma.
  • the non-small cell lung cancer is a non-squamous cell carcinoma.
  • the solid cancer is esophageal squamous cell carcinoma.
  • the therapy is a first-line therapy, i.e., the subject has not been treated (e.g., with chemotherapy and/or immunotherapy) for the cancer (e.g., lung cancer).
  • the subject has progressed after prior chemotherapy or did not tolerate prior chemotherapy.
  • the human subject is a responder to treatment by at least one 13 4893-2664-4718.1 Atty. Dkt.
  • the claimed therapy is effective in the treatment of solid cancer (e.g., stage I, stage IIA, stage II or stage IIIA solid cancer, such as breast, colon or lung cancer).
  • the claimed therapy is effective in the treatment of the non-small cell lung cancer (e.g., e.g., stage I, stage IIA, stage II or stage IIIA non-small cell lung cancer).
  • the inventors of this application discovered unexpected clinical benefits of the treatment regimen described herein for specified populations of human patients with solid tumor types, such as, e.g., non-small cell lung cancer.
  • Example 1 describes a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study that was conducted, comparing the efficacy of tislelizumab (i.e., an anti-PD-1 antibody) + platinum doublet (e.g., cisplatin or carboplatin + etoposide) (Arm A) and placebo + platinum doublet (Arm B) as first-line treatment in 453 patients with treatment-naive, resectable, confirmed squamous or non-squamous stage II- IIA NSCLC.
  • tislelizumab i.e., an anti-PD-1 antibody
  • platinum doublet e.g., cisplatin or carboplatin + etoposide
  • Arm B placebo + platinum doublet
  • Example 3 describes an ongoing Phase 2, Multicenter, Open-Label, 2- cohort Study to investigate the efficacy and safety of positron emission tomography (PET) guided neoadjuvant treatment with Tislelizumab (BGB-A317) plus chemotherapy/chemoradiotherapy in patients R-ESCC.
  • PET positron emission tomography
  • BGB-A317 Tislelizumab
  • chemotherapy/chemoradiotherapy in patients R-ESCC.
  • the purpose of this study was to evaluate 14 4893-2664-4718.1 Atty. Dkt.
  • Example 3 detailed significant differences in MPR rates (exceeding 40.0%) and pCR rates (35.0%) favouring the tislelizumab group. [0067] Finally, Example 4 describes a study demonstrating significant improvements in event-free survival, major pathological response, and pathological complete response following perioperative tislelizumab combined with neoadjuvant chemotherapy.
  • perioperative tislelizumab combined with neoadjuvant chemotherapy offered meaningful clinical benefit as compared to neoadjuvant placebo plus chemotherapy.
  • tislelizumab was administered at 400 mg on a 6-week cycle for up to eight cycles, providing a more flexible and convenient dosing schedule for patients than evaluated with other PD-(L)1 antibodies.
  • This phase 3 trial evaluated an extended dose interval for anti–PD-(L)1 antibodies in the perioperative setting.
  • the safety profile of tislelizumab, both as monotherapy and when combined with chemotherapy was manageable and consistent with the known safety profiles of the individual agents. II.
  • PD-1 Programmed Death-1
  • PD-1 also known as Programmed Death-1, PD1, Pdcd-1 and CD279
  • PD-1 is a 55 KD receptor protein related to CD28/CTLA4 co-stimulatory/inhibitory receptor family (Blank et al., 2005 Cancer Immunol Immunother 54:307-314).
  • the genes and cDNAs coding for PD-1 were cloned and characterized in mouse and human (Ishida et al., 1992 EMBO J 11:3887-3395; Shinohara et al., 1994 Genomics 23:704-706).
  • the full-length PD-1 contains 288 amino acid residues (NCBI accession number: NP_005009).
  • PD-1 protein kinase-like protein
  • T-cells T-cells
  • B-cells monocytes and natural killer cells
  • NK natural killer cells
  • high level of PD-1 expression is often associated with activation of immune cells.
  • human T-cell line Jurkat
  • PHA phytohaemagglutinin
  • phorbol ester (12-O-tetradecanoylphorbol-13- acetate, or TPA)
  • TILs tumor-infiltrating lymphocytes
  • PD-1 ligand expression in tumor cells were reported in varieties of cancers involved in different types of tissues and organs such as lung (Konishi et al., 2004 Clin Cancer Res 10:5094-5100), liver (Shi et al., 2008 Int J Cancer 128:887-896; Gao et al., 2009 Clin Cancer Res 15:971-979), stomach (Wu et al., 2006 Acta Histochem 108:19-24), kidney (Thompson et al., 2004 Proc Natl Acad Sci 101:17174-17179; Thompson et al., 2007 Clin Cancer Res 13:1757-1761), breast (Ghebeh et al., 2006 Neoplasia 8:190-198), ovary (Hamanishi et al.2007 Proc Natl Acad Sci 104:3360-3365), pancreas (Nomi et al., 2007 Clin
  • PD-1 blockade can be accomplished by a variety of mechanisms including antibodies that bind PD-1 or its ligands.
  • PD-1 and PD-L1 blockers also named PD-1 and PD- L1 inhibitors
  • PD-1 and PD-L1 blockers are described in US7488802; US7943743; US8008449; US8,168,757; US8217149, and WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, WO2011161699, and WO2015035606, the entire contents of each of which are incorporated herein by reference.
  • the methods described herein comprise administering an anti- PD-1 antibody or an antigen-binding fragment thereof.
  • the anti-PD-1 antibody is any antibody known in the art or described herein. In some embodiments, the anti-PD-1 antibody is any antibody that specifically binds to PD-1. In some embodiments, the anti-PD-1 antibody inhibits PD-1-mediated cellular signaling and activity in immune cells. In some embodiments, the anti-PD- 1 antibody binds to amino acid residues requires for its ligand binding and/or inhibits ligand binding. [0075] In some embodiments, the antibodies and fragments described herein are isolated and purified.
  • the present disclosure is directed to an antibody or antigen- binding fragment thereof, wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab′ fragment, or a F(ab′)2 fragment.
  • the anti-PD-1 antibody is a monoclonal antibody.
  • the anti-PD-1 antibody is a humanized antibody.
  • the anti- PD-1 antibody is a human antibody.
  • the anti-PD-1 antibody is a chimeric antibody.
  • anti-PD-1 antibody wherein the antibody 17 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 is an immunoglobulin comprising any VH and VL regions described herein.
  • the immunoglobulin molecules that can be used are of any type (e.g., IgG, IgE, IgM, IgD, IgY, IgA).
  • the immunoglobulin molecules that can be used are of any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, IgA2).
  • the anti-PD-1 antibody is an IgG4 antibody. In some embodiments, the present disclosure is directed to an antibody or antigen-binding fragment thereof, wherein the Fc domain is of an IgG4. [0080] In some embodiments, the anti-PD-1 antibody is an IgG1 antibody. In some embodiments, the present disclosure is directed to an antibody or antigen-binding fragment thereof, wherein the Fc domain is of an IgG1. [0081] In some embodiments, the anti-PD-1 antibody is a monoclonal humanized IgG1 antibody. [0082] In some embodiments, the anti-PD-1 antibody is a monoclonal humanized IgG4 antibody.
  • the contemplated anti-PD-1 antibodies and fragments comprise any CDRs described herein. In some embodiments, the contemplated anti-PD-1 antibodies and fragments comprise CDRs of any of the antibodies described herein. Complementarity-determining regions (CDRs) are defined in various ways in the art, including the Kabat, Chothia, AbM, Contact, and IMGT. In some embodiments, the CDRs of an antibody are defined according to the Kabat system. [0084] In some embodiments, the contemplated anti-PD-1 antibodies and fragments comprise any light chain variable region described herein and/or any heavy chain variable region described herein.
  • the described anti-PD-1 antibodies and fragments comprise a light chain variable region having a sequence with at least 85%, 90% or 95% identity to any light chain variable region described herein and/or a heavy chain variable region having a sequence with at least 85%, 90% or 95% identity to any heavy chain variable region described herein. In some embodiments, the described anti-PD-1 antibodies and fragments comprise a light chain variable region having a sequence with at least 85%, 90% or 95% identity to any light 18 4893-2664-4718.1 Atty. Dkt.
  • the contemplated anti-PD-1 antibodies and fragments comprise light chain variable region and/or any heavy chain variable region of any antibody described herein.
  • the anti-PD-1 antibody is any antibody described in WO2015/035606 A1 or US2015-0315274, the entire disclosures of which are incorporated by reference herein in their entireties, and in particular in respect to description therein of anti-PD-1 antibodies.
  • the anti-PD-1 antibody is any antibody described in any of: U.S. Patent Nos.: 8,735,553, 9,217,034, 9,834,606, 9,988,450, 10,519,235 and 11,186,637.
  • Patent Nos.: 8,735,553, 9,217,034, 9,834,606, 9,988,450, 10,519,235 and 11,186,637 are incorporated by reference herein in their entireties, and in particular in respect to description therein of anti-PD-1 antibodies.
  • the anti-PD-1 antibody is selected from one of the following: nivolumab (MDX 1106, BMS 936558, ONO-4538, Opdivo®) described in US8008449B2, a fully human IgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2; pembrolizumab (lambrolizumab, MK-3475 or SCH 900475, Keytruda®) disclosed in US8168757B2, a humanized monoclonal IgG4 antibody against PD-1; pidilizumab (CT-011), a humanized antibody that binds PD-1; AMP-224, a fusion protein of B7-DC; an antibody Fc portion; BMS-936559 (MDX-1105-01) for PD-L1 (B7-H1) blockade for PD-1 blockade.
  • nivolumab MDX 1106, BMS 936558, ONO
  • the anti-PD-1 antibody is pembrolizumab, nivolumab, cemiplimab, dostarlimab, or retifanlimab.
  • the anti-PD-1 antibody is an antibody which comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising any set of the complementarity determining regions (CDRs) listed below (with three Vh CDRs and three Vl CDRs): Table 1 19 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibody comprises a heavy chain variable region (Vh) comprising complementarity determining regions (CDRs) CDR-H1, CDR-H2 and CDR-H3 of SEQ ID NOs: 31, 32, 33, respectively, and a light chain variable region (Vl) comprising CDRs CDR-L1 , CDR-L2 and CDR-L3 of SEQ ID NOs: 34, 35, 36, respectively.
  • Vh heavy chain variable region
  • CDRs complementarity determining regions
  • Vl light chain variable region
  • the anti-PD-1 antibody comprises Vh and Vl CDRs of the 317-4B6 antibody described herein.
  • the anti-PD-1 antibody is an antibody which comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) that contain any combinations of the CDRs listed below (with three Vh CDRs and three Vl CDRs): Table 2 (a) CDR-H1 (SEQ ID NO 31), CDR-H2 (SEQ ID NO 12, 32, 59 or 60) and CDR-H3 (SEQ ID NO 33), CDR-L1 ( SEQ ID NO 14, 34 or 61), CDR-L2 (SEQ ID NO 35) and CDR-L3 (SEQ ID NO 36); or (b) CDR-H1 (SEQ ID NO 37), CDR-H2 (SEQ ID NO 18, 38 or 62) and CDR-H3 (SEQ ID NO 39), CDR-L1 (SEQ ID NO 40), CDR-L2 (SEQ ID NO 41) and CDR-L3 (SEQ ID NO 42).
  • Vh heavy chain variable region
  • Vl light chain variable region
  • the anti-PD-1 antibody comprises a heavy chain variable region (Vh) comprising an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the amino acid sequence of SEQ ID NO:24 and a light chain variable region (Vl) comprising an amino acid sequence at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the amino acid sequence of SEQ ID NO:26.
  • Vh heavy chain variable region
  • Vl light chain variable region
  • the anti-PD-1 antibody comprises a heavy chain variable region (Vh) or light chain variable region (Vl) encoded by the cDNA of one of more of SEQ ID NO:23, 25, 27, 29, 47, 49, 55, 57.
  • the antibody comprises an IgG4 Fc region having a serine to proline mutation at position 228 (EU numbering system). In some embodiments, this mutation is referred to as the S228P mutation. In some embodiments, the antibody comprises an IgG4 Fc region having a mutation at one or more of positions 233, 234, 235, 265, 309, and 409 (EU numbering system).
  • the antibody comprises an IgG4 region having a mutation at 228 and at least one other position, wherein the at least one other mutation results in reduced binding to one or more Fc ⁇ R.
  • the antibody comprises an IgG4 region having a mutation at position 228 and at least two, at least 3, at least 4, at least 5, or at least 6 additional positions, wherein one or more of the additional mutations results in reduced binding to one or more Fc ⁇ R.
  • the antibody comprises an IgG4 region having mutations at positions 234 and 235.
  • the antibody comprises an IgG4 region having mutations at positions 233, 235, and 235.
  • the antibody comprises an IgG4 region having mutations at positions 234, 235, and 265. In some 23 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 embodiments, the antibody comprises an IgG4 region having mutations at positions 233, 234, 235, and 265. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 234, 235, 265, and 409. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 233, 234, 235, 265, and 409.
  • the antibody comprises an IgG4 region having mutations at positions 234, 235, 265, 309, and 409. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 233, 234, 235, 265, 309, and 409.
  • the mutation at position 234 may be a phenylalanine to valine substitution or a phenylalanine to alanine substitution.
  • the mutation at position 235 may be a leucine to alanine substitution.
  • the mutation at position 233 may be a glutamic acid to proline substitution.
  • the mutation at position 265 may be a aspartic acid to valine substitution or an aspartic acid to threonine substitution.
  • the mutation at position 309 may be a leucine to valine substitution.
  • the anti-PD-1 antibody is an antibody which comprises a IgG4 heavy chain effector or constant domain comprising any of SEQ ID NOs: 83-88 or 91-106.
  • the anti-PD-1 antibody comprises an IgG constant region comprising any one of the amino acid sequences: SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87 and SEQ ID NO:88.
  • the anti-PD-1 antibody comprises an IgG constant region comprising any one of the amino acid sequences: SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105 and SEQ ID NO:106.
  • the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:83.
  • the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:84. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:85. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:86. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:87. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:88. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region 24 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:92. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:93. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:94. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:95. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:96.
  • the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:97. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:98. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:99. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:100. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:101. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:102. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:103.
  • the anti- PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:104. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:105. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO:106. [0096] In some embodiments, the anti-PD-1 antibody is an antibody which contains a F(ab) or F(ab)2 comprising a heavy chain variable region (Vh), a light chain variable region (Vl) and a IgG4 heavy chain effector or constant domain.
  • Vh heavy chain variable region
  • Vl light chain variable region
  • IgG4 heavy chain effector or constant domain IgG4 heavy chain effector or constant domain.
  • the anti-PD-1 antibody is an antibody which comprises a heavy chain variable region (Vh) and a light chain variable region (Vl), and a IgG4 heavy chain effector or constant domain comprising SEQ ID NOs:87 or 88, wherein the heavy chain variable region (Vh) and the light chain variable region (Vl) comprise: Table 4 a) mu317 (SEQ ID NOs:4 and 6, p) 317-3H1 (SEQ ID NOs:69 and 26, respectively); respectively); 25 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibody is an antibody which comprises a heavy chain variable region (Vh) and a light chain variable region (Vl), and a IgG4 heavy chain effector or constant domain comprising SEQ ID NOs:88.
  • the anti-PD-1 antibody is an antibody which comprises a heavy chain CDR-H1, CDR-H2, and CDR-H3 according to SEQ ID NOs:11, 32, and 13, 26 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibody is an antibody which comprises a heavy chain CDR-H1, CDR-H2 and CDR-H3 according to SEQ ID NOs:31, 32, 33, respectively; and a light chain CDR-L1 , CDR-L2 and CDR-L3 according to SEQ ID NOs:34, 35, 36, respectively.
  • the anti-PD-1 monoclonal antibody is an antibody which comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO:24 and SEQ ID NO:26, respectively.
  • the anti-PD-1 antibody is an antibody which comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) (comprising SEQ ID NO:24 and SEQ ID NO:26, respectively) and a IgG4 heavy chain effector or constant domain (comprising SEQ ID NO:88).
  • the anti-PD-1 antibody specifically binds to PD-1, such as to PD-1 residues including K45 and I93; or I93, L95 and P97, and inhibits PD- 1-medidated cellular signaling and activities in immune cells, with the antibody binding to a set of amino acid residues required for its ligand binding.
  • the anti-PD-1 antibody can be monoclonal.
  • the antibody is monoclonal and humanized.
  • the antibody is monoclonal, humanized, IgG4 antibody.
  • the anti-PD-1 antibody is a monoclonal antibody or a fragment thereof, comprising a heavy chain variable region (Vh) amino acid sequence of SEQ ID NO:24, a light chain variable region (Vl) amino acid sequence of SEQ ID NO:26, and an IgG4 constant domain amino acid sequence of SEQ ID NO:88.
  • the anti-PD-1 antibody is Tislelizumab. The sequence of Tislelizumab is known in the art. [00103]
  • the present disclosure provides for anti-PD1 antibodies and antigen-binding fragments thereof having the sequences provided in the Table below.
  • the anti-PD1 antibody or antigen-binding fragment thereof specifically binds human PD1 and comprises the six CDRs provided in the Table below. In some embodiments, the anti-PD1 antibody or antigen-binding fragment thereof specifically binds human PD1 and comprises a heavy chain variable region and a light chain variable region comprising the 27 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 sequences provided in the Table below. In some embodiments, the anti-PD1 antibody comprises an IgG4 constant domain comprising any of the sequences provided below.
  • the IgG4 constant domain comprises one of the last two sequences provided in Table 5.
  • Table 5 Sequences of anti-PD1 antibody Domain SEQ ID NO: Amino Acid Sequence CDR-H1 SEQ ID NO:31 GFSLTSYGVH CDR-H2 SEQ ID NO:32 VIYADGSTNYNPSLKS CDR-H3 SEQ ID NO:33 ARAYGNYWYIDV CDR-L1 SEQ ID NO:34 KSSESVSNDVA CDR-L2 SEQ ID NO:35 YAFHRFT CDR-L3 SEQ ID NO:36 HQAYSSPYT Vh SEQ ID NO:24 QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGVHWIRQ PPGKGLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQV SLKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTV TVSS Vl SEQ ID NO:26 DIVMTQSPDSLAVSLGER
  • the anti-PD1 antibodies include those where the amino acids 29 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibodies and antigen-binding fragments thereof described herein can be made by any method known in the art and/or described herein. Methods of making monoclonal antibodies are well known in the art. See e.g., Harlow E and Lane D, Antibodies: A Laboratory Manual (Cold Spring Harbor Press, 2nd ed.1988); Hammerling GJ et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563 (Elsevier, NY, 1981); Kohler G and Milstein C, 1975, Nature 256:495; Goding JW (Ed), Monocolonal Antibodies: Principles and Practice, pp.59-103 (Academic Press, 1986).
  • anti-PD1 monoclonal antibodies and antibody fragments thereof may be prepared in accordance with the disclosure of WO2015/035606A1 or US 2015-0315274, the entire disclosures of which are incorporated by reference herein.
  • the anti-PD-1 antibody (e.g., any of the antibodies described herein) is administered by any suitable means.
  • the anti-PD-1 antibody is administered parenterally.
  • the anti-PD-1 antibody is administered intravenously (IV).
  • the anti-PD-1 antibody is administered by IV infusion.
  • the anti-PD-1 antibody is infused over 60 minutes or more.
  • the anti-PD-1 antibody is infused over 30 minutes or more.
  • the anti-PD-1 antibody is administered subcutaneously.
  • the anti-PD-1 antibody is administered intramuscularly. In some embodiments, the anti-PD-1 antibody is administered peritoneally. [00109] In some embodiments, an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered parenterally. In some embodiments, an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered intravenously (IV).
  • IV intravenously
  • Tislelizumab is administered by IV infusion. In some embodiments, the IV infusion is over 60 minutes or more. In some embodiments, the IV infusion is over 30 minutes or more. [00110] In some embodiments, the anti-PD-1 antibody (e.g., any of the antibodies described herein) is administered at a fixed dose. In some embodiments, an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered at a fixed dose. [00111] In some embodiments, the anti-PD-1 antibody is administered at a dose of 200 mg or about 200 mg.
  • an anti-PD-1 antibody comprising the CDRs of the 317- 4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered at a dose of 200 mg or about 200 mg. In some embodiments, Tislelizumab is administered at a dose of 200 mg. [00112] In some embodiments, the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to about 200 mg/kg (and any value in between).
  • the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to about 5 mg/kg (e.g., 2 mg/kg to 5 31 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 mg/kg). In some embodiments, the anti-PD-1 antibody is administered at a dose of 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg (or any value in between these values).
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered at a dose from about 2 mg/kg to about 5 mg/kg (e.g., 2 mg/kg to 5 mg/kg).
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered at a dose at a dose of 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg (or any value in between these values). In some embodiments, Tislelizumab is administered at a dose of 2 mg/kg to 5 mg/kg.
  • the anti-PD-1 antibody is administered at a dosage of about 2 mg/kg Q3W to about 200 mg/kg once every three-weeks (Q3W). In some embodiments, the anti- PD-1 antibody is administered at a dosage of about 2mg/kg Q3W, 5mg/kg Q3W or 200 mg flat Q3W. [00114] In some embodiments, the anti-PD-1 antibody is administered once every three- weeks.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered once every three-weeks (e.g., in 200 mg dose).
  • Tislelizumab is administered at dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg.
  • the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks. [00115] In some embodiments, the anti-PD-1 antibody is administered once every three- weeks for 4 cycles or at least 4 cycles.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered once every three-weeks for 4 cycles or at least 4 cycles (e.g., in 200 mg dose).
  • the anti-PD-1 antibody is administered once every three- weeks for 3 cycles or at least 3 cycles.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered once every three-weeks for 3 cycles or at least 3 cycles (e.g., in 200 mg dose).
  • the anti-PD-1 antibody is administered at a dose of 400 mg or about 400 mg.
  • an anti-PD-1 antibody comprising the CDRs of the 317- 4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered at a dose of 400 mg or about 400 mg. In some embodiments, Tislelizumab is administered at a dose of 400 mg. [00118] In some embodiments, the anti-PD-1 antibody is administered at a dose more than about 200 mg/kg to about 400 mg/kg. [00119] In some embodiments, the anti-PD-1 antibody is administered at a dosage of about 400 mg/kg once every six-weeks (Q6W).
  • the anti-PD-1 antibody is administered at a dosage of about 400 mg flat Q6W. [00120] In some embodiments, the anti-PD-1 antibody is administered once every six-weeks. In some embodiments, an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered once every six-weeks (e.g., in 400 mg dose). [00121] In some embodiments, the anti-PD-1 antibody is administered once every six-weeks for 8 cycles or at least 8 cycles.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered once every six-weeks for 8 cycles or at least 8 cycles (e.g., in 400 mg dose). [00122] In some embodiments, the anti-PD-1 antibody is administered once every six-weeks for less than 8 cycles.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered once every six-weeks for less than 8 cycles (e.g., in 400 mg 33 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 dose). [00123] In some embodiments, the anti-PD-1 antibody is administered in one treatment cycle. In some embodiments, the anti-PD-1 antibody is administered in two treatment cycles.
  • the anti-PD-1 antibody is administered in three treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in four treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in five treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in six treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in seven treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in eight treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in nine treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in ten treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in eleven treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in twelve treatment cycles.
  • the anti-PD-1 antibody is administered in thirteen treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in fourteen treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in fifteen treatment cycles. In some embodiments, a treatment cycle is three-weeks. In some embodiments, a treatment cycle is six- weeks. [00124] In some embodiments, the anti-PD-1 antibody is administered on Day 1 of the cycle (e.g., Day 1 of 21 day or 3-week cycle, or Day 1 of 42 day or 6-week cycle). [00125] In some embodiments, the anti-PD-1 antibody is IV infused over 60 minutes or more (e.g., in the neoadjuvant phase).
  • the anti-PD-1 antibody is IV infused over 60 minutes or more in cycle 1, and IV infused over 30 minutes or about 30 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle). In some embodiments, the anti-PD-1 antibody is IV infused over 60 minutes or more in cycle 1, and IV infused over less than 60 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle). In some embodiments, the infusion time for the anti-PD-1 antibody is reduced from 60 minutes to 30 minutes if, and only if, the 60-minute infusion time is well tolerated by the treated subject. In some embodiments, during the adjuvant 34 4893-2664-4718.1 Atty.
  • the anti-PD-1 antibody is IV infused over 90 minutes or more (at lease in cycle 1 of the adjuvant phase). In some embodiments, during the adjuvant phase, the infusion time for the anti- PD-1 antibody is reduced from 90 minutes to 60 minutes to 30 minutes if, and only if, the longer infusion time is well tolerated by the treated subject. [00126] In some embodiments, the anti-PD-1 antibody is administered in an induction treatment period (or neoadjuvant phase). In some embodiments, the anti-PD-1 antibody is administered in a maintenance treatment period (or adjuvant phase).
  • the induction treatment period is followed by the maintenance treatment period. In some embodiments, the induction treatment period is followed by surgical removal of a tumor, which is then followed by the maintenance treatment period. In some embodiments, the dose of anti- PD-1 antibody is different between the maintenance period and the induction period. In some embodiments, the dose of anti-PD-1 antibody in the induction (neoadjuvant) period is 200 mg and the dose in the maintenance (adjuvant) period is 400 mg. In some embodiments, the induction (neoadjuvant) treatment period comprises administering an anti-PD-1 antibody once every 3 weeks. In some embodiments, the induction treatment period comprises three or four three-week cycles.
  • the maintenance (adjuvant) treatment period comprises administering an anti-PD-1 antibody once every 6 weeks.
  • the maintenance treatment period comprises one six-week cycle.
  • the maintenance treatment period comprises two six-week cycles.
  • the maintenance treatment period comprises three six-week cycles.
  • the maintenance treatment period comprises four six-week cycles.
  • the maintenance treatment period comprises five six-week cycles.
  • the maintenance treatment period comprises six six-week cycles.
  • the maintenance treatment period comprises seven six-week cycles.
  • the maintenance treatment period comprises eight six-week cycles.
  • the maintenance treatment period comprises nine six-week cycles.
  • the maintenance treatment period comprises ten six-week cycles.
  • the anti-PD-1 antibody is administered intravenously at a fixed dose of 200 mg. In some embodiments, the anti-PD-1 antibody is administered intravenously at a 35 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 fixed dose of 200 mg once every three-weeks.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 is administered intravenously at a fixed dose of 200 mg.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 is administered intravenously at a fixed dose of 200 mg once every three-weeks.
  • the IV administration is by IV infusion.
  • the anti-PD-1 antibody is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg). In some embodiments, the anti-PD-1 antibody is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg) once every three-weeks.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg).
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab) is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg) every three-weeks.
  • the IV administration is by IV infusion.
  • the anti-PD-1 antibody is administered intravenously at a fixed dose of 400 mg.
  • the anti-PD-1 antibody is administered intravenously at a fixed dose of 400 mg once every three-weeks.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 is administered intravenously at a fixed dose of 400 mg.
  • an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 is administered intravenously at a fixed dose of 400 mg once every three-weeks.
  • the IV administration is by IV infusion.
  • an anti-PD-1 antibody e.g., Tislelizumab
  • an anti-PD-1 antibody is administered at 200 mg in a neoadjuvant phase, and administered at 400 mg in an adjuvant phase.
  • the cancer being treated is resected or removed (completely or partially) between 36 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 the neoadjuvant treatment phase and the adjuvant treatment phase.
  • the dosage and treatment regimens described herein are for administration to human subjects.
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, wherein: the cancer is a solid cancer, and the solid cancer is selected from the group consisting of a lung cancer, a breast cancer, and a colon cancer, the method comprises parenterally administering to the subject a dose of an anti-PD-1 antibody (e.g., Tislelizumab), or an antigen-binding fragment thereof, wherein the dose is: (i) about 50 to800 mg, or (ii) about 2 mg/kg to about 5 mg/kg; and the anti-PD-1 antibody comprises: (a) a VH CDR1, VH CDR2, and a VH CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:31, 32 and 33, and (b) a VL CDR1, VL CDR2, and a VL CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:34, 35 and 36.
  • an anti-PD-1 antibody e.g., Tis
  • the present disclosure relates to a method of treating a cancer in a subject in need thereof, wherein the cancer is a solid cancer, comprising parenterally administering to the subject an anti-PD-1 antibody, or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody is administered: (i) at a dose from about 50 to 800 mg, or (ii) at a dose from about 2 mg/kg to about 5 mg/kg; and the anti-PD-1 antibody comprises: (a) a VH CDR1, VH CDR2, and a VH CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:31, 32 and 33, and (b) a VL CDR1, VL CDR2, and a VL CDR3 comprising amino acid sequences as set forth in SEQ ID NOs:34, 35 and 36; and the method further comprises administering a therapeutically effective amount of chemotherapeutic drugs comprising (i) a platinum chemotherapy drug, or (ii) carboplatin, and
  • the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to 5 mg/kg, optionally wherein the anti-PD-1 antibody is administered at a dose of about 2mg/kg Q3W, 5mg/kg Q3W or 200 mg Q3W, optionally wherein the anti-PD-1 antibody is administered at a dose of about 400 mg, optionally wherein the anti-PD-1 antibody is administered at a dose of about 150 mg Q2W, optionally wherein the anti-PD-1 antibody is administered at a dose of about 300 mg Q4W, and optionally wherein the anti-PD-1 antibody is administered at a dose of about 400 mg Q6W.
  • the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg.
  • the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, optionally wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks.
  • the PD-1 antibody is administered at a first dose prior to surgical removal of the solid cancer, and wherein the PD-1 antibody is administered at a second dose after surgical removal of the solid cancer.
  • the first dose is: about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, or about 2 mg/kg to about 5 mg/kg; optionally wherein the first dose is 200 mg once every three-weeks (Q3W); and wherein the second dose is: about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, or about 2 mg/kg to about 5 mg/kg; optional
  • a subject described herein is administered an anti-cancer agent.
  • anti-cancer agent refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents, including cellular therapies.
  • the anti-PD-1 antibodies and antigen-binding fragments of the present disclosure are used in combination with one or more anti-cancer agents.
  • a subject described herein is administered an anti-PD-1 antibody and further administered an anti-cancer agent described herein.
  • the anti-PD-1 antibodies of the present disclosure are used in combination with one or more chemotherapeutic agents or drugs (e.g., one, two or three chemotherapeutic agents or drugs).
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure and one or more chemotherapeutic drugs (e.g., one, two or three chemotherapeutic drugs).
  • a subject e.g., a human
  • one or more chemotherapeutic drugs e.g., one, two or three chemotherapeutic drugs.
  • Classes of chemotherapeutic agents that can be used include, but are not limited to: microtubule inhibitors, e.g., taxanes (paclitaxel, docetaxel), and vinca alkaloids (vincristine, vinblastine, vinorelbine); antimetabolites (5-fluorouracil, capecitabine, gemcitabine), and antifolates (methotrexate, pemetrexed); kinase inhibitors (crizotinib, erlotinib, sunitinib); topoisomerase inhibitors (deruxtecan, topotecan, irinotecan, anthracyclines, etoposide); cell- cycle independent drugs, e.g., platinum compounds and analogues (oxaliplatin), triazenes, alkylating agents (cyclophosphamide), spindle poison plant alkaloids (doxorubicin), cytotoxic/antitumor antibiotics (bleomycin,
  • the chemotherapeutic agent is selected from one or more of the following: paclitaxel or a paclitaxel agent; (e.g., Abraxane®), docetaxel; carboplatin; topotecan; deruxtecan; cisplatin; 5-fluorouracil, irinotecan, doxorubicin, lenalidomide, 5- azacytidine, ifosfamide, oxaliplatin, pemetrexed disodium, cyclophosphamide, etoposide, decitabine, fludarabine, vincristine, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, and pemetrexed disodium.
  • paclitaxel or a paclitaxel agent e.g., Abraxane®
  • docetaxel e.g., carboplatin
  • topotecan topot
  • the chemotherapeutic drug is a platinum chemotherapy.
  • the chemotherapeutic drug is cisplatin.
  • the chemotherapeutic drug is carboplatin.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure and either cisplatin or carboplatin. In some embodiments, it is in physician’s discretion whether to administer cisplatin or carboplatin.
  • the chemotherapeutic drug is pemetrexed.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure and pemetrexed.
  • the chemotherapeutic drug is paclitaxel.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure and paclitaxel.
  • the chemotherapeutic drug is etoposide.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure and etoposide.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of (i) an anti-PD-1 antibody of the present disclosure, (ii) either cisplatin or carboplatin, and (iii) pemetrexed or paclitaxel.
  • the chemotherapeutic agent is 5-fluorouracil.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of (i) an anti-PD-1 antibody of the present disclosure, (ii) 5-fluorouracil, and (iii) cisplatin.
  • the dosing of the chemotherapy drugs can be any dosing known in the art (e.g., any dose and administration regimen known in the art to be effective) or any dosing described herein.
  • A. Cisplatin [00150] In some embodiments, a patient described herein is administered Cisplatin in combination with an anti-PD-1 antibody described herein. In some embodiments, a patient is administered Cisplatin in combination with Tislelizumab.
  • a patient is administered Cisplatin in combination with an anti-PD-1 antibody described herein and either pemetrexed or paclitaxel. In some embodiments, a patient is administered Cisplatin in combination with Tislelizumab and one or both of pemetrexed and paclitaxel. In some embodiments, a patient is administered Cisplatin in combination with Tislelizumab and 5- fluorouracil. [00151] In some embodiments, Cisplatin is administered parenterally. In some embodiments, Cisplatin is administered at a dose of about 20 mg/m 2 to about 100 mg/m 2 .
  • Cisplatin is administered at about 20 mg/m 2 , 25 mg/m 2 , 30 mg/m 2 , 35 mg/m 2 , 40 mg/m 2 , 45 mg/m 2 , 50 mg/m 2 , 55 mg/m 2 , 60 mg/m 2 , 65 mg/m 2 , 70 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 85 mg/m 2 , 90 mg/m 2 , 95 mg/m 2 , or 100 mg/m 2 (or any value in between of these values).
  • Cisplatin is administered at about 75 mg/m 2 . In some embodiments, Cisplatin is administered at 75 mg/m 2 .
  • Cisplatin is administered intravenously. In some embodiments, Cisplatin is administered as an intravenous infusion over at least 2 hours. In some embodiments, Cisplatin is administered as an intravenous infusion over 2 hours. In some 41 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 embodiments, Cisplatin is administered once every week. In some embodiments, Cisplatin is administered once every 3 weeks. In some embodiments, Cisplatin is administered on Day 1 once every 3 weeks. In some embodiments, Cisplatin is administered on Day 2 once every 3 weeks.
  • Cisplatin is administered on Days 1-3 every 3 weeks. In some embodiments, Cisplatin is administered on Days 1-5 every 3 weeks. [00153] In some embodiments, Cisplatin is administered for 1 cycle. In some embodiments, Cisplatin is administered for 2 cycles. In some embodiments, Cisplatin is administered for 3 cycles. In some embodiments, Cisplatin is administered for 4 cycles. In some embodiments, a cycle is 3 weeks. [00154] In some embodiments, Cisplatin is administered for 4 three-week cycles. [00155] In some embodiments, Cisplatin is administered on Day 1 of each cycle. In some embodiments, Cisplatin is administered on Day 2 of each cycle.
  • Cisplatin is administered on Day 3 of each cycle. In some embodiments, Cisplatin is administered on Day 4 of each cycle. In some embodiments, Cisplatin is administered on Day 5 of each cycle.
  • the methods described herein comprise administration of Cisplatin once every cycle, wherein each cycle is three-weeks, on Day 1 of each cycle for 4 cycles. [00157] In some embodiments, the methods described herein comprise intravenous administration of 75 mg/m 2 Cisplatin on Day 1 of each 21 days cycle (and optionally wherein Cisplatin is infused over 2 hours), and optionally the administration is for 4 cycles or more.
  • Carboplatin [00158] In some embodiments, a patient described herein is administered Carboplatin in combination with an anti-PD-1 antibody described herein. In some embodiments, a patient is administered Carboplatin in combination with Tislelizumab. In some embodiments, a patient is administered Carboplatin in combination with an anti-PD-1 antibody described herein and either pemetrexed or paclitaxel. In some embodiments, a patient is administered Carboplatin in combination with Tislelizumab and one or both of pemetrexed and paclitaxel. [00159] In some embodiments, Carboplatin is administered parenterally. In some 42 4893-2664-4718.1 Atty. Dkt.
  • Carboplatin is administered as a target of AUC 4 mg/mL/min to 6 mg/mL/min (and any value in between, e.g., 5 to 6 mg/mL/min). In some embodiments, Carboplatin is administered as a target of AUC 4 mg/mL/min. In some embodiments, Carboplatin is administered as a target of AUC 5 mg/mL/min. In some embodiments, Carboplatin is administered as a target of AUC 6 mg/mL/min.
  • the term “Area under the Curve” or “AUC” defines the dose of carboplatin administered to a subject.
  • the AUC is area under the plasma concentration-time curve.
  • a subject is administered carboplatin to achieve the above-noted AUC, e.g., AUC of 5 mg/mL/min.
  • the dosing of carboplatin is calculated according to Calvert formula dosing. A skilled artisan can calculate the amount of carboplatin necessary to achieve a given AUC in a subject. See Calvert et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function.
  • Carboplatin is administered intravenously. In some embodiments, Carboplatin is administered as an intravenous infusion over 15 to 60 minutes (or any value in between). In some embodiments, Carboplatin is administered as an intravenous infusion 15 minutes. In some embodiments, Carboplatin is administered as an intravenous infusion 30 minutes. In some embodiments, Carboplatin is administered as an intravenous infusion 45 minutes. In some embodiments, Carboplatin is administered as an intravenous infusion 60 minutes.
  • Carboplatin is administered once every week. In some embodiments, Carboplatin is administered once every 3 weeks. In some embodiments, Carboplatin is administered on Day 1 once every 3 weeks. [00162] In some embodiments, Carboplatin is administered for 1 cycle. In some embodiments, Carboplatin is administered for 2 cycles. In some embodiments, Carboplatin is administered for 3 cycles. In some embodiments, Carboplatin is administered for 4 cycles. In some embodiments, a cycle is 3 weeks. [00163] In some embodiments, Carboplatin is administered for 4 three-week cycles. In some embodiments, Carboplatin is administered on Day 1 of each cycle. 43 4893-2664-4718.1 Atty.
  • the methods described herein comprise administration of Carboplatin once every cycle, wherein each cycle is three-weeks, on Day 1 of each cycle for 4 cycles.
  • the methods described herein comprise intravenous administration of AUC5 Carboplatin on Day 1 of each 21 days cycle (and optionally wherein Carboplatin is infused over 15 to 60 minutes), and optionally the administration is for 4 cycles or more.
  • carboplatin is administered to achieve AUC of 5 mg/mL/min in accordance with Calvert formula dosing (e.g., as described herein).
  • C. Pemetrexed [00166] In some embodiments, a patient described herein is administered pemetrexed in combination with an anti-PD-1 antibody described herein. In some embodiments, a patient is administered pemetrexed in combination with Tislelizumab. In some embodiments, a patient is administered a combination of the anti-PD-1 antibody described herein, Carboplatin or Cisplatin, and pemetrexed.
  • a patient is administered a combination of Tislelizumab, Carboplatin or Cisplatin, and pemetrexed.
  • the cancer is a non- squamous cell carcinoma (e.g., non-squamous cell NSCLC).
  • pemetrexed is administered parenterally. In some embodiments, pemetrexed is administered at a dose of about 250 mg/m 2 to about 1000 mg/m 2 (or any value in between). In some embodiments, pemetrexed is administered at about 500 mg/m 2 . In some embodiments, pemetrexed is administered at 500 mg/m 2 .
  • pemetrexed is administered intravenously. In some embodiments, pemetrexed is administered as an intravenous infusion over about 10 minutes or at least 10 minutes. In some embodiments, pemetrexed is administered as an intravenous infusion over 10 minutes. [00169] In some embodiments, pemetrexed is administered once every three weeks. In some embodiments, pemetrexed is administered on Day 1 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on Day 2 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on Day 3 of a 3-week (21 day) cycle. In some 44 4893-2664-4718.1 Atty. Dkt.
  • pemetrexed is administered on Day 4 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on Day 5 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on Days 1-3 every 3 weeks. In some embodiments, pemetrexed is administered on Days 1-5 every 3 weeks. [00170] In some embodiments, pemetrexed is administered for 1 cycle. In some embodiments, pemetrexed is administered for 2 cycles. In some embodiments, pemetrexed is administered for 3 cycles.
  • pemetrexed is administered for 4 cycles. In some embodiments, a cycle is 3 weeks. [00171] In some embodiments, pemetrexed is administered for 4 three-week cycles. [00172] In some embodiments, pemetrexed is administered on Day 1 of each cycle. [00173] In some embodiments, the methods described herein comprise administration of pemetrexed once every cycle, wherein each cycle is three-weeks, for 3 or 4 cycles. [00174] In some embodiments, the methods described herein comprise intravenous administration of 500 mg/m 2 pemetrexed on Day 1 of each 21 days cycle (and optionally wherein pemetrexed is infused over 10 minutes), and optionally the administration is for 3, 4 cycles or more. D.
  • a patient described herein is administered paclitaxel in combination with an anti-PD-1 antibody described herein.
  • a patient is administered paclitaxel in combination with Tislelizumab.
  • a patient is administered a combination of the anti-PD-1 antibody described herein, Carboplatin or Cisplatin, and paclitaxel.
  • a patient is administered a combination of Tislelizumab, Carboplatin or Cisplatin, and paclitaxel.
  • the cancer is a squamous cell carcinoma (e.g., squamous cell NSCLC).
  • paclitaxel is administered parenterally. In some embodiments, paclitaxel is administered at a dose of about 80 mg/m 2 to about 400 mg/m 2 (or any value in between). In some embodiments, paclitaxel is administered at about 175 mg/m 2 . In some embodiments, paclitaxel is administered at 175 mg/m 2 . 45 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 [00177] In some embodiments, paclitaxel is administered intravenously.
  • paclitaxel is administered as an intravenous infusion over about 3 hours or at least 3 hours. In some embodiments, paclitaxel is administered as an intravenous infusion over 3 hours. [00178] In some embodiments, paclitaxel is administered once every three weeks. In some embodiments, paclitaxel is administered on Day 1 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on Day 2 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on Day 3 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on Day 4 of a 3-week (21 day) cycle.
  • paclitaxel is administered on Day 5 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on Days 1-3 every 3 weeks. In some embodiments, paclitaxel is administered on Days 1-5 every 3 weeks. [00179] In some embodiments, paclitaxel is administered for 1 cycle. In some embodiments, paclitaxel is administered for 2 cycles. In some embodiments, paclitaxel is administered for 3 cycles. In some embodiments, paclitaxel is administered for 4 cycles. In some embodiments, a cycle is 3 weeks. [00180] In some embodiments, paclitaxel is administered for 4 three-week cycles. [00181] In some embodiments, paclitaxel is administered on Day 1 of each cycle.
  • the methods described herein comprise administration of paclitaxel once every cycle, wherein each cycle is three-weeks, for 3 or 4 cycles. In some embodiments, the methods described herein comprise intravenous administration of 175 mg/m 2 paclitaxel on Day 1 of each 21 days cycle (and optionally wherein paclitaxel is infused over 3 hours), and optionally the administration is for 3, 4 cycles or more.
  • E. Etoposide [00183] In some embodiments, a patient described herein is administered Etoposide in combination with an anti-PD-1 antibody described herein. In some embodiments, a patient is administered Etoposide in combination with Tislelizumab.
  • a patient is administered a combination of the anti-PD-1 antibody described herein, Carboplatin or Cisplatin, 46 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 and Etoposide.
  • a patient is administered a combination of Tislelizumab, Carboplatin or Cisplatin, and Etoposide.
  • Etoposide is administered parenterally.
  • Etoposide is administered at a dose of about 80 mg/m2 to about 140 mg/m2 (or any value in between).
  • Etoposide is administered at 80 mg/m2. In some embodiments, Etoposide is administered at 90 mg/m2. In some embodiments, Etoposide is administered at 100 mg/m2. In some embodiments, Etoposide is administered at 110 mg/m2. In some embodiments, Etoposide is administered at 120 mg/m2. In some embodiments, Etoposide is administered at 130 mg/m2. In some embodiments, Etoposide is administered at 140 mg/m2. [00185] In some embodiments, Etoposide is administered intravenously. In some embodiments, Etoposide is administered as an intravenous infusion over at least 60 minutes. In some embodiments, Etoposide is administered as an intravenous infusion over 60 minutes.
  • Etoposide is administered once every week. In some embodiments, Etoposide is administered three times in three-weeks. In some embodiments, Etoposide is administered 3 times in the first week of a 3-week (21 day) cycle. In some embodiments, Etoposide is administered on Day 1 of a 3-week (21 day) cycle. In some embodiments, Etoposide is administered on Day 2 of a 3-week (21 day) cycle. In some embodiments, Etoposide is administered on Day 3 of a 3-week (21 day) cycle. In some embodiments, Etoposide is administered on Day 4 of a 3-week (21 day) cycle. In some embodiments, Etoposide is administered on Day 5 of a 3-week (21 day) cycle.
  • Etoposide is administered on Days 1-3 every 3 weeks. In some embodiments, Etoposide is administered on Days 1-5 every 3 weeks. [00187] In some embodiments, Etoposide is administered for 1 cycle. In some embodiments, Etoposide is administered for 2 cycles. In some embodiments, Etoposide is administered for 3 cycles. In some embodiments, Etoposide is administered for 4 cycles. In some embodiments, a cycle is 3 weeks. [00188] In some embodiments, Etoposide is administered for 4 three-week cycles. [00189] In some embodiments, Etoposide is administered on Day 1, Day 2 and Day 3 of each 47 4893-2664-4718.1 Atty. Dkt.
  • Etoposide is administered on Day 1, Day 2, Day 3, Day 4 and Day 5 of each cycle.
  • the methods described herein comprise administration of Etoposide three times every cycle, wherein each cycle is three-weeks, for 4 cycles.
  • the methods described herein comprise intravenous administration of 100 mg/m2 Etoposide on Day 1 to Day 3 of each 21 days cycle (and optionally wherein Etoposide is infused over 60 minutes), and optionally the administration is for 4 cycles or more.
  • a patient described herein is administered 5-fluorouracil in combination with an anti-PD-1 antibody described herein.
  • a patient is administered 5-fluorouracil in combination with Tislelizumab.
  • a patient is administered 5-fluorouracil in combination with an anti-PD-1 antibody described herein and cisplatin.
  • a patient is administered Cisplatin in combination with Tislelizumab and 5-fluorouracil.
  • 5-fluorouracil is administered intravenously.
  • 5-fluorouracil is administered at a dose of about 200 mg/m 2 to about 3000 mg/m 2 .
  • 5-fluorouracil is administered at about 200 mg/m 2 , 300 mg/m 2 , 400 mg/m 2 , 500 mg/m 2 , 600 mg/m 2 , 700 mg/m 2 , 800 mg/m 2 , 900 mg/m 2 , 1000 mg/m 2 , 1200 mg/m 2 , 1500 mg/m 2 , 1700 mg/m 2 , 2000 mg/m 2 , 2200 mg/m 2 , 2500 mg/m 2 , 2700 mg/m 2 , or 3000 mg/m 2 (or any value in between of these values). [00194] In some embodiments, 5-fluorouracil is administered intravenously.
  • 5-fluoruracil is administered as an intravenous bolus. In some embodiments, 5- fluorouracil is administered as an intravenous infusion. In some embodiments, 5-fluorouracil is administered as an intravenous infusion over 24 hours. In some embodiments, 5-fluorouracil is administered as an intravenous infusion over 46 hours. In some embodiments, 5-fluoruracil is administered every week. In some embodiments, 5-fluoruracil is administered every two weeks. In some embodiments, 5-fluorouracil is administered every week for two weeks and then is 48 4893-2664-4718.1 Atty. Dkt.
  • 5-fluorouracil is administered for 1 cycle. In some embodiments, 5-fluorouracil is administered for 2 cycles. In some embodiments, 5-fluorouracil is administered for 4 cycles. In some embodiments, 5-fluorouracil is administered for 6 cycles. In some embodiments, 5-fluorouracil is administered for 8 cycles.
  • 5-fluorouracil is administered at 400 mg/m 2 by intravenous bolus on Day 1 of a treatment cycle, followed by 2400 mg/m 2 to 3000 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks.
  • 5-flourouracil is administered at 500 mg/m 2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 of a treatment cycle in 8-week cycles.
  • 5-fluorouracil is administered at 500 mg/m 2 or 600 mg/m 2 intravenously on Days 1 and 8 of a treatment cycle every 28 days for 6 cycles.
  • 5-fluorouracil is administered at 200 mg/m 2 to 1000 mg/m 2 intravenously as a continuous infusion over 24 hours. In some embodiments, 5-fluorouracil is administered at 400 mg/m 2 by intravenous bolus on Day 1 of a treatment cycle followed by 2400 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks.
  • G. Radiotherapy [00197] In some embodiments, a patient described herein is administered radiotherapy in combination with an anti-PD-1 antibody described herein. In some embodiments, a patient is administered radiotherapy in combination with Tislelizumab.
  • a patient is administered radiotherapy in combination with an anti-PD-1 antibody described herein and one or both of cisplatin and paclitaxel or cisplatin and 5-fluorouracil.
  • a patient is administered radiotherapy in combination with Tislelizumab and one or both of cisplatin and paclitaxel or cisplatin and 5-fluorouracil.
  • radiotherapy is administered at about 10 gray to about 80 gray.
  • radiotherapy is administered at about 10 gray.
  • radiotherapy is administered at about 20 gray.
  • radiotherapy is administered at about 30 gray.
  • radiotherapy is administered at about 40 gray.
  • radiotherapy is administered at about 50 gray. In some 49 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 embodiments, radiotherapy is administered at about 60 gray. In some embodiments, radiotherapy is administered at about 70 gray. In some embodiments, radiotherapy is administered at about 80 gray. [00199] In some embodiments, radiotherapy is administered over about 5 fractions. In some embodiments, radiotherapy is administered over about 10 fractions. In some embodiments, radiotherapy is administered over about 15 fractions. In some embodiments, radiotherapy is administered over about 20 fractions. In some embodiments, radiotherapy is administered over about 25 fractions.
  • radiotherapy is administered over about 30 fractions. In some embodiments, radiotherapy is administered over about 35 fractions. In some embodiments, radiotherapy is administered over about 40 fractions. [00200] In some embodiments, radiotherapy is administered at 40 gray/20 fractions.
  • Combination Therapies [00201] The combination therapy may be administered as a simultaneous, or separate or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes co-administration, using separate formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or each of) active agents simultaneously exert their biological activities.
  • the combination therapies provided herein provide a synergistic and/or statistically improved effect relative to either therapy when used as a single agent.
  • the combination therapies disclosed herein result in significant improvement in patient outcome in early-stage NSCLC or mid-stage NSCLC.
  • the combination therapies in some embodiments, prolong patient survival and progression-free survival while having a manageable toxicity profile in patients suffering from early-stage NSCLC or mid-stage NSCLC.
  • Suitable dosages for any of the above co-administered agents are those presently used and may be lowered due to the combined action (synergy), such as to increase the therapeutic index or mitigate toxicity or other side-effects or consequences.
  • the anti-PD-1 antibody and one or more chemotherapy drug (or combination treatment regimens described herein) may be further combined with any other therapy.
  • the anti-PD-1 antibody and one or more chemotherapy drug (or combination treatment regimens described herein) may be further combined with any therapy except any one or more therapies listed in the exclusion criteria described in the example section of this application.
  • the anti-PD-1 antibody and one or more chemotherapy drug (or combination treatment regimens described herein) may be further combined with, e.g., radiotherapy.
  • the anti-PD-1 antibody and one or more chemotherapy drug may be further combined with, e.g., a steroid or hormone therapy, optionally wherein the steroid or hormone therapy is administered to alleviate incidence of immune-mediated adverse events.
  • the combination therapy is any combination therapy described herein, including without limitation the combination therapies, dosing, duration and regimens described in the example section of this application.
  • the combination therapy described herein can be combined with additional therapies consistent with the inclusion criteria described in the example section of this application.
  • the combination therapy described herein can be combined with additional therapies consistent with the exclusion criteria described in the example section of this application (i.e., wherein the therapies listed in the exclusion criteria are excluded or not selected for the combination).
  • the additional therapy can be one or more of the following: tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib), multikinase inhibitor (e.g., MGCD265, RGB-286638), CD-20 targeting agent (e.g., rituximab, ofatumumab, RO5072759, LFB-R603), CD52 targeting agent (e.g., alemtuzumab), prednisolone, darbepoetin alfa, lenalidomide, Bcl-2 inhibitor (e.g., oblimersen sodium), aurora kinase inhibitor (e.g., MLN8237,
  • tyrosine kinase inhibitor e
  • the additional therapy is a radiotherapy.
  • radiotherapy is administered after surgical resecting or removal of the tumor or cancerous tissue.
  • radiotherapy is administered before maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., at 400 mg dose).
  • radiotherapy is administered 30 to 60 days (e.g., 30, 40, 50 or 60 days) after the surgical resecting of the tumor or cancer. In some embodiments, radiotherapy is administered at least 30 days after the surgical resecting of the tumor or cancer. In some embodiments, radiotherapy is administered not more than 60 days after the surgical resecting of the tumor or cancer.
  • the maintenance or adjuvant treatment period with an anti-PD-1 antibody e.g., at 400 mg dose
  • the maintenance or adjuvant treatment period with an anti-PD-1 antibody starts at least 7 days after the radiotherapy.
  • the maintenance or adjuvant treatment period with an anti-PD-1 antibody starts not more than 30 days after the radiotherapy.
  • the subject is not treated with radiotherapy.
  • the surgical resecting is not followed by radiotherapy.
  • the treatment regimen described herein does not comprise radiotherapy.
  • the maintenance or adjuvant treatment period with an anti-PD-1 antibody starts between 2 and 8 weeks (e.g., 2, 3, 4, 5, 6, 7, or 8 weeks) after the surgical resection of the tumor or cancer.
  • the maintenance or adjuvant treatment period with an anti-PD-1 antibody starts at least 2 weeks after the surgical resection of the tumor or cancer. In some embodiments, the maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., at 400 mg dose) starts not more than 8 weeks after the surgical resection of the tumor or cancer.
  • the additional therapy can be an antibody binding to another immune checkpoint molecule.
  • the amounts of the anti-PD-1 antibody disclosed herein and the one or chemotherapy drugs, as well as their relative timings of administration be determined 52 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibody is administered before (e.g., 60 minutes or more before) administration of one or more chemotherapy drugs. In some embodiments, the anti-PD-1 antibody is administered before (e.g., 30 minutes or more before) administration of one or more chemotherapy drugs. In some embodiments, the anti-PD-1 antibody is administered 60 minutes or more before administration of one or more chemotherapy drugs in cycle 1 and optionally cycle 2.
  • the anti-PD-1 antibody is administered 30 minutes or more before administration of one or more chemotherapy drugs in cycle 3, cycle 4, and/or any cycle subsequent to cycle 3.
  • the dosing, frequency and/or duration of administration of the anti-PD-1 antibody and one or more chemotherapeutic agents is as described herein.
  • the anti-PD-1 antibody and the one or more chemotherapeutic drugs described herein are administered on the same day.
  • the anti-PD-1 antibody and the one or more chemotherapeutic drugs described herein are administered at least 30 minutes apart from each other.
  • the anti-PD-1 antibody and the one or more chemotherapeutic drugs described herein are administered in any sequence.
  • the anti-PD-1 antibody is administered before the administration of the one or more chemotherapeutic drugs as described herein (e.g., at least 30 minutes before).
  • anti-PD-1 antibody (such as an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO:24, and/or the Vl of SEQ ID NO:26 (e.g., Tislelizumab)) is administered intravenously at a dose of 200 mg on Day 1 of each 21 cycle; cisplatin or carboplatin is administered intravenously on Day 1 of each 21 day cycle; and pemetrexed or paclitaxel is administered intravenously on Day 1 of each 21 day cycle.
  • cisplatin is administered IV at 75 mg/m2 (and optionally infused over 2 hours) or carboplatin is administered IV at AUC5 (and optionally infused over 15-60 minutes to achieve an AUC of 5 mg/mL/min).
  • pemetrexed is administered IV at 500 mg/m 2 (and optionally infused over 10 minutes) or paclitaxel is administered IV at 175 mg/m 2 (and optionally infused over 3 hours). In some of these 53 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibody in cycle 1, is administered 60 minutes or more before administration of cisplatin, carboplatin, pemetrexed and/or paclitaxel (and optionally the anti- PD-1 antibody is infused over 60 minutes). In some of these embodiments, in cycle 2, the anti- PD-1 antibody is administered 60 minutes or more before administration of cisplatin, carboplatin, pemetrexed and/or paclitaxel (and optionally the anti-PD-1 antibody is infused over 30 minutes).
  • the anti-PD-1 antibody in cycles 3 and 4, is administered 30 minutes or more (e.g., less than 60 minutes) before administration of cisplatin, carboplatin, pemetrexed and/or paclitaxel (and optionally the anti-PD-1 antibody is infused over 30 minutes).
  • the anti-PD-1 antibody in subsequent cycles (after cycle 4), is administered alone (without chemotherapy), and optionally the anti-PD-1 antibody is infused over 30 minutes or more (e.g., for less than 60 minutes).
  • Cancers Treated As Provided Herein Treatment regimens for solid cancers (e.g., lung cancer, esophageal cancer) are disclosed herein.
  • the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is esophageal cancer. [00217] In some embodiments, the solid cancer is resectable (surgically removable). In some embodiments, the solid cancer is not locally advanced or metastatic. [00218] In some embodiments, the solid cancer is stage I. In some embodiments, the solid cancer is stage IIA. In some embodiments, the solid cancer is stage IIB. In some embodiments, the solid cancer is stage IIIA. In some embodiments, the solid cancer is stage IIIB. [00219] In some embodiments, the cancer is chemotherapy-resistant. In some embodiments, the cancer has progressed after prior chemotherapy.
  • NSCLC non-small cell lung cancer
  • the cancer is esophageal cancer.
  • the solid cancer is resectable (surgically removable). In some embodiments, the solid cancer is not locally advanced or metastatic.
  • the solid cancer is stage I. In some embodiments, the solid cancer is stage IIA. In some embodiments, the solid
  • the NSCLC is a squamous cell carcinoma. In some embodiments, the NSCLC is a non-squamous carcinoma. In some embodiments, the NSCLC is an adenocarcinoma. In some embodiments, the NSCLC is a large cell carcinoma. In some such embodiments, the esophageal cancer is an esophageal squamous cell carcinoma. In some such embodiments, the esophageal cancer is an esophageal adenocarcinoma. [00221] In some embodiments, the NSCLC is resectable. In some embodiments, the NSCLC 54 4893-2664-4718.1 Atty. Dkt.
  • the esophageal cancer is resectable (e.g., resectable esophageal squamous cell carcinoma). In some embodiments, the esophageal cancer (e.g., esophageal squamous cell carcinoma) is not locally advanced or metastatic.
  • the NSCLC is stage I. In some embodiments, the NSCLC is stage IIA. In some embodiments, the NSCLC is stage IIB. In some embodiments, the NSCLC is stage IIIA.
  • the NSCLC is stage IIIB. In some embodiments, the NSCLC is stage IV. In some embodiments, the cancer is extensive-stage small cell lung cancer (NSCLC). In some embodiments, extensive-stage cancer has spread outside of the lung in which it began or to other parts of the body. In some embodiments, the NSCLC is unresectable. In some embodiments, the NSCLC is locally advanced. In some embodiments, the NSCLC is metastatic. In some embodiments, the esophageal cancer is stage I. In some embodiments, the esophageal cancer is stage IIA. In some embodiments, the esophageal cancer is stage IIB. In some embodiments, the esophageal cancer is stage IIIA.
  • NSCLC extensive-stage small cell lung cancer
  • the esophageal cancer is stage IIIB. In some embodiments, the esophageal cancer is stage IV. In some embodiments, the esophageal cancer is unresectable. In some embodiments, the esophageal cancer is locally advanced. In some embodiments, the esophageal cancer is metastatic. [00223] In some embodiments, the lung cancer is characterized by one or more of liver, lung, lymph node, bone, or adrenal gland metastasis. In some embodiments, the cancer is characterized by liver metastasis. In some embodiments, the cancer is characterized by lung metastasis. In some embodiments, the cancer is characterized by lymph node metastasis.
  • the cancer is characterized by bone metastasis. In some embodiments, the cancer is characterized by adrenal gland metastasis.
  • the cancer (such as lung cancer, e.g., NSCLC) is assessed for expression of immune-mediated biomarkers that are related to response or clinical benefit of the anti-PD-1 antibody, such as tislelizumab, e.g., using tumor biopsy.
  • the biomarker can be, without limitation, PD-L1, TMB, GEP and MSI. Biomarkers expression can be assessed by multiplex immunohistochemistry assay (IHC).
  • the cancer to be treated can be a cancer that has a detectable expression of PD-L1.
  • the cancer to be treated can be a cancer that has a detectable expression of TMB.
  • the cancer to be treated can be a cancer that has a detectable gene 55 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 expression profile (GEP), (such as an immune-mediated GEP).
  • GEP PCT/CN2023/135545
  • the cancer to be treated can be a cancer that has a detectable expression of MSI.
  • the cells of the lung cancer comprise high level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the total tumor area.
  • the subject has a low level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the total tumor area.
  • the subject has less than 1% of PD-L1 expression as measured by PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the total tumor area.
  • the subject has equal or more than 1% of PD-L1 expression as measured by PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the total tumor area.
  • the cells of the lung cancer have intermediate or high tumor mutational burden, optionally wherein the tumor has more than 5 or between 5 and 20 mutations, more than 20 or between 20 and 50 mutations, or more than 50 mutations.
  • the cells of the lung cancer comprise an epidermal growth factor (EGFR) mutation.
  • EGFR epidermal growth factor
  • the cells of the lung cancer comprise a v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. In some embodiments, the cells of the lung cancer comprise an ALK mutation.
  • the cells of the lung cancer are EGFR genomic aberration negative. In some embodiments, the cells of the lung cancer are KRAS genomic aberration negative. In some embodiments, the cells of the lung cancer are ALK genomic aberration negative.
  • the NSCLC is characterized by expression of one or more of INSM1, CD56/NCAM, synptophysin, or chromogranin A.
  • the NSCLC is characterized by expression of INSM1. In some embodiments, the NSCLC is characterized by 56 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 expression of CD56/NCAM. In some embodiments, the NSCLC is characterized by expression of synptophysin. In some embodiments, the NSCLC is characterized by expression of chromogranin. [00230] In some embodiments, the NSCLC is characterized by more than 16.3 ng/ml of neuron-specific enolase (NSE).
  • NSE neuron-specific enolase
  • the NSCLC is characterized by more than 66 pg/ml progastrin-releasing peptide (ProGRP). In some embodiments, the NSCLC is characterized by more than 2.5 ng/ml carcinoembryonic antigen (CEA). In some embodiments, the NSCLC is characterized by more than 10 ng/ml carcinoembryonic antigen (CEA). In some embodiments, the NSCLC is characterized by more than 16.3 ng/ml of neuron-specific enolase (NSE), more than 66 pg/ml progastrin-releasing peptide (ProGRP), and more than 2.5 ng/ml or more than 10 ng/ml carcinoembryonic antigen (CEA).
  • NSE neuron-specific enolase
  • ProGRP neuron-specific enolase
  • the patient is a mammal. In some embodiments, the mammal is human. In some embodiments, the patient is an adult. In some embodiments, the patient is 18 years of age or over 18 years of age. In some embodiments, the patient is over 40 years of age, over 45 years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age, over 70 years of age, over 75 years of age, or over 80 years of age. In some embodiments, the patient is 65 years or older. [00232] In some embodiments, the patient is male. In some embodiments, the patient is female. [00233] In some embodiments, the patient is a current smoker.
  • the patient is a former smoker. In some embodiments the patient has never smoked or was never a smoker.
  • the subject has (e.g., has been diagnosed with) a solid cancer. In some embodiments, the subject has (e.g., has been diagnosed with) a resectable solid cancer. In some embodiments, the subject has (e.g., has been diagnosed with) lung cancer. In some embodiments, the subject has (e.g., has been diagnosed with) esophageal cancer. In some embodiments, the subject has any of the cancers described herein. In some embodiments, the 57 4893-2664-4718.1 Atty. Dkt.
  • the subject has (e.g., has been diagnosed with) small cell lung cancer. In some embodiments, the subject has (e.g., has been diagnosed with) non-small cell lung cancer (NSCLC). In some embodiments, the subject has (e.g., has been diagnosed) with stage I NSCLC. In some embodiments, the subject has (e.g., has been diagnosed) with stage IIA NSCLC. In some embodiments, the subject has (e.g., has been diagnosed) with stage IIB or IIIA NSCLC.
  • NSCLC non-small cell lung cancer
  • the subject has (e.g., has been diagnosed) with squamous cell carcinoma. In some embodiments, the subject has (e.g., has been diagnosed) non-squamous small cell carcinoma. [00235] In some embodiments, the subject has (e.g., has been diagnosed with) esophageal cancer. In some embodiments, the subject has (e.g., has been diagnosed with) esophageal squamous cell carcinoma (e.g., restectable esophageal squamous cell carcinoma). In some embodiments, the subject has (e.g., has been diagnosed) with stage I esophageal squamous cell carcinoma.
  • the subject has (e.g., has been diagnosed) with stage cT3NanyM0 esophageal squamous cell carcinoma. In some embodiments, the subject has (e.g., has been diagnosed) with esophageal adenocarcinoma. [00236] In some embodiments, the subject has (e.g., has been diagnosed with) metastatic cancer. In some embodiments, the subject has one or more of liver, lung, lymph node, bone, and/or adrenal gland metastasis. In some embodiments, the subject has liver, lung or lymph node metastasis. In some embodiments, the subject has liver metastasis. In some embodiments, the subject has lung metastasis.
  • the subject has lymph node metastasis. In some embodiments, the subject has bone metastasis. In some embodiments, the subject has adrenal gland metastasis. In some embodiments, the subject has 1, 2, 3, or more metastatic sites. In some embodiments, the subject has 1 or more metastatic sites. In some embodiments, the subject has 2 or more metastatic sites. In some embodiments, the subject has 3 or more 58 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 metastatic sites. In some embodiments, the subject does not have brain metastasis. In other embodiments, the subject has brain metastasis.
  • the subject has been diagnosed using histological markers. In some embodiments, the subject has been diagnosed using cytological markers. In some embodiments, the subject has been diagnosed using histological and cytological markers. In some embodiments, the subject has been diagnosed using a biopsy. In some embodiments, the subject has been diagnosed using a solid biopsy. In some embodiments, the subject has been diagnosed with a liquid biopsy. Solid tissue biopsy involves sampling a piece of tissue from a node or tumor for examination. Liquid biopsy is a minimally invasive approach for sample procurement, mostly body fluids, and it is used to detect molecular alterations in shed, circulating tumor cells. [00238] In some embodiments, the subject has not previously been treated with an immunotherapy.
  • the subject has not previously been treated with a chemotherapy (e.g., platinum-based chemotherapy). In some embodiments, the subject has not previously been treated with any immune checkpoint inhibitor. In some embodiments, the subject has not previously been treated with an immunotherapy or a chemotherapy. In some embodiments, the subject has not previously been treated with an immunotherapy and/or a chemotherapy for the cancer being treated in accordance with the methods described herein. In some embodiments, the subject has not received prior chemotherapy for NSCLC. In some of the embodiments where the subject has been treated for limited stage NSCLC, there is a treatment- free interval of 6 months or more before the diagnosis of NSCLC and/or the initiation of the treatment described herein.
  • a chemotherapy e.g., platinum-based chemotherapy
  • any immune checkpoint inhibitor e.g., the subject has not previously been treated with an immunotherapy or a chemotherapy. In some embodiments, the subject has not previously been treated with an immunotherapy and/or a chemotherapy for the cancer being treated in accordance with the methods described herein. In some embodiments,
  • the subject has not received prior therapy (e.g., chemotherapy) for esophageal squamous cell carcinoma.
  • prior therapy e.g., chemotherapy
  • the subject has not received systemic treatment with either corticosteroids or other immunosuppressive agents within 14 days of treatment described herein.
  • the subject has received prior chemotherapy treatment (e.g., for the cancer being treated).
  • prior immunotherapy treatment e.g., for the cancer being treated.
  • the subject has adequate organ function, e.g., as measured by 59 4893-2664-4718.1 Atty. Dkt.
  • the subject has no renal dysfunction. In some embodiments, the subject does not have sever renal dysfunction. In some embodiments, the subject has a moderate renal dysfunction as described herein. In some embodiments, the subject has glomerular filtration rate of more than 30 mL/min/1.73 m2 and less than 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration equation.
  • the neoadjuvant and adjuvant treatment of resectable NSCLC comprises platinum-based doublet chemotherapy with either cisplatin or carboplatin for patients with comorbidities or who are not able to tolerate cisplatin (NCCN Guideline 2019, Postmus et al 2017; CSCO 2018).
  • Either platinum may be combined with a variety of chemotherapeutics, including vinorelbine, etoposide, gemcitabine, docetaxel, paclitaxel and pemetrexed.
  • neoadjuvant chemotherapy may consist of platinum in combination with either pemetrexed or paclitaxel for patients with non-squamous and squamous histology, respectively. Dosing of chemotherapeutics are summarized in the Table below. [00243]
  • the disclosure relates to a method of treating lung cancer (such as NSCLC) or esophageal cancer (e.g., esophageal squamous cell carcinoma) in a subject (e.g., a human), the method comprising administering to the subject effective amounts of an anti-PD-1 antibody and one or more chemotherapeutic drug (e.g., a platinum chemotherapy drug).
  • lung cancer such as NSCLC
  • esophageal cancer e.g., esophageal squamous cell carcinoma
  • the one or more chemotherapeutic drugs is cisplatin or carboplatin. In some embodiments, the one or more chemotherapeutic drugs is pemetrexed or paclitaxel. In some embodiments, the one or more chemotherapeutic drugs is etoposide. In some embodiments, the one or more chemotherapeutic drugs is 5-fluorouracil.
  • the disclosure relates to a method of treating lung cancer (such as NSCLC) or esophageal cancer (e.g., esophageal squamous cell carcinoma) in a subject (e.g., a human), the method comprising administering to the subject an effective amounts of an anti-PD- 1 antibody, cisplatin or carboplatin, and pemetrexed or paclitaxel or 5-fluorouracil.
  • the subject is treated in accordance with a treatment regimen (such as dosing, 60 4893-2664-4718.1 Atty. Dkt.
  • the anti-PD-1 antibody and one or more chemotherapeutic drugs disclosed herein may be administered parenterally.
  • parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the anti-PD-1 antibody and chemotherapeutic drug(s) may be administered by different routes.
  • the anti-PD-1 antibody is administered intravenously, and the one or more chemotherapeutic drugs are also administered intravenously.
  • described herein is a method of treating lung cancer (e.g., NSCLC) or esophageal cancer (e.g., esophageal squamous cell carcinoma) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti- PD-1 antibody, wherein the PD-1 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR)-H1 comprising SEQ ID NO:31, CDR- H2 comprising SEQ ID NO:32, and CDR-H3 comprising SEQ ID NO:33, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO:34, CDR-L2 comprising SEQ ID NO:35, and CDR-L3 comprising SEQ ID NO:36, and a therapeutically
  • CDR complementarity determining region
  • lung cancer e.g., NSCLC
  • esophageal cancer e.g., esophageal squamous cell carcinoma
  • administering comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody, wherein the PD-1 antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO:24 and SEQ ID NO:26, respectively, and a therapeutically effective amount of one or more chemotherapeutic drugs.
  • Vh heavy chain variable region
  • Vl light chain variable region
  • lung cancer e.g., NSCLC
  • esophageal cancer e.g., esophageal squamous cell carcinoma
  • administering comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody, wherein the PD-1 antibody is a monoclonal antibody or a fragment thereof (e.g., a humanized antibody or fragment), comprising a heavy chain variable region (Vh) amino acid sequence of SEQ ID NO:24, a light chain variable region (Vl) amino acid sequence of SEQ ID NO:26, and an IgG4 constant domain amino acid sequence of SEQ ID NO:88.
  • Vh heavy chain variable region
  • Vl light chain variable region amino acid sequence of SEQ ID NO:26
  • IgG4 constant domain amino acid sequence of SEQ ID NO:88 an IgG4 constant domain amino acid sequence of SEQ ID NO:88.
  • a method of treating lung cancer e.g., NSCLC
  • esophageal cancer e.g., esophageal squamous cell carcinoma
  • a subject is administered one or more, or all of the study drugs provided in Table 6, at the treatment regimen described therein.
  • the choice between cisplatin and carboplatin is at treating physician’s discretion.
  • Table 6 Selection and Timing of Dose for Each Patient Study Drug Dose Frequency of Route of Duration of Administration Administration Treatment Tislelizumab 200 mg Day 1 of every IV 3 weeks 3 to 4 cycles during the Placebo NA Day 1 of every IV neoadjuvant phase 3 weeks Tislelizumab 400 mg Day 1 of every IV 6 weeks Up to 8 cycles during Placebo NA Day 1 of every IV the adjuvant phase 6 weeks Cisplatin 75 mg/m 2 Day 1 of every IV 3 weeks 3 to 4 cycles during the Carboplatin AUC of 5 Day 1 of every IV neoadjuvant phase mg/mL/min 3 weeks Pemetrexed 500 mg/m 2 Day 1 of every IV 3 to 4 cycles during the 3 weeks neoadjuvant phase (for non-squamous) Paclitaxel 175 mg/m 2 Days 1 of every IV 3 to 4 cycles during the 3 weeks ne
  • an anti-PD-1 antibody (Tislelizumab) at the dose of 400 mg once every 6 weeks. This dosage was selected for the adjuvant phase by matching dose and exposure (AUC) with the exposure of 200 mg once every 3 weeks regimen during the neoadjuvant phase.
  • AUC dose and exposure
  • an administration regimen comprising administering Tislelizumab 200 mg once every 3 weeks during neoadjuvant phase, followed by 400 mg once every 6 weeks during adjuvant phase.
  • patients may receive treatment with platinum-based doublet chemotherapy during the neoadjuvant phase (Table 6).
  • patients may receive treatment with 5-fluorouracil and cistplatin during the neoadjuvant phase.
  • Cisplatin 75 mg/m2 may be administered as an intravenous infusion over 2 hours on Day 1 of each 3 week cycle for 3 to 4 cycles.
  • Carboplatin AUC of 5 mg/mL/min may be administered as an intravenous infusion over 1 hour on Day 1 of each 3-week cycle for 3 to 4 cycles.
  • Carboplatin can replace cisplatin per the investigator’s discretion in consideration of patient’s tolerability to cisplatin.
  • Pemetrexed 500 mg/m2 may be administered as an intravenous infusion over 10 minutes on Day 1 of each 3-week cycle for 3 to 4 cycles.
  • Paclitaxel 175 mg/m2 may be administered as an intravenous infusion over 3 hours on Day 1 of each 3-week cycle for 3 to 4 cycles.
  • Embodiments of the present disclosure also include the agents and combinations described herein (i) for use in, (ii) for use as a medicament or composition for, or (iii) for use in the preparation of a medicament for: b. therapy (e.g., of the human body); c. medicine; d. induction of or augmenting an anti-tumor immune response; e.
  • the treating is clinically effective or the subject is a responder to the treating by at least one measure of response to treatment.
  • the response to treatment is measured by overall survival, progression-free or event-free survival, major pathological response (“MPR”), pathological complete response (“pCR”), overall 64 4893-2664-4718.1 Atty. Dkt.
  • the response to treatment is measured by tumor volume.
  • the treating reduces tumor volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 75%.
  • the subject has greater than 30% probability of survival at 24 months.
  • the treating is effective as demonstrated by patient population overall survival rate at 24 months of greater than 30%.
  • the subject has greater than 15% or 20% probability of event-free survival at 12 months.
  • the treating is effective as demonstrated by a patient population event-free survival rate at 12 months of greater than 20%.
  • the response to treatment is measured by a major pathological response (“MPR”), which is defined as less than 10% residual viable tumor after neoadjuvant therapy.
  • MPR major pathological response
  • the MPR is twice that observed in the control group.
  • the MPR is at least 25%.
  • the treating results in the MPR in the subject.
  • the MPR is at least twice that observed in the control group not treated with the anti-PD-1 antibody.
  • the subject has at least 25%, 35%, 40%, 45% or 50% probability of the MPR.
  • the treating is effective as demonstrated by patient population MPR of at least 25%, 35%, 40%, 45% or 50%.
  • the treating results in the pCR in the subject.
  • the subject has at least 15%, 20%, 25%, 30%, 35%, or 40% probability of the pCR.
  • the treating is effective as demonstrated by patient population pCR of at least 15%, 20%, 25%, 30%, 35%, or 40%.
  • Adopting meaningful surrogate endpoints may expedite the evaluation of new therapeutics in cancer treatment. Pathological response as a surrogate endpoint is adopted in breast cancer.
  • pathological complete response pCR
  • MPR pathological response after surgical resection of NSCLC
  • the patient is responsive to treatment by one, two, three or more criteria described herein and/or known in the art.
  • the responsiveness criteria are any criterial described herein, including but not limited to those described in the example section of this application.
  • the treatment described herein reduces tumor volume, size, or diameter.
  • the treatment described herein reduces tumor volume, size or diameter by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.
  • the treatment described herein reduces the diameter of a cancer lesion by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.
  • the measurements are made by CT or MRI.
  • the measurements are made and results are assessed as described herein (see, e.g., the example section).
  • the reduction is relative to the tumor volume, size or diameter in the subject prior to the start of the treatment.
  • the methods described herein improve overall survival. In some embodiments, the improvement is relative to probability of survival without treatment or with a standard of care treatment.
  • the response to treatment in a subject is measured by overall survival, progression-free survival, event-free survival, overall response rate, objective response rate, partial response, duration of response, or a combination thereof. In some embodiments, the response to treatment in a subject is measured by overall survival. In some embodiments, the response to treatment in a subject is measured by progression-free survival. In some embodiments, the response to treatment in a subject is measured by event-free survival. In some embodiments, the response to treatment in a subject is measured by overall response rate.
  • the response to treatment in a subject is measured by objective response rate. In some embodiments, the response to treatment in a subject is measured by partial response. In some embodiments, the response to treatment in a subject is measured by duration of response. [00263] In some embodiments, the patient survives for at least 24 months. In some embodiments, the patient survives for at least 27 months. In some embodiments, the patient survives for at least 30 months. In some embodiments, the patient survives for at least 36 months.
  • the patient survives for at least 39 months. In some embodiments, the patient survives for at least 42 months. In some embodiments, the patient survives for at least 45 months. In some embodiments, the patient survives for at least 48 months or at least 4 years. In some embodiments, the patient survives for at least 5 years. In some embodiments, the survival determination is starting from the initiation of treatment (e.g., the specified months since the treatment initiation). [00264] In some embodiments, the subject has a greater than 30% probability of survival at 24 months from initiation of a treatment regimen described herein. In some embodiments, the treating prolongs survival of the human patient which prolonged survival can be free of progression of the lung cancer.
  • the treating prolongs survival of the human patient which prolonged survival can be free of progression of the small cell lung cancer.
  • the subject has a greater than 15% probability of event-free survival at 12 months from initiation of a treatment regimen described herein. In some embodiments, the subject has a greater than 20% probability of event-free survival at 12 months from initiation of a treatment regimen described herein. [00265]
  • the patient survives free of progression of the NSCLC for at least 4 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 5 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 6 months.
  • the patient survives free of progression of the NSCLC for at least 7 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 8 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 9 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 10 months. In some embodiments, the patient survives 67 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 free of progression of the NSCLC for at least 11 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 12 months.
  • the patient survives free of progression of the NSCLC for at least 15 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 18 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 21 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 24 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 30 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 34 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 35 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 36 months or 3 years.
  • the patient survives free of progression of the NSCLC for at least 39 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 42 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 45 months. In some embodiments, the patient survives free of progression of the NSCLC for at least 48 months or 4 years. In some embodiments, the patient survives free of progression of the NSCLC for at least 5 years. In some embodiments, the survival free of progression determination is starting from the initiation of treatment (e.g., the specified months since the treatment initiation).
  • the patient survives free of progression of the esophageal squamous cell carcinoma (ESCC) (e.g., resectable ESCC) for at least 4 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 5 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 6 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 7 months.
  • ESCC esophageal squamous cell carcinoma
  • the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 8 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 9 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 10 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 11 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., 68 4893-2664-4718.1 Atty. Dkt.
  • ESCC e.g., 68 4893-2664-4718.1 Atty. Dkt.
  • the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 30 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 34 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 35 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 36 months or 3 years. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 39 months.
  • the ESCC e.g., resectable ESCC
  • the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 42 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 45 months. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 48 months or 4 years. In some embodiments, the patient survives free of progression of the ESCC (e.g., resectable ESCC) for at least 5 years. In some embodiments, the survival free of progression determination is starting from the initiation of treatment (e.g., the specified months since the treatment initiation).
  • the patient exhibits the duration of response of at least 6 months. In some embodiments, the patient exhibits the duration of response of at least 12 months. In some embodiments, the patient exhibits the duration of response of at least 18 months. In some embodiments, the patient exhibits the duration of response of at least 24 months. In some embodiments, the patient exhibits the duration of response of at least 30 months. In some embodiments, the patient exhibits the duration of response of at least 33 months. In some embodiments, the patient exhibits the duration of response of at least 36 months. In some embodiments, the patient exhibits the duration of response of at least 39 months. In some embodiments, the patient exhibits the duration of response of at least 42 months.
  • the patient exhibits the duration of response of at least 45 69 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 months. In some embodiments, the patient exhibits the duration of response of at least 48 months or 4 years. In some embodiments, the patient exhibits the duration of response of at least 5 years. In some embodiments, the responsiveness determination is starting from the initiation of treatment (e.g., the specified months since the treatment initiation). [00268] In some embodiments, the response to treatment in a subject is measured by overall response rate, complete response and/or partial response.
  • a human responder to treatment exhibits stable disease. In some embodiments, a human responder to treatment exhibits stable disease for, or at least for, 3 months, 6 months, 9 months, 12 months, 18 months, 21 months, 24 months, 30 months, 36 months, 42 months, 48 months or 5 years. In some embodiments, the determination is starting from the initiation of treatment (e.g., the specified months since the treatment initiation). [00270] In some embodiments, a human responder to treatment does not exhibit progressive disease, and/or exhibits delay in the cancer progression.
  • a human responder to treatment does not exhibit progressive disease, and/or exhibits delay in the cancer progression for, or at least for, 3 months, 6 months, 9 months, 12 months, 18 months, 21 months, 24 months, 30 months, 36 months, 42 months, 48 months or 5 years.
  • the determination is starting from the initiation of treatment (e.g., the specified months since the treatment initiation).
  • a human responder to treatment exhibits a response (such as an improvement or delay of progression response) in one or more patient-reported outcome (PRO) assessments, such as any one of the PRO assessments described herein (including but not limited to Quality of Life assessments using any of the Questionnaires described herein).
  • PRO patient-reported outcome
  • a positive response on a PRO assessment is observed for, or at least for, 3 months, 6 months, 9 months, 12 months, 18 months, 21 months, 24 months, 30 months, 36 months, 42 months, 48 months or 5 years starting from the initiation of treatment.
  • a human responder to treatment as described herein has been diagnosed and treated for a resectable NSCLC.
  • a human responder to 70 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 treatment as described herein has been diagnosed and treated for Stage I NSCLC.
  • a human responder to treatment as described herein has been diagnosed and treated for Stage IIA NSCLC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage IIB NSCLC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage IIIA NSCLC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage IIIB NSCLC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage IV NSCLC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for NSCLC.
  • a human responder to treatment as described herein has been diagnosed and treated for metastatic NSCLC.
  • a human responder to treatment is free of progression of a resectable NSCLC.
  • a human responder to treatment is free of progression of Stage I NSCLC.
  • a human responder to treatment is free of progression of Stage IIA NSCLC.
  • a human responder to is free of progression of Stage IIB NSCLC.
  • a human responder to treatment is free of progression of Stage IIIA NSCLC.
  • a human responder to treatment is free of progression of Stage IIIB NSCLC.
  • a human responder to treatment is free of progression of Stage IV NSCLC. In some embodiments, a human responder to treatment is free of progression of NSCLC. In some embodiments, a human responder to treatment is free of progression of metastatic NSCLC. [00274] In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for a resectable ESCC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage I ESCC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage IIA ESCC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage IIB ESCC.
  • a human responder to treatment as described herein has been diagnosed and treated for Stage IIIA ESCC. In some embodiments, a human responder to treatment as described herein has been diagnosed 71 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 and treated for Stage IIIB ESCC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for Stage IV ESCC. In some embodiments, a human responder to treatment as described herein has been diagnosed and treated for ESCC (e.g., resectable ESCC).
  • ESCC e.g., resectable ESCC
  • a human responder to treatment as described herein has been diagnosed and treated for metastatic ESCC.
  • a human responder to treatment is free of progression of a resectable ESCC.
  • a human responder to treatment is free of progression of Stage I ESCC.
  • a human responder to treatment is free of progression of Stage IIA ESCC.
  • a human responder to is free of progression of Stage IIB ESCC.
  • a human responder to treatment is free of progression of Stage IIIA ESCC.
  • a human responder to treatment is free of progression of Stage IIIB ESCC.
  • compositions including pharmaceutical formulations, comprising an anti-PD-1 antibody or an antigen-binding fragment thereof described herein.
  • the composition, including a pharmaceutical formulation comprises an anti-PD-1 antibody or an antigen-binding fragment thereof and one or more chemotherapeutic drugs.
  • compositions of an anti-PD-1 antibody or antigen-binding fragment as described herein are prepared by mixing such antibody or antigen-binding fragment having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
  • Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not 72 4893-2664-4718.1 Atty. Dkt.
  • the surfactant is a polysorbate.
  • exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.).
  • sHASEGP soluble neutral-active hyaluronidase glycoproteins
  • rHuPH20 HYLENEX®, Baxter International, Inc.
  • Certain exemplary sHASEGPs and methods of use, including rHuPH20 are described in US Patent Nos. US 7,871,607 and 2006/0104968.
  • a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
  • Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958.
  • Aqueous antibody formulations include those described in US Patent No.6,171,586 and WO2006/044908, the latter formulations including a histidine-acetate buffer.
  • the formulations include a histidine-citric acid buffer.
  • Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • the formulations to be used for in vivo administration are generally sterile.
  • the pharmaceutical composition or formulation comprises a formulation buffer comprising histidine, acetate, citrate, succinate, phosphate, 73 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 mixture of histidine and acetic acid, mixture of histidine and citric acid, salt or hydrate thereof, or any combination of them.
  • the formulation buffer comprises a histidine buffer that comprises histidine, histidine hydrochloride, L-histidine, L-histidine hydrochloride, L-histidine hydrochloride hydrate, L-histidine hydrochloride monohydrate, or a combination thereof.
  • the histidine buffer comprises L-histidine/L-histidine hydrochloride monohydrate buffer (His/His HCl).
  • the histidine buffer comprises histidine/L-histidine hydrochloride monohydrate buffer and citric acid monohydrate.
  • the concentration of the histidine buffer is between about 5 mM to about 30 mM. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine/L-histidine hydrochloride monohydrate) is between about 5 mM to about 10 mM, between about 5 mM to about 15 mM, between about 5 mM to about 20 mM, between about 10 mM to about 15 mM, between about 10 mM to about 20 mM, between about 10 mM to about 25 mM, between about 15 mM to about 20 mM, between about 15 mM to about 25 mM, between about 15 mM to about 30 mM, between about 20 mM to about 25 mM, or between about 25 mM to about 30 mM.
  • the concentration of the histidine buffer is about 5 mM or more, about 10 mM or more, about 15 mM or more, about 20 mM or more, about 25 mM or more, about 30 mM or more. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine/L-histidine hydrochloride monohydrate) is 10mM. [00280] In some embodiments, the concentration of the histidine is about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM.
  • the concentration of the L-histidine hydrochloride monohydrate is about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM.
  • the formulation comprises histidine at a concentration of about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM, and L-histidine hydrochloride monohydrate at a concentration of about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM.
  • the formulation buffer is a mixture of histidine, L-histidine hydrochloride monohydrate, citric acid monohydrate, and sodium citrate; wherein the formulation comprises histidine at a 74 4893-2664-4718.1 Atty. Dkt.
  • the pharmaceutical composition or formulation comprises a stabilizer.
  • the stabilizer comprises trehalose, sucrose, sorbitol, mannitol, L-arginine hydrochloride, maltose, dextran, (2-hydroxypropyl)-b- cyclodextrin, sodium chloride, magnesium chloride, calcium chloride, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or a combination thereof.
  • the stabilizer comprises trehalose, sucrose, L-arginine hydrochloride, sodium chloride, or a combination thereof.
  • the stabilizer is trehalose.
  • the trehalose is a-trehalose dihydrate.
  • the concentration of the stabilizer is between about 50 mM to about 300 mM. In some embodiments, the concentration of the stabilizer is between about 50 mM to about 100 mM, between about 50 mM to about 150 mM, between about 50 mM to about 200 mM, between about 100 mM to about 150 mM, between about 100 mM to about 200 mM, between about 100 mM to about 250 mM, between about 150 mM to about 200 mM, between about 150 mM to about 250 mM, or between about 150 mM to about 300 mM.
  • the concentration of the stabilizer is about 50 mM or more, about 60 mM or more, about 70 mM or more, about 80 mM or more, about 90 mM or more, about 100 mM or more, about 110 mM or more, about 120 mM or more, about 130 mM or more, about 140 mM or more, about 150 mM or more, about 160 mM or more, about 170 mM or more, about 180 mM or more, about 190 mM or more, about 200 mM or more, about 210 mM or more, about 220 mM or more, about 230 mM or more, about 240 mM or more, about 250 mM or more, about 260 mM or more, about 270 mM or more, about 280 mM or more, about 290 mM or more, or about 300 mM or more.
  • the concentration of the stabilizer is about 190 mM.
  • the pharmaceutical composition or formulation comprises a non-ionic surfactant.
  • the non-ionic surfactant comprises polysorbate 80 75 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 (PS80), polysorbate 20 (PS20), poloxamer188 (P188), or a combination thereof.
  • the non-ionic surfactant is PS20.
  • the concentration of the non-ionic surfactant is between about 0.01% to about 1%.
  • the concentration of the non-ionic surfactant is between about 0.01% to about 0.03%, between about 0.01% to about 0.06%, between about 0.01% to about 0.09%, between about 0.03% to about 0.06%, between about 0.03% to about 0.09%, between about 0.03% to about 0.2%, between about 0.06% to about 0.09%, between about 0.06% to about 0.2%, between about 0.06% to about 0.5%, between about 0.09% to about 0.2%, between about 0.09% to about 0.5%, between about 0.09% to about 0.8%, between about 0.2% to about 0.5%, between about 0.2% to about 0.8%, between about 0.2% to about 1%, between about 0.5% to about 0.8%, between about 0.5% to about 1%, or between about 0.8% to about 1%.
  • the concentration of the non-ionic surfactant is about 0.01% or more, is about 0.02% or more, is about 0.03% or more, is about 0.04% or more, is about 0.05% or more, is about 0.06% or more, is about 0.07% or more, is about 0.08% or more, is about 0.09% or more, is about 0.1% or more, is about 0.2% or more, is about 0.3% or more, is about 0.4% or more, is about 0.5% or more, is about 0.6% or more, is about 0.7% or more, is about 0.8% or more, is about 0.9% or more, or is about 1% or more. In some embodiments, the concentration of the non-ionic surfactant is 0.2%.
  • the pharmaceutical composition or formulation comprises between about 1 mg/ml to about 10 mg/ml of the antibody such as tislelizumab as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises between about 1 mg/ml to about 2 mg/ml, between about 1 mg/ml to about 3 mg/ml, between about 1 mg/ml to about 4 mg/ml, between about 2 mg/ml to about 3 mg/ml, between about 2 mg/ml to about 4 mg/ml, between about 2 mg/ml to about 5 mg/ml, between about 3 mg/ml to about 4 mg/ml, between about 3 mg/ml to about 5 mg/ml, between about 3 mg/ml to about 6 mg/ml, between about 4 mg/ml to about 5 mg/ml, between about 4 mg/ml to about 6 mg/ml, between about 4 mg/ml to about 7 mg/ml, between about 5 mg/ml to about 6 mg/ml, between
  • the pharmaceutical composition or formulation comprises about 1 mg/ml or more, 2 mg/ml or more, 3 mg/ml or more, 4 mg/ml or more, 5 mg/ml or more, 6 mg/ml or more, 7 mg/ml or more, 8 mg/ml or more, 9 mg/ml or more, or 10 mg/ml or more of the antibody disclosed herein.
  • the pharmaceutical composition or formulation comprises 10 mg/ml of the antibody (e.g. PD-1 antibody or tislelizumab) disclosed herein. [00284] In some embodiments, the pharmaceutical composition or formulation has a pH of between about 4.5 to about 7.5.
  • the pharmaceutical composition or formulation has a pH of between about 4.5 to about 5.0, between about 4.5 to about 5.5, between about 4.5 to about 6.0, between about 5.0 to about 5.5, between about 5.0 to about 6.0, between about 5.0 to about 6.5, between about 5.5 to about 6.0, between about 5.5 to about 6.5, between about 5.5 to about 7.0, between about 6.0 to about 6.5, between about 6.0 to about 7.0, between about 6.0 to about 7.5, between about 6.5 to about 7.0, between about 6.5 to about 7.5, or between about 7.0 to about 7.5.
  • the pharmaceutical composition or formulation has a pH of about 4.5 or more, about 5.0 or more, about 5.5 or more, about 6.0 or more, about 6.5 or more, about 7.0 or more, or about 7.5 or more. In some embodiments, the pharmaceutical composition or formulation has a pH of 6.5.
  • the antibody e.g. PD-1 antibody or tislelizumab
  • the antibody is formulated in a pharmaceutical composition comprising a histidine buffer, a surfactant and a stabilizer.
  • the surfactant is a polysorbate.
  • the stabilizer is trehalose.
  • the PD-1 antibody e.g.
  • tislelizumab is formulated in a pharmaceutical composition
  • a pharmaceutical composition comprising citric acid monohydrate, histidine, L- histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, and trehalose.
  • pharmaceutical composition refers to preparations with pharmaceutically acceptable excipients which are in such form as to permit the active ingredients to be effective, and which contains no additional components which are toxic to the subjects to which the composition would be administered.
  • a pharmaceutical composition may be formulated for administration in solid or liquid form, comprising, without limitation, a form 77 4893-2664-4718.1 Atty. Dkt.
  • PCT/CN2023/135545 and PCT/CN2023/124264 adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or
  • compositions e.g., pharmaceutically acceptable compositions, which include an anti-PD-1 antibody described herein, formulated together with at least one pharmaceutically acceptable excipient.
  • pharmaceutically acceptable refers to a molecule or composition that, when administered to a recipient, is not deleterious to the recipient thereof, or that any deleterious effect is outweighed by a benefit to the recipient thereof.
  • materials which may serve as pharmaceutically acceptable carriers comprise: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic sa
  • a “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion). 78 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 [00290]
  • the compositions disclosed herein can be in a variety of forms.
  • liquid, semi-solid and solid dosage forms such as liquid solutions (e.g., injectable and infusion solutions), dispersions or suspensions, liposomes, and suppositories.
  • a suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusion solutions.
  • One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • the antibody is administered by way of a syringe infusion system.
  • kits comprising anti-PD-1 antibodies or antigen-binding fragments thereof, and instructions for use and/or administration.
  • a kit comprises at least one anti-PD-1 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier, and instructions for use and/or administration.
  • a kit comprises at least one anti-PD-1 antibody or antigen- binding fragment thereof, at least one chemotherapeutic agent, and a pharmaceutically acceptable carrier, and instructions for use and/or administration.
  • kits for use in various methods disclosed herein. Instructions can comprise a description of administering of one or more pharmaceutical compositions described herein to a subject to achieve an intended activity in a subject.
  • a kit may further comprise a description of selecting a human suitable for treatment based on identifying whether the human is in need of treatment.
  • instructions comprise a description of administering at least one anti-PD-1 antibody or antigen-binding fragment thereof to a subject who is in need of the treatment.
  • Instructions relating to administering one or more doses of at least one anti-PD-1 79 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 antibody or antigen-binding fragment thereof, and/or one or more chemotherapeutic drug generally include information as to dosage, dosing schedule, and route of administration for an intended treatment.
  • Containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits provided herein are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like.
  • packages for use in combination with a specific device such as an infusion device.
  • a kit may have a sterile access port (for example, a container may be an intravenous solution bag or a vial having a stopper pierce able by a hypodermic injection needle).
  • Kits can include additional components such as buffers and interpretive information.
  • a kit can comprise a container and a label or one or more package inserts on or associated with a container.
  • the disclosure provides articles of manufacture comprising contents of kits described above.
  • Embodiments described herein are further illustrated by, though in no way limited to, the following examples. (c) Definitions [00297] For the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the Specification.
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • the terms “e.g.,” and “i.e.,” as used herein, are used merely by way of example, 81 4893-2664-4718.1 Atty. Dkt.
  • Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another case includes from the 82 4893-2664-4718.1 Atty. Dkt.
  • nucleotides includes 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, and 0 nucleot
  • any lesser number or fraction in between is any lesser number or fraction in between.
  • the terms “plurality”, “at least two”, “two or more”, “at least second”, and the like, are understood to include but not limited to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 1920, 21, 22, 23, 24, 25, 83 4893-2664-4718.1 Atty. Dkt.
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • subject refers to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, and includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, horse, cattle), and most preferably a human.
  • anti-cancer agent refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents, including cellular therapies.
  • Antibodies are large, complex molecules (molecular weight of ⁇ 150,000 or about 1320 amino acids) with intricate internal structure.
  • the term “antibody” (Ab) includes, without limitation, a glycoprotein immunoglobulin which binds specifically to an antigen.
  • antibodies are large, complex molecules (molecular weight of ⁇ 150,000 or about 1320 amino acids) with an intricate internal structure.
  • An antibody can comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof.
  • Each H chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH or Vh) and a heavy chain constant region.
  • the heavy chain constant region 84 4893-2664-4718.1 Atty.
  • Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 comprises three constant domains, CH1, CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL or Vl) and a light chain constant region.
  • LCVR light chain variable region
  • Vl light chain constant region
  • antibody refers to a polypeptide of the immunoglobulin family that can bind a corresponding antigen non-covalently, reversibly, and in a specific manner.
  • the light and heavy chain variable regions come together in 3-dimensional space to form a variable region that binds the antigen (for example, a receptor on the surface of a cell).
  • variable regions of each light/heavy chain (Vl/Vh) pair form the antibody binding site.
  • an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are, generally, the same in primary sequence.
  • CDRs complementarity determining regions
  • CDR-L1 refers to the complementarity determining regions (CDR) 1, 2, and 3 of the variable light (L) chain of an antibody.
  • the variable light chain provided herein includes in N-terminal to C-terminal direction a CDR-L1, a CDR-L2 and a CDR-L3.
  • CDR-H1 refers to the complementarity determining regions (CDR) 1, 2, and 3 of the variable heavy (H) chain of an antibody.
  • variable heavy chain includes in N-terminal to C-terminal direction a CDR-H1, a CDR-H2 and a CDR-H3.
  • CDR-H1 a CDR-H1
  • CDR-H2 a CDR-H3
  • CDR-H3 a CDR-H3
  • the position and length of the CDRs have been precisely defined by Kabat, E. et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1983, 1987.
  • Naturally-produced antibodies are also glycosylated, e.g., on the CH2 domain.
  • FR The part of a variable region not contained in the CDRs is called the framework (“FR”), which forms the environment for the CDRs.
  • each VH and VL comprises three CDRs and four FRs, arranged from 85 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • variable regions of the heavy and light chains contain the binding domain that interacts with an antigen
  • the constant regions of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • the AbM definition is a compromise between the two used by Oxford Molecular’s AbM antibody modelling software.
  • the contact definition is based on an analysis of the available complex crystal structures.
  • the positions of the CDRs and framework regions can be determined using various definitions well known in the art, e.g., Kabat, Chothia, AbM and IMGT (see, e.g., Johnson et al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia et al., Nature, 342:877-883 (1989); Chothia et al., J. Mol.
  • the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).
  • the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL.
  • the CDR amino acid residues in the VH are numbered approximately 26-35 (HCDR1), 51-57 (HCDR2) and 93- 102 (HCDR3), and the CDR amino acid residues in the VL are numbered approximately 27-32 (LCDR1), 50-52 (LCDR2), and 89-97 (LCDR3) (numbering according to Kabat).
  • the CDR regions of an antibody can be determined using the program IMGT/DomainGapAlign. [00317]
  • the CDRs of an antibody can be determined according to the Chothia numbering scheme, which refers to the location of immunoglobulin structural loops (see, e.g., Chothia C.
  • the Chothia CDR-H1 loop is present at heavy chain amino acids 26 to 32, 33, or 34
  • the Chothia CDR-H2 loop is present at heavy chain amino acids 52 to 56
  • the Chothia CDR-H3 loop is present at heavy chain amino acids 95 to 102
  • the Chothia CDR-L1 loop is present at light chain amino acids 24 to 34
  • the Chothia CDR-L2 loop is present at light chain amino acids 50 to 56
  • the Chothia CDR-L3 loop is present at light chain amino acids 89 to 97.
  • the end of the Chothia CDR-HI loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is 87 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the CDRs of the antibodies described herein have been determined according to the Chothia numbering scheme.
  • an antibody is said to comprise CDRs by a certain definition of CDRs (e.g., Kabat) that definition specifies the minimum number of CDR residues present in the antibody (i.e., the Kabat CDRs). It does not exclude the fact that other residues falling within another conventional CDR definition but outside the specified definition are also present.
  • an antibody comprising CDRs defined by Kabat includes among other possibilities, an antibody in which the CDRs contain Kabat CDR residues and no other CDR residues, and an antibody in which HCDRl is a composite Chothia-Kabat HCDR1 and other CDRs contain Kabat CDR residues and no additional CDR residues based on other definitions.
  • a CDR is substantially identical to one found in a reference antibody (e.g., an antibody of the present disclosure) and/or the sequence of a CDR provided in the present disclosure.
  • a CDR is substantially identical to a reference CDR (e.g., a CDR provided in the present disclosure) in that it is either identical in sequence or contains between 1, 2, 3, 4, or 5 (e.g., 1-5) amino acid substitutions as compared with the reference CDR.
  • a CDR is substantially identical to a reference CDR in that it shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR (e.g., 85-90%, 85-95%, 85-100%, 90-95%, 90-100%, or 95-100%). In some embodiments a CDR is substantially identical to a reference CDR in that it shows at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR.
  • a CDR is substantially identical to a reference CDR in that one amino acid within the CDR is deleted, added, or substituted as compared with the reference CDR while the CDR has an amino acid sequence that is otherwise identical with that of the reference CDR.
  • a CDR is substantially identical to a reference CDR in that 2, 3, 4, or 5 (e.g., 2-5) amino acids within the CDR are deleted, added, or substituted as compared with the reference CDR while the CDR has an amino acid sequence that is otherwise identical to the reference CDR.
  • an antigen binding fragment binds a same antigen as a reference antibody. 88 4893-2664-4718.1 Atty. Dkt.
  • antibody further includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and anti-idiotypic (anti-Id) antibodies.
  • Antibodies can include, for example, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, engineered antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, intrabodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, F(ab′)2 fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred
  • antibodies described herein refer to polyclonal antibody populations.
  • Antibodies may also comprise, for example, Fab′ fragments, Fd′ fragments, Fd fragments, isolated CDRs, single chain Fvs, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof), camelid antibodies, single chain or Tandem diabodies (TandAb®), Anticalins®, Nanobodies® minibodies, BiTE®s, ankyrin repeat proteins or DARPINs®, Avimers®, DARTs, TCR-like antibodies, Adnectins®, Affilins®, Trans-Bodies®, Affibodies®, TrimerX®, MicroProteins, Fynomers®, Centyrins®, and KALBITOR®s.
  • An immunoglobulin may derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG, IgE, IgM, IgD, IgA and IgY.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
  • antibody and “immunoglobulin” or “lg” may be used interchangeably herein. [00322]
  • the term “antibody” includes intact antibodies and binding fragments thereof.
  • fragments compete with the intact antibody from which they were derived for specific 89 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 binding to the target. Fragments include separate heavy chains, light chain Fab, Fab′, F(ab′)2, Fv fragments and single domain antibodies.
  • Single (variable) domain antibodies include VH regions separated from their VL partners (or vice versa) in conventional antibodies (Ward et al., 1989, Nature 341: 544-546) as well as VH regions (sometimes known as VHH) from species such as Camelidae or cartilaginous fish (e.g., a nurse shark) in which VH regions are not associated with VL regions (see, e.g., WO 9404678).
  • VHH VHH
  • natural single variable region antibodies from Camelidae include a VHH variable region, and CH2 and CH3 constant regions.
  • Single domain antibodies can be subject to humanization by analogous approaches to conventional antibodies. The Dabs type of antibodies are usually obtained from antibodies of human origin.
  • Nanobody types of antibodies are of Camelidae or shark origin and can be subject to humanization. Fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins.
  • the term “antibody” also includes bi-, tri- and multi-specific antibodies.
  • a bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites (see, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol., 79:315-321 (1990); Kostelny et al., J. Immunol., 148:1547-53 (1992)).
  • Antibodies can exist, e.g., as intact immunoglobulins or as a number of well- characterized fragments produced by digestion with various peptidases. For example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)′2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)′2 dimer into an Fab′ monomer.
  • the Fab′ monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed.1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al. (1990)). 90 4893-2664-4718.1 Atty. Dkt.
  • an “antigen binding molecule,” “antigen binding portion,” or “antibody fragment” refers to any molecule that comprises the antigen binding parts (e.g., CDRs) of the antibody from which the molecule is derived.
  • antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, and Fv fragments, dAb, linear antibodies, scFv antibodies, and multispecific antibodies formed from antigen binding molecules.
  • Peptibodies i.e., Fc fusion molecules comprising peptide binding domains
  • suitable antigen binding molecules are another example of suitable antigen binding molecules.
  • the antigen binding molecule binds to an antigen on a tumor cell. In certain embodiments, the antigen binding molecule binds to PD-1. In further embodiments, the antigen binding molecule is an antibody fragment that specifically binds to the antigen, including one or more of the complementarity determining regions (CDRs) thereof. In further embodiments, the antigen binding molecule is a single chain variable fragment (scFv). [00325] Unless otherwise indicated, an “antigen-binding fragment” means antigen-binding fragments of antibodies, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g., fragments that retain one or more CDR regions.
  • antigen-binding fragments include, but not limited to, Fab, Fab′, F(ab′)2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., single chain Fv (ScFv); nanobodies and multi-specific antibodies formed from antibody fragments.
  • the antigen binding molecule binds to an antigen on a tumor cell.
  • the antigen binding molecule binds to PD-1.
  • An antigen binding fragment may be produced by any means.
  • an antigen binding fragment may be enzymatically or chemically produced by fragmentation of an intact antibody.
  • an antigen binding fragment may be recombinantly produced (i.e., by expression of an engineered nucleic acid sequence.
  • an antigen binding fragment may be wholly or partially synthetically produced.
  • an antigen binding fragment may have a length of at least about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 amino acids or more; in some embodiments at least about 200 amino acids (e.g., 50-100, 50-150, 50-200, or 100-200 amino acids).
  • An “anti-tumor effect” as used herein, refers to a biological effect that can present as 91 4893-2664-4718.1 Atty.
  • Anti-tumor response when referring to a cancer patient treated with a therapeutic regimen, such as a therapy described herein, means at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, reduced rate of tumor metastasis or tumor growth, or progression-free survival.
  • Positive therapeutic effects in cancer can be measured in a number of ways (See, e.g., Weber, W.A. “Assessing tumor response to therapy.” Journal of nuclear medicine 50.Suppl 1 (2009): 1S-10S); Eisenhauer et al., supra).
  • an anti- tumor response to a therapy described herein is assessed using RECIST 1.1 criteria, bidimentional irRC or unidimensional irRC.
  • an anti-tumor response is any of SD, PR, CR, PFS, or DFS.
  • Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles.
  • the most commonly occurring exchanges are isoleucine/valine, tyrosine/phenylalanine, aspartic acid/glutamic acid, lysine/arginine, methionine/leucine, aspartic acid/asparagine, glutamic acid/glutamine, leucine/isoleucine, methionine/isoleucine, threonine/serine, tryptophan/phenylalanine, tyrosine/histidine, tyrosine/tryptophan, glutamine/arginine, histidine/asparagine, histidine/glutamine, lysine/asparagine, lysine/glutamine, lysine/glutamic acid, phenylalanine/leucine, phenylalanine/methionine, serine/a
  • a “conservative amino acid substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.) such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and/ or specificity.
  • conservative amino acid substitutions in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., p.224 (4th Ed.)).
  • “buffer” encompasses those agents which maintain the solution pH of the compositions of the present disclosure in an acceptable range.
  • “Chemotherapeutic agent” refers to a chemical or biological substance that can cause death of cancer cells, or interfere with growth, division, repair, and/or function of cancer cells.
  • Classes of chemotherapeutic agents include, but are not limited to: microtubule inhibitors, e.g., taxanes (paclitaxel, docetaxel), and vinca alkaloids (vincristine, vinblastine, vinorelbine); antimetabolites (5-fluorouracil, capecitabine, gemcitabine), and antifolates (methotrexate, pemetrexed); kinase inhibitors (crizotinib, erlotinib, sunitinib); topoisomerase inhibitors (deruxtecan, topotecan, irinotecan, anthracyclines, etoposide); cell-cycle independent drugs, e.g., 94 4893-2664-4718.1 Atty.
  • microtubule inhibitors e.g., taxanes (paclitaxel, docetaxel), and vinca alkaloids (vincristine, vinblastine, vinorelbine); antimetabolites (5-fluor
  • SOC Current standard of care treatments for certain cancers, such as colon, in the early-line setting include chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan used in combination or sequentially, with option for monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (e.g., bevacizumab, ziv-aflibercept) or its receptors (e.g., ramucirumab), and in patients with Ras wild type tumors, monoclonal antibodies targeting the epidermal growth factor (EGF) receptor (e.g., cetuximab, panitumumab).
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • Treatment options for heavily pre-treated patients beyond the second-line setting are especially limited and associated toxicities can be severe.
  • Co-administration means that the agents are administered so as to have overlapping therapeutic activities, and not necessarily that the agents are administered simultaneously to the subject.
  • the agents may or may not be in physical combination prior to administration.
  • the agents are administered to a subject simultaneously or at about the same time.
  • the agents may be contained in separate vials, when in liquid solution, may be mixed into the same intravenous infusion bag or injection device, and administered simultaneously to the patient.
  • Combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic moieties).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some 95 4893-2664-4718.1 Atty. Dkt.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
  • Such administration also encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids can be reconstituted or diluted to a desired dose prior to administration.
  • the phrase “in combination with” means that an anti-PD-1 antibody is administered to a subject at the same time as, just before, or just after administration of an additional therapeutic agent.
  • an anti-PD-1 antibody is administered as a co-formulation with an additional therapeutic agent.
  • the constant region is an antibody portion, e.g., a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to an antigen but which can exhibit various effector functions, such as interaction with the Fc receptor.
  • the constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain.
  • Constantly modified variants or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.) such that the changes can frequently be made without altering the biological 96 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 activity or other desired property of the protein, such as antigen affinity and/or specificity.
  • the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., an antigen binding system or antibody) for administration to a subject. Generally, each such unit contains a predetermined quantity of active agent.
  • an active agent e.g., an antigen binding system or antibody
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population.
  • the total amount of a therapeutic composition or agent administered to a subject is determined by one or more medical practitioners and may involve administration of more than one dosage forms.
  • the term “dosing regimen” may be used to refer to a set of one or more unit doses that are administered individually to a subject.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • a dosing regimen comprises a plurality of doses and consecutive doses are separated from one another by time periods of equal length; in some embodiments, a dosing regimen comprises a plurality of doses and consecutive doses are separated from one another by time periods of at least two different lengths. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen is periodically adjusted to achieve a desired or beneficial outcome.
  • a “Durable Stable Disease Rate” means stable disease (SD) for ⁇ 23 weeks, where SD 97 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 is cancer that is neither decreasing nor increasing in extent or severity.
  • Effective cell refers to a cell of the immune system that expresses one or more Fc receptors and mediates one or more effector functions.
  • effector cells may comprise, without limitation, one or more of monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, large granular lymphocytes, Langerhans’ cells, natural killer (NK) cells, T-lymphocytes, and B-lymphocytes.
  • Effector cells may be of any organism comprising, without limitation, humans, mice, rats, rabbits, and monkeys.
  • “Effector function” refers to a biological result of interaction of an antibody Fc region with an Fc receptor or ligand.
  • Effector functions comprise, without limitation, antibody- dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-mediated cytotoxicity (CMC).
  • An effector function may be antigen binding dependent, antigen binding independent, or both.
  • ADCC refers to lysis of antibody- bound target cells by immune effector cells. Without wishing to be bound by any theory, ADCC is generally understood to involve Fc receptor (FcR)-bearing effector cells recognizing and subsequently killing antibody-coated target cells (e.g., cells that express on their surface antigens to which an antibody is bound).
  • FcR Fc receptor
  • Effector cells that mediate ADCC may comprise immune cells, comprising yet not limited to, one or more of natural killer (NK) cells, macrophages, neutrophils, eosinophils.
  • excipient refers to an agent that may be comprised in a composition, for example to provide or contribute to a desired consistency or stabilizing effect.
  • a suitable excipient may comprise, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, or the like.
  • the term “heavy chain” when used in reference to an antibody can refer to any distinct type, e.g., alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), ⁇ ( ⁇ ) and mu ( ⁇ ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3 and IgG4.
  • a “host cell” refers to any cell of any organism that is used for the 98 4893-2664-4718.1 Atty. Dkt.
  • a “mammalian recombinant host cell” refers to a mammalian host cell that comprises a heterologous expression vector, which may or may not be integrated into the host cell chromosome.
  • a “bacterial recombinant host cell” refers to a bacterial host cell that comprises a heterologous expression vector, which may or may not be integrated into the host cell chromosome.
  • the term “human antibody” herein means an antibody that comprises human immunoglobulin protein sequences only.
  • variable and constant domain sequences generated may be assembled, or derived from human immunoglobulin sequences, or sequences indistinguishable therefrom.
  • a human antibody can contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody or rat antibody mean an antibody that comprises only mouse or rat immunoglobulin protein sequences, respectively.
  • antibodies (or antibody components) may be considered to be “human” even though their amino acid sequences comprise residues or elements not encoded by human germline immunoglobulin sequences (e.g., variations introduced by in vitro random or site-specific mutagenesis or introduced by in vivo somatic mutation).
  • humanized or “humanized antibody” means forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non- human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the prefix “hum,” “hu,” “Hu,” or “h” is added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies.
  • the humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions can be included to increase affinity, 99 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 increase stability of the humanized antibody, remove a post-translational modification or for other reasons.
  • a “humanized” antibody comprises one or more framework domains having substantially the amino acid sequence of a human framework domain, and one or more complementary determining regions having substantially the amino acid sequence as that of a non-human antibody.
  • a humanized antibody comprises at least a portion of an immunoglobulin constant region (Fc), generally that of a human immunoglobulin constant domain.
  • a humanized antibody may comprise a CH1, hinge, CH2, CH3, and, optionally, a CH4 region of a human heavy chain constant domain.
  • High titers of monoclonal antibodies can be obtained in in vivo production where cells from the individual hybridomas are injected intraperitoneally into mice, such as pristine-primed Balb/c mice to produce ascites fluid containing high concentrations of the desired antibodies.
  • Monoclonal antibodies of isotype IgM or IgG can be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
  • the term “hypervariable region” means the amino acid residues of an antibody that are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” (i.e., CDR-L1, CDR-L2 and CDR-L3 in the light chain variable domain and CDR-H1, CDR-H2 and CDR-H3 in the heavy chain variable domain).
  • CDR complementarity determining region
  • variable domain residues other than the hypervariable region residues defined herein as CDR residues.
  • the variable domains of both the heavy and light chains comprise three hypervariable regions, also called “complementarity determining regions (CDRs)”, which are located between relatively conserved framework regions (FR).
  • CDRs complementarity determining regions
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C- 100 4893-2664-4718.1 Atty. Dkt.
  • both light and heavy chain variable domains comprise FR-1 (or FR1), CDR-1 (or CDR1), FR-2 (FR2), CDR-2 (CDR2), FR-3 (or FR3), CDR-3 (CDR3), and FR-4 (or FR4).
  • the assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al., National Institutes of Health, Bethesda, Md. ; 5 ⁇ m> ed.; NIH Publ.
  • identity refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules.
  • identity is a numeric score determined for a pair of aligned amino acid or nucleic acid sequences. Percent identity measures the number of identical residues (“identity”) between two sequences in relation to the length of the alignment across a “comparison window.” The number shows the % of amino acid residues or nucleotides that are the same between two sequences and indicates the degree of primary structure similarity. [00354] Methods for the calculation of a percent identity as between two provided polypeptide sequences are known.
  • Calculation of the percent identity of two nucleic acid or polypeptide sequences may be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps may be introduced in one or both of a first and a second sequences for optimal alignment and non-identical sequences may be disregarded for comparison purposes).
  • the nucleotides or amino acids at corresponding positions are then compared.
  • a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position.
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, optionally considering the number of gaps, and the length of each gap, which may need to be introduced for optimal alignment of the two sequences. Comparison or alignment of sequences and determination of percent identity between two sequences may be accomplished using a mathematical algorithm, such as BLAST (basic local alignment search tool). In some embodiments, polymeric molecules are considered to be 101 4893-2664-4718.1 Atty. Dkt.
  • test and reference sequences may be entered into a computer, subsequent coordinates may be designated, if necessary, and sequence algorithm program parameters may be designated.
  • a polypeptide may be considered to be identical or substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Methods of alignment of sequences for comparison are well-known in the art.
  • GCG program package which includes GAP (Devereux et al., 1984, Nucl. Acid Res.12:387; Genetics Computer Group, University of Wisconsin, Madison, Wis.).
  • the computer algorithm GAP is used to align the two polypeptides or polynucleotides for which the percent sequence identity is to be determined.
  • the sequences are aligned for optimal matching of their respective amino acid or nucleotide (the “matched span,” as determined by the algorithm).
  • a standard comparison matrix see, Dayhoff et al., 1978, Atlas of Protein Sequence and Structure 5:345-352 for the PAM 250 comparison matrix; Henikoff et al., 1992, Proc. Natl. Acad. Sci. U.S.A.89:10915-10919 for the BLOSUM 62 comparison matrix) is also used by the algorithm.
  • two sequences are considered to be substantially similar if at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more of their corresponding residues are similar and/or identical over a relevant stretch of residues (e.g., 85-90%, 85-95%, 85-100%, 90-95%, 90-100%, or 95-100%).
  • the relevant stretch is a complete sequence.
  • the relevant stretch is at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500 or more residues. Sequences with substantial sequence similarity may be homologs of one another.
  • T/C ⁇ 42% is the minimum level of anti-tumor activity.
  • a T/C ⁇ 10% is considered a high anti-tumor activity level.
  • the treatment achieved by administration of a composition of the present disclosure is any of progression free survival (PFS), disease free survival (DFS) or overall survival (OS).
  • PFS also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • DFS refers to the length of time during and after treatment that a subject remains free of disease.
  • OS refers to a prolongation in life expectancy as 103 4893-2664-4718.1 Atty. Dkt.
  • MPR major pathological response
  • pCR pathological complete response
  • compositions, treatment methods, and uses of the present disclosure may not be effective in achieving a positive therapeutic effect in every patient, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi 2 -test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Cochran-Mantel-Haenszel chi-square test methodology, Jonckheere-Terpstra-test or the Wilcoxon-test.
  • any statistical test known in the art such as the Student’s t-test, the chi 2 -test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Cochran-Mantel-Haenszel chi-square test methodology, Jonckheere-Terpstra-test or the Wilcoxon-test.
  • an “immune response” refers to the action of a cell of the immune system (for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules produced by any of these cells or the liver (including Abs, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and/or elimination from a vertebrate’s body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • a cell of the immune system for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils
  • soluble macromolecules produced by any of these cells or the liver (including Abs, cytokines, and complement) that results
  • immunospecifically binds are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope or immune complex) as such binding is understood by one skilled in the art.
  • an antigen e.g., epitope or immune complex
  • a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, BIACORE®, KinExA 3000 instrument (Sapidyne Instruments, Boise, Id.), or other assays known in the art.
  • the antibodies or antigen-binding fragments thereof specifically bind to a particular antigen at least two (2) fold when compared to the background level and do not 104 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 specifically bind in a significant amount to other antigens present in the sample.
  • the antibodies or antigen-binding fragments thereof specifically bind to a particular antigen at least ten (10) fold when compared to the background level of binding and do not specifically bind in a significant amount to other antigens present in the sample.
  • An antibody that “specifically binds to” a specified target protein is an antibody that exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity.
  • An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g. without producing undesired results such as false positives.
  • Antibodies or binding fragments thereof, useful in the present invention will bind to the target protein with an affinity that is at least two fold greater, at least ten times greater, at least 20-times greater, or at least 100-times greater than the affinity with non-target proteins.
  • an antibody herein is said to bind specifically to a polypeptide comprising a given amino acid sequence, e.g. the amino acid sequence of a mature human PD-1 molecule, if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.
  • immunotherapy refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response. Examples of immunotherapy include, but are not limited to, T and NK cell therapies.
  • T and NK cell therapies can include adoptive cell therapies, tumor-infiltrating lymphocyte (TIL) immunotherapies, autologous cell therapies, engineered autologous cell therapy (eACTTM), and allogeneic T and NK cell transplantation.
  • TIL tumor-infiltrating lymphocyte
  • eACTTM engineered autologous cell therapy
  • allogeneic T and NK cell transplantation can include adoptive cell therapies, tumor-infiltrating lymphocyte (TIL) immunotherapies, autologous cell therapies, engineered autologous cell therapy (eACTTM), and allogeneic T and NK cell transplantation.
  • TIL tumor-infiltrating lymphocyte
  • eACTTM engineered autologous cell therapy
  • allogeneic T and NK cell transplantation allogeneic T and NK cell transplantation.
  • an appropriate reference measurement may comprise a measurement in certain system (e.g., in a single individual) under otherwise comparable conditions absent presence of (e.g., prior to and/or after) an agent or treatment, or
  • isolated refers to a substance that (1) has been separated from at least some components with which it was associated at an earlier time or with which the substance would otherwise be associated, and/or (2) is present in a composition that comprises a limited or defined amount or concentration of one or more known or unknown contaminants.
  • An isolated substance in some embodiments, may be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% (e.g., 85-90%, 85-95%, 85-100%, 90-95%, 90-100%, or 95-100%) of other non- substance components with which the substance was associated at an earlier time, e.g., other components or contaminants with which the substance was previously or otherwise would be associated.
  • a substance is isolated if it is present in a composition that comprises a limited or reduced amount or concentration of molecules of a same or similar type.
  • a nucleic acid, DNA, or RNA substance is isolated if it is present in a composition that comprises a limited or reduced amount or concentration of non- substance nucleic acid, DNA, or RNA molecules.
  • a polypeptide substance is isolated if it is present in a composition that comprises a limited or reduced amount or concentration of non-substance polypeptide molecules.
  • an amount may be, e.g., an amount measured relative to the amount of a desired substance present in a composition.
  • a limited amount may be an amount that is no more than 100% of the amount of substance in a composition, e.g., no more than 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the amount of substance in a composition (e.g., 85-90%, 85-95%, 85-100%, 90-95%, 90-100%, or 95-100%).
  • a composition is pure or substantially pure with respect to a selected substance.
  • an isolated substance is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure (e.g., 85-90%, 85-95%, 85-100%, 90-95%, 90-100%, or 95-100%).
  • Isotype refers to the antibody class or subclass (e.g., IgM or IgG1) that is encoded 106 4893-2664-4718.1 Atty. Dkt.
  • antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or nonhuman antibodies; wholly synthetic antibodies; and single chain antibodies.
  • a nonhuman Ab may be humanized by recombinant methods to reduce its immunogenicity in man.
  • the term “antibody” also includes an antigen binding fragment or an antigen-binding portion of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, and a single chain Ab.
  • the term “Kabat numbering” and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen-binding molecule thereof.
  • the CDRs of an antibody can be determined according to the Kabat numbering system (see, e.g., Kabat E.A. & Wu T.T.
  • CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3).
  • CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).
  • CDRs of the antibodies described herein have been determined according to the Kabat numbering scheme.
  • the term “light chain” when used in reference to an antibody can refer to any distinct type, e.g., kappa ( ⁇ ) or lambda ( ⁇ ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In specific embodiments, the light chain is a human light chain.
  • the term “monoclonal antibody” or “mAb” or “Mab” herein means a population of substantially homogeneous antibodies, i.e., the antibody molecules comprised in the population 107 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 are identical in amino acid sequence except for possible naturally occurring mutations that can be present in minor amounts.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies comprising different amino acid sequences in their variable domains, particularly their complementarity determining regions (CDRs), which are often specific for different epitopes.
  • Monoclonal antibodies can be obtained by methods known to those skilled in the art (see, e.g., Kohler et al., Nature 1975256:495-497; U.S. Pat. No.4,376,110; Ausubel et al., Current Protocols in Molecular Biology 1992; Harlow et al., Antibodies: A Laboratory Manual, Cold spring Harbor Laboratory 1988; and Colligan et al., Current Protocols in Immunology 1993).
  • PD-L1 expression positive refers to a Tumor Proportion Score, Mononuclear Inflammatory Density Score or Combined Positive Score of at least 1%; or elevated level of PD- L1 expression (protein and/or mRNA) by malignant cells and/or by infiltrating immune cells within a tumor compared to an appropriate control.
  • the elevated level of PD-L1 expression is at least 1%, 2%, 5%, 10%, 20%, or 50%.
  • pharmaceutical composition refers to preparations with pharmaceutically acceptable excipients which are in such form as to permit the active ingredients to be effective, and which contains no additional components which are toxic to the subjects to which the composition would be administered.
  • a pharmaceutical composition may be formulated for administration in solid or liquid form, comprising, without limitation, a form adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal 108 4893-2664-4718.1 Atty.
  • oral administration
  • compositions e.g., pharmaceutically acceptable compositions, which include an anti-PD-1 antibody described herein, formulated together with at least one pharmaceutically acceptable excipient.
  • compositions e.g., pharmaceutically acceptable compositions, which include a chemotherapeutic drug described herein, formulated together with at least one pharmaceutically acceptable excipient.
  • compositions that, when administered to a recipient, is not deleterious to the recipient thereof, or that any deleterious effect is outweighed by a benefit to the recipient thereof.
  • materials which may serve as pharmaceutically acceptable carriers comprise: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,
  • a “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion).
  • the compositions disclosed herein can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusion solutions), dispersions or suspensions, liposomes, and suppositories. A suitable form depends on the intended mode of administration and therapeutic application.
  • Typical suitable compositions are in the form of injectable or infusion solutions.
  • One suitable mode of 109 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • the antibody is administered by way of a syringe infusion system.
  • purifying an antibody or antigen-binding fragment of interest or “purified composition” refers to increasing the degree of purity of the antibody or antigen binding fragment in the composition by removing (completely or partially) at least one impurity from the composition.
  • the impurity can be host cell components such as serum, proteins or nucleic acids, cellular debris, growth medium or antibody aggregates. The term is not intended to refer to a complete absence of such biological molecules or to an absence of water, buffers, or salts or to components of a pharmaceutical composition that includes the antibody or antigen binding fragment.
  • “RECIST 1.1 Response Criteria” as used herein means the definitions set forth in Eisenhauer et al., Eur.
  • an agent, animal, individual, population, sample, sequence, or value of interest is compared with a reference or control that is an agent, animal, individual, population, sample, sequence, or value.
  • a reference or control is tested, measured, and/or determined substantially simultaneously with the testing, measuring, or determination of interest.
  • a reference or control is a historical reference or control, optionally embodied in a tangible medium.
  • a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. When sufficient similarities are present to justify reliance on and/or comparison to a selected reference or control. 110 4893-2664-4718.1 Atty. Dkt.
  • stage of cancer refers to a qualitative or quantitative assessment of the level of advancement of a cancer.
  • criteria used to determine the stage of a cancer may comprise, without limitation, one or more of where the cancer is located in a body, tumor size, whether the cancer has spread to lymph nodes, whether the cancer has spread to one or more different parts of the body, etc.
  • cancer may be staged using the so-called TNM System, according to which T refers to the size and extent of the main tumor, usually called the primary tumor; N refers to the number of nearby lymph nodes that have cancer; and M refers to whether the cancer has metastasized.
  • T refers to the size and extent of the main tumor, usually called the primary tumor
  • N refers to the number of nearby lymph nodes that have cancer
  • M refers to whether the cancer has metastasized.
  • a cancer may be referred to as Stage 0 (abnormal cells are present without having spread to nearby tissue, also called carcinoma in situ, or CIS; CIS is not cancer, though could become cancer), Stage I-III (cancer is present; the higher the number, the larger the tumor and the more it has spread into nearby tissues), or Stage IV (the cancer has spread to visceral organs and/or distant parts of the body).
  • a cancer may be assigned to a stage selected from the group consisting of: in situ; localized (cancer is limited to the place where it started, with no sign that it has spread); regional (cancer has spread to nearby lymph nodes, tissues, or organs): distant (cancer has spread to distant parts of the body); and unknown (there is not enough information to determine the stage).
  • subject in the context of the present disclosure is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein).
  • an “effective amount” refers to an amount effective to treat a disease or disorder in a subject, and that will elicit, to some significant extent, the biological or medical 111 4893-2664-4718.1 Atty. Dkt.
  • a “therapeutically effective amount,” “effective dose,” “effective amount,” or “therapeutically effective dosage” of a therapeutic agent is any amount that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • the “therapeutically effective amount” can vary with the antibody, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
  • treatment regimen “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination of the invention.
  • Tumor as it applies to a subject diagnosed with, or suspected of having, cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and 30 lymphomas. 112 4893-2664-4718.1 Atty. Dkt.
  • Tumor burden also referred to as “tumor load”, refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone marrow.
  • Tumor burden can be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • tumor size refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g.
  • “Unidimensional irRC” refers to the set of criteria described in Nishino et al., Developing a Common Language for Tumor Response to Immunotherapy: Immune-related Response Criteria using Unidimensional measurements. Clin Cancer Res.2013;19(14):3936- 3943. These criteria utilize the longest diameter (cm) of each lesion.
  • tumor size refers to the total size of the tumor which can be measured as the length and width of a tumor.
  • Tumor size may be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.
  • TPS Tumor Proportion Score
  • variable region or “variable domain” as used herein means the segment of IgG chains which is variable in sequence between different antibodies. Typically, it extends to Kabat residue 109 in the light chain and 113 in the heavy chain. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). 113 4893-2664-4718.1 Atty. Dkt.
  • variable region is a human variable region.
  • variable region comprises rodent or murine CDRs and human framework regions (FRs).
  • FRs human framework regions
  • the variable region is a primate (e.g., non- human primate) variable region.
  • the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).
  • variable regions of each light/heavy chain (Vl/Vh) pair form the antibody binding site.
  • an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are, in general, the same.
  • a HCVR sequence having at least 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti- PD-1 antibody or antigen-binding fragment thereof comprising that sequence retains the ability to specifically bind to PD-1.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:24.
  • a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:24.
  • the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).
  • a LCVR sequence having at least 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to the amino acid sequence of SEQ ID NO:26 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti- 114 4893-2664-4718.1 Atty. Dkt.
  • This Example describes a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study that was conducted, comparing the efficacy of tislelizumab (i.e., an anti-PD-1 antibody) + platinum doublet (e.g., cisplatin or carboplatin + etoposide) (Arm A) and placebo + platinum doublet (Arm B) as first-line treatment in 453 patients with treatment-naive, resectable, confirmed squamous or non-squamous stage II-IIA NSCLC.
  • tislelizumab i.e., an anti-PD-1 antibody
  • platinum doublet e.g., cisplatin or carboplatin + etoposide
  • Arm B placebo + platinum doublet
  • MPR major pathological response
  • BIPR Blinded Independent Pathology Review
  • MPR was assessed at the time of surgery, and has been proposed by several groups as a surrogate marker for recurrence and survival in patients with solid tumor types, such colon cancer (Adam, R., 2014. Annals of Surgical Oncology, 21, pp.1763-1764), breast cancer (Conforti, F. et al., 2021 Bmj, 375), and NSCLC after neoadjuvant (perioperative) treatment.
  • EFS event-free-survival
  • BICR Blinded Independent Central Review
  • MPR can be observed more frequently than a pathological complete response (pCR), defined as no viable residual tumor.
  • pCR pathological complete response
  • a secondary objective was to evaluate and compare the BIPR-assessed pCR rate of neoadjuvant treatment with tislelizumab versus placebo plus platinum-based doublet chemotherapy, where the pCR rate was defined as the proportion of patients with absence of residual tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant therapy as assessed by BIPR.
  • Another secondary objective was to evaluate and compare overall survival (OS) of neoadjuvant treatment with tislelizumab plus platinum-based doublet chemotherapy followed by 116 4893-2664-4718.1 Atty. Dkt.
  • OS overall survival
  • tissue and blood-based biomarkers and clinical efficacy with Tislelizumab, functional and resistance mechanisms, and patient prognosis were also evaluated, such as Other exploratory tissue-based biomarkers (including gene expression profiling [GEP], tumor mutation burden [TMB]/microsatellite instability(MSI)/mutation profile, multiplex immunohistochemistry [mIHC] in archival and/or fresh tumor tissue) before neoadjuvant treatment, at surgery and/or at disease progression/end of treatment (EOT) and blood-based biomarkers (including T-cell receptor [TCR] sequencing, peripheral blood immunophenotyping, and circulating tumor DNA [ctDNA]) before and after treatment to explore the predictive value for clinical efficacy, functional and resistance mechanisms of tislelizumab, and patient prognosis.
  • Other exploratory tissue-based biomarkers including gene expression profiling [GEP], tumor mutation burden [TMB]/microsatellite instability(MSI)/mutation profile, multiplex immunohistochemistry [
  • the primary endpoint was major pathological response rate (MPR) after completion of neoadjuvant treatment plus event-free survival (EFS) as determined by RECIST v1.1 by blinded independent review (BIRC).
  • MPR pathological response rate
  • EFS event-free survival
  • the key secondary endpoints were pCR and safety. 117 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 Tumor lesions were measured by CT scan or X-ray before treatment and then after 200 mg.
  • Test Product (Investigational Drug) (Arm A): (1) Tislelizumab: 200 mg, Day 1 of each 3-week cycle, administered as an intravenous (IV) infusion for 3 to 4 cycles during the neoadjuvant phase. (2) Tislelizumab: 400 mg, Day 1 of each 6-week cycle, administered as an IV infusion for up to 8 cycles during the adjuvant phase.
  • Comparator (Arm B): (1) Placebo: Day 1 of each 3-week cycle, administered as an IV infusion for 3 to 4 cycles during the neoadjuvant phase. (2) Placebo: Day 1 of each 6-week cycle, administered as an IV infusion for up to 8 cycles during the adjuvant phase.
  • ⁇ Patients with large cell neuroendocrine carcinoma LCNEC.
  • LCNEC large cell neuroendocrine carcinoma
  • Known EGFR mutation or ALK gene translocation ⁇ Patients with non-squamous NSCLC and unknown EGFR mutation status were required to be tested locally or at a central laboratory before enrollment.
  • Patients with squamous NSCLC and unknown EGFR mutation status were not required to be tested at screening.
  • Patients (non-squamous or squamous histology) with unknown ALK fusion oncogene status were not required to be tested.
  • Presence of locally advanced unresectable regardless of stage or metastatic disease Stage IV.
  • Mediastinal lymph node samples are required for clinical staging to assess nodal involvement in patients with mediastinal adenopathy on CT scan to rule out Stage IIIB/C disease.
  • Adrenal replacement steroid (dose ⁇ 10 mg daily of prednisone or equivalent) and topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption, and short course ( ⁇ 7 days) of corticosteroid prescribed prophylactically or for the treatment of a non-autoimmune condition were permitted.
  • Neoadjuvant Phase Eligible patients were stratified by disease stage (II versus IIIA), histology (squamous versus non squamous) and PD-L1 expression ( ⁇ 1% versus ⁇ 1%/not evaluable/indeterminate), and randomized in a 1:1 ratio to 1 of the following treatment arms: • Arm A: tislelizumab (200 mg) + platinum-based doublet chemotherapy on a 3- week cycle for 3 to 4 cycles, followed by surgical resection, and then adjuvant tislelizumab (400 mg) on a 6-week cycle for up to 8 cycles 119 4893-2664-4718.1 Atty. Dkt.
  • neoadjuvant phase patients who were found to have disease progression (at scheduled tumor assessments or at any time during neoadjuvant treatment) or who discontinued neoadjuvant treatment early with tumor(s) still deemed to be resectable and nonmetastatic proceeded to surgery if amenable.
  • Surgery Upon completion of neoadjuvant therapy, patients underwent surgical resection of their tumor. Surgical specimens were assessed for pathological response (MPR and pCR) by a BIPR. In addition, exploratory biomarker analysis of surgical specimens (primary tumor tissue and dissected lymph nodes) were performed. [00417] Before surgery, the investigator assessed the patient to reconfirm disease resectability.
  • PORT began between 30 and 60 days after surgery and was in accordance with the American Society for Radiation Oncology recommended guidelines or local guidelines. Adjuvant treatment was administered between 7 and 30 days after the last scheduled PORT treatment and patients when recovered from any radiation-associated toxicities.
  • Patients continued to receive adjuvant tislelizumab (400 mg) (Arm A) or placebo (Arm B) on a 6-week cycle until any of the following occurred: administration of 8 cycles of tislelizumab/placebo as adjuvant treatment, disease recurrence, unacceptable AE, death, or patient and/or investigator’s decision to discontinue study treatment.
  • CT computed tomography
  • MRI contrast enhanced magnetic resonance imaging
  • PET positron emission tomography
  • Chest CT + abdomen CT + pelvis CT + bone scan were an alternative option for sites that could not provide PET scan for various reasons.
  • the investigator reassessed the patient to reconfirm disease resectability. The presurgical visits and associated assessments occurred within 14 days of surgery and in accordance with local institutional practice.
  • MPR rate assessed by the BIPR was defined as the proportion of patients with ⁇ 10% residual viable tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant therapy as assessed by BIPR. Patients who did not receive surgical resection were considered as non-responders in the analysis.
  • EFS assessed by the BICR was defined as the time from randomization until any of the following events, whichever occurs first: disease progression precluding surgery, local or distant recurrence assessed by BICR, or death due to any cause.
  • EFS per BICR was be compared between Arm A and Arm B, using stratified log-rank test methodology.
  • Biomarkers [00430] Archival tumor tissues (formalin-fixed paraffin-embedded [FFPE] block or approximately 15 [ ⁇ 6] unstained slides) were sent for immunohistochemistry assay (IHC) of PD-L1 status. In addition to PD-L1 expression, other predictive biomarkers, such as TMB and immune-mediated GEP (gene expression profiles), biomarkers expression by multiplex IHC, and other immune-mediated markers that are related to response or clinical benefit of tislelizumab were evaluated. If no archival samples were available, a fresh tumor biopsy at screening was taken, if feasible.
  • IHC immunohistochemistry assay
  • acceptable samples included core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
  • Blood samples were taken at baseline (pre-dose at Day 1 of Cycle 1) and optionally at the time of disease progression and/or at the time of first tumor response (CR/PR) (10 mL each timepoint) for all randomized patients to explore the association of blood-based biomarkers with response, resistance, and prognosis to tislelizumab in combination with chemotherapy or chemotherapy alone.
  • CR/PR first tumor response
  • Results Summary of Results [00433] The study enrolled patients with treatment-naive, resectable, confirmed squamous or non-squamous stage II-IIA NSCLC who were eligible for platinum doublet chemotherapy, with ECOG PS ⁇ 1 and no known EGFR mutation (nsq) or ALK gene translocation (sq & nsq). Patients stratified by histology, disease stage, and PD-L1 expression were randomized (1:1) to 3- 4 cycles of Tislelizumab 200 mg IV (Q3W) or placebo plus platinum double chemotherapy, followed by surgery plus 8 cycles of adjuvant Tislelizumab 400 mg IV Q6W or placebo.
  • the primary endpoint was major pathological response rate after completion of neoadjuvant treatment plus event-free survival (EFS) as determined by RECIST v1.1 by blinded independent review.
  • EFS event-free survival
  • Neoadjuvant Anti-PD-1 Therapy Plus Chemotherapy Is Effective for the Treatment of Lung Cancer Clinical Trial Efficacy
  • Major pathological response (MPR) and pathological complete response (pCR) rates were significantly improved with Tislelizumab in combination with chemotherapy versus placebo plus chemotherapy (56.2 percent for the combination of Tislelizumab and chemotherapy prior to surgery versus 15.0 percent for placebo plus chemotherapy alone).
  • MPR pathological response
  • pCR pathological complete response
  • Example 2 A Study to Compare the Efficacy and Safety of Neoadjuvant Treatment With Tislelizumab (BGB-A317, Anti-PD-1 Antibody) or Placebo Plus Platinum-Based Doublet Chemotherapy Followed By Adjuvant Tislelizumab or Placebo in Resectable Stage II or IIIA Non-Small Cell Lung Cancer
  • This example describes a Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Compare the Efficacy and Safety of Neoadjuvant Treatment With Tislelizumab (BGB- A317, Anti-PD-1 Antibody) or Placebo Plus Platinum-Based Doublet Chemotherapy followeded By Adjuvant Tislelizumab or Placebo in Resectable Stage II or IIIA Non-Small Cell Lung Cancer.
  • EFS by BICR is defined as the time from randomization until any of the following events, whichever occurs first: disease progression precluding surgery, local or distant recurrence assessed by BICR, or death due to any cause.
  • Secondary Objectives and Endpoints [00440] Objectives: - To evaluate and compare BIPR-assessed pathological complete response (pCR) rate of neoadjuvant treatment with tislelizumab- versus placebo plus platinum-based doublet chemotherapy.
  • Endpoints - The pCR rate is defined as the proportion of patients with absence of residual tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant therapy as assessed by BIPR.
  • - OS is defined as the time from the date of randomization to the date of death due to any cause.
  • 2-year/3-year OS rate is defined as the proportion of patients alive at 2 years and 3 years after randomization estimated using the Kaplan-Meier method.
  • - Objective response rate is the proportion of patients who had complete response (CR) or partial response (PR) as assessed by BICR and by the investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in all randomized patients with measurable disease at baseline.
  • - DFS by BICR is defined as the time from the first date of no disease to local or distant recurrence or death due to any cause, whichever occurs first, as determined by BICR during the adjuvant treatment and safety follow-up.
  • - EFS by investigator is defined as the time from randomization until any of the following events, whichever occurs first: disease progression precluding surgery, local or distant recurrence 127 4893-2664-4718.1 Atty. Dkt.
  • EFS rate is defined as the proportion of patients free from EFS events at 2 years and 3 years after randomization estimated using the Kaplan-Meier method.
  • SAEs serious adverse events
  • imAEs immune mediated adverse events
  • PK pharmacokinetics
  • NSCLC non-small cell lung cancer
  • exploratory tissue based biomarkers including gene expression profiling [GEP], tumor mutation burden [TMB]/microsatellite instability(MSI)/mutation profile, multiplex immunohistochemistry [mIHC] in archival and/or fresh tumor tissue) before neoadjuvant treatment, at surgery and/or at disease progression/end of treatment (EOT) and blood based biomarkers (including T-cell receptor [TCR] sequencing, peripheral blood immunophenotyping, and circulating tumor DNA [ctDNA]) before and after treatment to explore the predictive value for clinical efficacy, functional and resistance mechanisms of tislelizumab, and patient prognosis.
  • GEP gene expression profiling
  • TMB tumor mutation burden
  • MSI microsatellite instability
  • mIHC multiplex immunohistochemistry
  • ctDNA circulating tumor DNA
  • the study is designed as a randomized, double-blind, placebo-controlled Phase 3 study to compare the efficacy and safety of neoadjuvant treatment with tislelizumab plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab treatment versus neoadjuvant treatment with placebo plus platinum-based doublet chemotherapy followed by placebo in patients with resectable Stage II or IIIA NSCLC.
  • the study consists of a screening phase, a treatment phase that includes a neoadjuvant phase, surgery and an adjuvant phase, a safety follow-up phase, and a survival follow-up phase.
  • the study schema is presented in FIG.1.
  • Eligible patients are stratified by disease stage (II versus IIIA), histology (squamous versus non squamous) and PD-L1 expression ( ⁇ 1% versus ⁇ 1%/not evaluable/indeterminate), 129 4893-2664-4718.1 Atty. Dkt.
  • Carboplatin can replace cisplatin per physician’s discretion in consideration of patient’s tolerability to cisplatin.
  • appropriate chemotherapy regimen is decided by physicians based on the major histological components assessed by pathologists.
  • Surgery Upon completion of neoadjuvant therapy, patients undergo surgical resection of their tumor.
  • Surgical specimens are assessed for pathological response (MPR and pCR) by a BIPR.
  • exploratory biomarker analysis of surgical specimens is performed.
  • physician reassesses the patient to reconfirm disease resectability.
  • the presurgical visit and associated assessments should occur within 14 days of surgery and in accordance with local institutional practice.
  • the surgical procedure should be performed between 4 and 6 weeks after the last dose of neoadjuvant study treatment as best as possible.
  • patients undergo tumor assessment by CT every 6 weeks ( ⁇ 1 week) since last tumor assessment with ethical considerations.
  • PORT postoperative radiotherapy
  • the first dose of tislelizumab/placebo (Cycle 1 in the adjuvant phase) should be administered between 2 and 8 weeks after surgery; initial dosing beyond 8 weeks should be discussed with the medical monitor.
  • PORT is optional for patients with pathologically confirmed N2+ disease after surgery at the investigator’s discretion.
  • Either PORT or another surgical procedure is administered for patients with positive surgical margins before starting adjuvant treatment per standard of care.
  • PORT should begin between 30 and 60 days after surgery and be in accordance with the American Society for Radiation Oncology recommended guidelines or local guidelines.
  • Adjuvant treatment should be administered between 7 and 30 days after the last scheduled PORT treatment and patients should have recovered from any radiation- associated toxicities.
  • CT computed tomography
  • MRI contrast enhanced magnetic resonance imaging
  • PET positron emission tomography
  • Chest CT + abdomen CT + pelvis CT + bone scan should be an alternative option for 131 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 sites that could not provide PET scan for various reasons.
  • physician reasseses the patient to reconfirm disease resectability. The presurgical visit and associated assessments should occur within 14 days of surgery and in accordance with local institutional practice.
  • Dosage and Administration [00456] Dosing schedules for the 2 study arms are provided in FIG.1 by arm. The first dose of study drug(s) is to be administered within 2 business days of randomization. All patients are monitored continuously for AEs. Treatment modifications (e.g, dose delay, reduction, or interruption), or discontinuation will be based on specific laboratory and AE criteria. [00457] During the neoadjuvant phase, for each cycle, tislelizumab or placebo are administered before chemotherapy drugs. The order of chemotherapy drug administration is conducted in accordance with the relevant local guidance and/or clinical practice. [00458] Patients should receive antiemetics and intravenous hydration for chemotherapy according to the standard of care and manufacturer’s instruction.
  • Tislelizumab or Placebo Tislelizumab 200 mg (or placebo) is administered on Day 1 of each 21-day cycle (once every 3 weeks) in the neoadjuvant phase, while in the adjuvant phase, tislelizumab 400 mg (or placebo) is administered on Day 1 of each 42-day cycle (once every 6 weeks). [00461] Tislelizumab or placebo is administered by intravenous infusion through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in- line or add-on filter. Specific instructions for product preparation and administration are provided in the Pharmacy Manual.
  • the initial infusion (Cycle 1, Day 1) in the neoadjuvant phase is delivered over 60 minutes; if this is well tolerated, then the subsequent infusions may be administered over 30 minutes, which is the shortest time period permissible for infusion.
  • the initial infusion (Cycle 1, Day 1) in the adjuvant phase is delivered over 90 minutes; if this is well tolerated, the second infusion may be administered over 60 minutes; and for each subsequent infusion, over 30 133 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 minutes if 60 minutes infusion is tolerated.
  • Cislelizumab or placebo must not be concurrently administered with any other drug.
  • Chemotherapy [00463] Patients receive treatment with platinum-based doublet chemotherapy during the neoadjuvant phase (Table 10). [00464] Cisplatin 75 mg/m 2 is administered as an intravenous infusion over 2 hours on Day 1 of each 3-week cycle for 3 to 4 cycles. All patients should receive adequate hydration (including pretreatment hydration) and diuretics. Urinary output must be maintained for at least 24 hours following cisplatin administration. Monitoring is performed according to local guidance and clinical practice. [00465] Carboplatin AUC of 5 mg/mL/min is administered as an intravenous infusion over 1 hour on Day 1 of each 3-week cycle for 3 to 4 cycles.
  • Carboplatin can replace cisplatin per the investigator’s discretion in consideration of patient’s tolerability to cisplatin. The reasons for intolerability should be documented.
  • Pemetrexed 500 mg/m 2 is administered as an intravenous infusion over 10 minutes on Day 1 of each 3-week cycle for 3 to 4 cycles. All patients should receive the appropriate supplementation of vitamin B12 and folic acid according to the approved product label and/or standard practice. In addition, all patients should receive the appropriate corticosteroid premedications as per the local approved label. Additional premedications should be administered as per standard practice.
  • Paclitaxel 175 mg/m 2 is administered as an intravenous infusion over 3 hours on Day 1 of each 3-week cycle for 3 to 4 cycles. In addition, all patients should receive the appropriate premedications as per the local approved labels. Additional premedications should be administered as per standard practice. [00468] The length of infusion period for cisplatin, carboplatin, pemetrexed, and paclitaxel could also follow the approved label or local practice. The administered dose could be adjusted within ⁇ 5% of the calculated dose at the investigator’s discretion. [00469] Patients are monitored continuously for AEs and are instructed to notify their 134 4893-2664-4718.1 Atty. Dkt.
  • the patients should resume tislelizumab or placebo treatment as soon as possible after the AEs recover to baseline or Grade 1 (whichever is more severe) and within 12 weeks after last dose of tislelizumab or placebo. If the patient is unable to resume tislelizumab or placebo within 12 weeks after the last dose of tislelizumab or placebo, then the patient should be discontinued from treatment. [00472] If a patient is benefiting from the study treatment while meeting the discontinuation criteria, resumption of study treatment may occur. Dose Delay, Interruption, or Modifications for Chemotherapy [00473] Treatment modifications for chemotherapy should be performed per prescribing information and per local practice according to the investigator’s clinical judgment.
  • Baseline body weight is used to calculate the required chemotherapy doses. Treatment modifications are required if the patient’s body weight changes by ⁇ 10% from baseline (or the new reference body weight). Chemotherapy doses should not be modified for any body weight change of ⁇ 10%.
  • Study drug-related toxicities must be resolved to baseline level, or Grade 0 or 1 before administering the next dose (except for alopecia or Grade 2 fatigue). A maximum of 2 dose reductions for each chemotherapeutic agent except for carboplatin are permitted. Only 1 dose reduction is permitted for carboplatin. Once the dose has been decreased, it should remain reduced for all subsequent administrations or further reduced if necessary. There are no dose escalations in this study.
  • the study population includes approximately 450 patients who have histologically confirmed Stage II or IIIA NSCLC.
  • Patient Inclusion Criteria Include: [00478] Each patient eligible to participate in this study must meet all the following criteria: 1. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments. 2. Age ⁇ 18 years on the day of signing the ICF (or the legal age of consent in the jurisdiction in which the study is taking place). 3.
  • NSCLC Histologically confirmed Stage II or IIIA NSCLC of squamous or non-squamous histology: • Staging should be based on the eighth edition of the American Joint Committee on Cancer/Union International Contre le Cancer NSCLC staging system. • T4 primary NSCLC will be allowed only on the basis of size (tumors > 7 cm). Invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, and separate tumor nodules in a different ipsilateral lobe is not permitted. • Patients with mixed NSCLC histology (squamous and non-squamous) or NSCLC not otherwise specified are eligible.
  • AST and ALT ⁇ 2.5 x ULN • For patients not receiving therapeutic anticoagulation: international normalized ratio or activated partial thromboplastin time ⁇ 1.5 x ULN.
  • Patient Exclusion Criteria Include: [00480] Patients who meet any of the following criteria are not eligible to enroll: 1. Any prior therapy for current lung cancer, including chemotherapy, or radiotherapy. 2. Prior treatment with an antibody or drug against immune checkpoint pathway, including but not limited to, anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4), anti PD-1, and anti-PD-L1 therapeutic antibodies. 3. Patients with large cell neuroendocrine carcinoma (LCNEC). 4. Known EGFR mutation or ALK gene translocation.
  • curatively e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast.
  • corticosteroids > 10 mg daily of prednisone or equivalent
  • other immunosuppressive medication ⁇ 14 days before randomization.
  • Adrenal replacement steroid dose ⁇ 10 mg daily of prednisone or equivalent
  • Short course ( ⁇ 7 days) of corticosteroid prescribed prophylactically e.g., for contrast dye allergy
  • a non-autoimmune condition e.g., delayed-type hypersensitivity reaction caused by contact allergen
  • Severe infections within 4 weeks before randomization including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. • Received therapeutic oral or intravenous antibiotics within 2 weeks before randomization. 12. A known history of HIV infection. 13. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose HBV DNA is ⁇ 500 IU/mL or patients with active hepatitis C virus (HCV) should be excluded. Note: Inactive hepatitis B surface antigen carriers, treated and stable hepatitis B (HBV DNA ⁇ 500 IU/mL), and cured hepatitis C patients can be enrolled. 14. Any major surgical procedure requiring general anesthesia ⁇ 28 days before randomization. 15.
  • HBV chronic hepatitis B virus
  • Patient Exclusion Criteria include: 16. Any of the following cardio/cerebrovascular risk factors: • Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ⁇ 28 days before randomization • Pulmonary embolism ⁇ 28 days before randomization • Any history of acute myocardial infarction ⁇ 6 months before randomization • Any history of heart failure meeting New York Heart Association Classification III or IV ⁇ 6 months before randomization • Any event of ventricular arrhythmia ⁇ Grade 2 in severity ⁇ 6 months before randomization • Any history of cerebrovascular accident ⁇ 6 months before randomization 140 4893-2664-4718.1 Atty. Dkt.
  • Prior Therapy The exclusion criteria specify that patients must not have received prior therapy for current lung cancer, including chemotherapy and radiotherapy, and prior treatment with an antibody or drug against immune checkpoint pathways, including but not limited to, anti-PD-1, anti-PD-L1, or anti-CTLA-4.
  • All prior and concomitant medications e.g, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements
  • received within 30 days before randomization and 30 days after the last dose of study treatment should be recorded.
  • prophylaxis antiviral therapy for patients with inactive HBsAg, treated and stable hepatitis B is at the discretion of the investigator, as aligned with local guidance; however, reason(s) must be documented in patient’s chart and recorded in the eCRF if a patient with active hepatitis B is not treated with antiviral prophylaxis.
  • Systemic corticosteroids given for the control of imAEs must be tapered gradually and be at nonimmunosuppressive doses ( ⁇ 10 mg/day of prednisone or equivalent) before the next tislelizumab/placebo administration.
  • Ibuprofen administration should be avoided or restricted in patients with a creatinine clearance between 45 mL/min and 79 mL/min. • If concomitant ibuprofen use cannot be avoided, at a minimum, administration of ibuprofen should be avoided for 2 days before the day of, and 2 days after administration of 142 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 pemetrexed, and monitor patients more frequently for adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity (pemetrexed prescribing information).
  • CT computed tomography
  • MRI contrast-enhanced magnetic resonance imaging
  • PET positron emission tomography
  • disease resectability is reconfirmed. The presurgical visit and associated assessments should occur within 14 days of surgery and in accordance with local institutional practice.
  • Immune-mediated AEs are reported until 90 days after the last dose of tislelizumab or placebo, regardless of whether the patient starts a new anticancer therapy.
  • HRQoL is assessed using the EORTC QLQ-LC13, EORTC QLQ-C30, and EQ-5D- 5L at baseline (predose at Day 1 of Cycle 1); at Cycle 3 during the neoadjuvant phase; at Cycles 1, 3, 5, and 7 during the adjuvant phase; and at the Safety Follow-up Visit.
  • the same radiographic procedure used to assess disease sites at screening are required to be used throughout the study (e.g., the same contrast protocol for CT scans).
  • ⁇ Screening evaluations are performed within 28 days before randomization. ⁇ If a patient is known to have a contraindication to CT contrast media or develops a contraindication during the study, a non-contrast CT of the chest plus a contrast-enhanced magnetic resonance imaging (MRI) (if possible) of abdomen should be performed. ⁇ If a CT scan for tumor assessment is performed on a PET/CT scanner, the CT acquisition must be consistent with the standards of a diagnostic CT scan. This replacement should be evaluated and confirmed at site level with BICR. [00493] For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell infiltration and other mechanisms leading to apparent increase of existing tumor masses or appearance of new tumor lesions.
  • MRI contrast-enhanced magnetic resonance imaging
  • the immunogenicity evaluation utilizes a risk-based immunogenicity strategy (Koren et al J Immunol Methods.2008;333(1-2):1-9; Worobec and Rosenberg BioPharm Intl 2004a;17(11); Worobec and Rosenberg BioPharm Intl 2004b;17(12)) to characterize ADA responses to tislelizumab.
  • This tiered strategy will include an assessment of whether ADA responses correlate with relevant clinical endpoints.
  • ⁇ ADA assays serum samples are tested for the presence of ADAs to tislelizumab using a validated immunoassay
  • ⁇ PK assay serum samples are assayed for tislelizumab concentration with use of a validated immunoassay Biomarker Testing
  • biomarker assessment archival tumor tissues (FFPE block or approximately 15 [ ⁇ 6] additional unstained slides) at baseline are sent for immunohistochemistry assessment of PD-L1 status as one of the stratification factors.
  • Other baseline tissue-based biomarkers including mIHC, immune-related GEP, and TMB/MSI/mutation profile are also assessed.
  • Surgical tumor tissue (FFPE block or approximately 15 [ ⁇ 6] unstained slides) is collected and sent for biomarker analysis (including PD-L1 expression, mIHC, immune-related GEP, and TMB/MSI/mutation profile).
  • biomarker analysis including PD-L1 expression, mIHC, immune-related GEP, and TMB/MSI/mutation profile.
  • acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
  • Blood samples are collected at Day 1 of Cycle 1 and Cycle 2 during both neoadjuvant and adjuvant phases (about 15 mL for each timepoint) to explore the association of blood-based 145 4893-2664-4718.1 Atty. Dkt.
  • the Safety Analysis Set includes all randomized patients who received ⁇ 1 dose of any component of study drugs; it will be the analysis set for the safety analyses. Patients are analyzed according to the actual treatment regimen received.
  • the PK Analysis Set includes all patients who receive ⁇ 1 dose of tislelizumab per the protocol, for whom any postbaseline PK data are available.
  • the Immunogenicity Analysis Set includes all patients who received ⁇ 1 dose of tislelizumab and for whom both baseline ADA and ⁇ 1 postbaseline ADA results are available.
  • the ITT Analysis Set is the primary analysis set for all efficacy analyses.
  • MPR rate assessed by the BIPR is defined as the proportion of patients with ⁇ 10% residual viable tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant therapy as assessed by BIPR. Patients who do not receive surgical resection are considered as nonresponders in analysis.
  • EFS assessed by the BICR is defined as the time from randomization until any of the following events, whichever occurs first: disease progression precluding surgery, local or distant recurrence assessed by BICR, or death due to any cause.
  • a disease progression not reaching the RECIST v1.1 criteria by BICR but still precludes surgery (progressive disease or tumor unresectability assessed by investigator) is considered an event.
  • Patients who do not undergo surgery due to reasons other than progressive disease and tumor unresectability are considered to have an event of RECIST v1.1 defined progression by BICR or death.
  • Actual tumor assessment visit date is used to calculate EFS.
  • Patients who die without a progression/disease recurrence are considered to have experienced an event on the date of their death. Patients who did not report progression/recurrence of disease or die are censored on the date of their last evaluable tumor assessment. Patients who did not have any on-study tumor assessment and did not die are censored on the date they were randomized. Patients who started any subsequent anticancer therapy outside of the protocol-specified adjuvant therapy without a prior reported progression/recurrence are censored at the last evaluable tumor assessment before initiation of the subsequent anticancer therapy.
  • MPR per BIPR is compared between tislelizumab combined with platinum-based doublet chemotherapy (Arm A) and placebo combined with platinum-based doublet chemotherapy (Arm B), using Cochran-Mantel-Haenszel chi-square test methodology.
  • EFS per BICR is compared between Arm A and Arm B, using stratified log-rank test methodology.
  • the 2 dual primary hypothesis tests are formed as follows: One-sided testing of MPR superiority of Arm A to Arm B: [00503] The null hypothesis to be tested is: 147 4893-2664-4718.1 Atty. Dkt.
  • EFS superiority of Arm A to Arm B [00504]
  • the null hypothesis to be tested is: H0: EFS in Arm A ⁇ EFS in Arm B
  • Ha EFS in Arm A > EFS in Arm B
  • the p-values from a stratified log-rank test is presented using stratification factors in the IRT at randomization.
  • the HR for EFS for Arm A versus Arm B is estimated using a stratified Cox regression model. The 95% CI for the HR will be provided. Unstratified analysis will also be presented.
  • Kaplan-Meier methodology is used to estimate median EFS for each treatment arm, and a Kaplan-Meier curve is constructed to provide a visual description of the difference among arms.
  • Subgroup Analysis for MPR and EFS is conducted to determine whether the treatment effect is consistent across various subgroups. On the basis of information available at the time of developing this analysis plan, attention is given to the following factors: ⁇ Histology (non-squamous versus squamous) ⁇ Disease stage (II versus IIIA) ⁇ PD-L1 expression in TC ( ⁇ 1% versus ⁇ 1%/not evaluable/indeterminate) 148 4893-2664-4718.1 Atty. Dkt.
  • OS is defined as the time from the date of randomization to the date of death due to any cause. Data for patients who are not reported as having died at the time of analysis is censored at the date last known to be alive.
  • OS distribution is estimated using Kaplan- Meier method. Comparison of OS between Arm A versus Arm B is tested at the earliest data cutoff when MPR, pCR, and EFS tests are statistically significant using the stratified log-rank test. 2-year/3-year OS rate 149 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 [00508] 2-year/3year OS rate is defined as the proportion of patients alive at 2 years and 3 years after randomization estimated using Kaplan-Meier method.
  • EFS by the investigator is defined as the time from randomization until any of the following events, whichever occurs first: disease progression precluding surgery, local or distant recurrence assessed by investigator, or death due to any cause.
  • the same analysis method and censoring rule of EFS by BICR is applied to analysis of EFS by investigator except that log-rank test for EFS by investigator is for descriptive purposes only.
  • 2-year/3-year EFS rate is defined as the proportion of patients free from EFS events at 2 years and 3 years after randomization estimated using Kaplan-Meier method. Similar methodology used to evaluate OS rate is applied to EFS rate analysis. Objective response rate per BICR and per the investigator [00511] Objective response rate (confirmation not required according to RECIST v1.1) is the proportion of patients who had CR or PR as assessed by BICR and by the investigator per RECIST v1.1 in all randomized patients with measurable disease at baseline. Patients without any postbaseline assessment are considered nonresponders. Similar methodology used to evaluate MPR per the BIPR is applied to objective response rate analysis.
  • DFS per the BICR is defined as the time from the first date of no disease to local or distant recurrence or death due to any cause, whichever occurs first, as determined by BICR during the adjuvant treatment and safety follow-up. DFS is analyzed only for patients who underwent R0 resection. If patients were alive without recurrence, DFS was determined from the first date of no disease to the date of last known date and is censored on the date of last known date. DFS is estimated using Kaplan-Meier methodology. 150 4893-2664-4718.1 Atty. Dkt.
  • CR Complete Response
  • PR Partial Response
  • PD Progressive Disease
  • the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression).
  • Stable Disease SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
  • Duration of Overall Response [00518] The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded on study). [00519] The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
  • Stable disease is measured from the start of the treatment (in randomized trials, from date of randomization) until the criteria for progression are met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the reference for calculation of PD).
  • Example 3 Tislelizumab and Chemotherapy/Chemoradiotherapy as Neoadjuvant Treatment for Resectable Esophageal Squamous Cell Carcinoma
  • R-ESCC locally advanced resectable esophageal squamous cell carcinoma
  • CRT perioperative chemoradiotherapy
  • esophagectomy is the current standard of care.
  • implementation of preoperative is CRT is not satisfactory for various reasons, including, for example, greater safety concerns than with neoadjuvant chemotherapy alone.
  • This example describes an ongoing Phase 2, Multicenter, Open-Label, 2-cohort Study to investigate the efficacy and safety of positron emission tomography (PET) guided neoadjuvant treatment with Tislelizumab (BGB-A317) plus chemotherapy/chemoradiotherapy in patients R- ESCC.
  • PET positron emission tomography
  • BGB-A317 Tislelizumab
  • chemotherapy/chemoradiotherapy in patients R- ESCC.
  • the purpose of this study was to evaluate the pathological complete response (pCR) in participants receiving tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant treatment. Primary analysis results are presented herein.
  • pCR Pathological complete response
  • R0 Resection Rate Defined as the proportion of participants with R0 resection. R0 resection rate will be monitored for approximately 5 years.
  • DFS 1-year/3-year Disease-free Survival Rate: The DFS was defined as the proportion of participants free from disease events at 1st year and 3rd year after the first date of no disease.
  • the DFS was defined as the time from the first date of no disease (R0 resection as surgery outcome) to local or distant recurrence or death due to any cause, whichever occurs first.
  • the DFS rate will be analyzed only for participants who undergo R0 resection.
  • the DFS rate will be monitored for approximately 5 years.
  • 1-year/3-year Event-free Survival (EFS) Rate The EFS was defined as the proportion of participants free from EFS events at 1st year and 3rd year after the first dose.
  • the EFS was defined as the time from the time of first dose until any of the following events, whichever occurs first: progression of disease that precludes definitive surgery, local or distant recurrence, or death due to any cause.
  • the EFS rate will be monitored for approximately 5 years.
  • ORR Objective Response Rate
  • the ORR was defined as the proportion of participants who have a complete response or partial response before surgery as assessed by the 153 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 investigator per RECIST v1.1 in all participants with measurable disease at baseline. The ORR will be monitored for approximately 5 years. [00531] Number Of Participants Experiencing Treatment-Emergent Adverse Events will be monitored for approximately 5 years. Screening Phase Key Inclusion Criteria: [00532] Eastern Cooperative Oncology Group Performance Status of 0 or 1.
  • any prior therapy for current ESCC including investigational agents, chemotherapy, radiotherapy, targeted therapy agents, or prior therapy with an anti-programmed cell death protein-1, anti-programmed cell death protein ligand-1, anti-programmed cell death protein ligand-2, or any other antibody or drug specifically targeting T-Cell co-stimulation or checkpoint pathways.
  • Controlled Type I diabetes, hypothyroidism only requiring hormone replacement, controlled celiac disease, skin diseases (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • infections requiring systemic antibacterial, antifungal, or antiviral therapy including tuberculosis infection o Severe infections within 4 weeks before first dose, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
  • a Efficacy evaluable analysis set includes all patients who received neoadjuvant treatment followed by surgery; b 95% CI was estimated using the Clopper-Pearson method; c Defined as the proportion of patients with ⁇ 10% residual viable tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant therapy; d Safety analysis set includes all enrolled patients who receive one or more dose of any component of study drugs; e ORR before surgery.
  • Treatment-related treatment emergent adverse events (TRAEs) of grade ⁇ 3 were reported in 46.7% and 82.5% of patients in responders and non-responders, respectively (Table 13).
  • TRAEs of grade ⁇ 3 reported in ⁇ 10% patients included neutrophil count decreased (36.7%) among responders, and neutrophil count decreased (65.0%), white blood cell count decreased (47.5%), lymphocyte count decreased (17.5%), and anemia (12.5%) among non-responders.
  • the majority of grade ⁇ 3 TRAEs were related to chemotherapy or radiotherapy components of treatment.
  • Tislelizumab-related treatment emergent adverse events (TEAEs) of grade ⁇ 3 were reported in 10.0% and 22.5% of patients in the responder and non-responder cohorts, respectively.
  • TEAE treatment-emergent adverse event. 159 4893-2664-4718.1 Atty. Dkt.
  • Adjuvant platinum-based chemotherapy remains the global standard of care for resectable, stage II–III NSCLC, although improvements in overall survival are modest and outcomes for these patients remain poor.
  • This study demonstrated significant improvements in event-free survival, major pathological response, and pathological complete response following perioperative tislelizumab combined with neoadjuvant chemotherapy.
  • perioperative tislelizumab combined with neoadjuvant chemotherapy offered meaningful clinical benefit compared with neoadjuvant placebo plus chemotherapy.
  • tislelizumab was administered at 400 mg on a 6-week cycle for up to eight cycles, providing a more flexible and convenient dosing schedule for patients than evaluated with other PD-(L)1 antibodies.
  • This phase 3 trial evaluated an extended dose interval for anti–PD-(L)1 antibodies in the perioperative setting. Additionally, the safety profile of tislelizumab, both as monotherapy and when combined with chemotherapy, was manageable and consistent with the known safety profiles of the individual agents.
  • Tislelizumab significantly improved EFS versus placebo (stratified hazard ratio 56% [95% CI 0 ⁇ 40–0 ⁇ 79]; p 0 ⁇ 0003). MPR rate was significantly higher for tislelizumab: 56% (95% CI 50–63) versus 15% (95% CI 11–20) than placebo (difference 41% [95% CI 33–49]; p ⁇ 0 ⁇ 0001). Grade ⁇ 3 and serious treatment-related 160 4893-2664-4718.1 Atty. Dkt.
  • Eligible patients were aged ⁇ 18 years with previously untreated, histologically confirmed stage II–IIIA squamous or non- squamous NSCLC (according to the 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control NSCLC staging system) and had no known EGFR mutation or ALK gene translocations, an evaluation by an attending thoracic surgeon to confirm eligibility for an R0 resection (no residual tumor) with curative intent, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before randomization. Men and women were eligible to participate in the study and patient sex was self- reported. A complete list of inclusion criteria is provided above in Example 2.
  • Patients were stratified by histology (squamous vs non-squamous), disease stage (II vs IIIA), and tumor PD-L1 expression (PD-L1 ⁇ 1% vs PD-L1 ⁇ 1%/not evaluable/indeterminate) and were or PBO placebo) group.
  • PD-L1 positive/negative was defined as patients with ⁇ 1%/ ⁇ 1% of tumor cells with PD- L1 membrane staining assessed using the VENTANA® SP263 assay (Ventana Medical Systems, Inc., Arlington, AZ, USA) at a central laboratory.
  • Permuted block-stratified randomization and concealed TIS or PBO allocation were performed using an interactive web response system, which was accessed by study site personnel to assign a unique number to each potential study participant. Double blinding was implemented to ensure that neither the investigator, patients, medical or ancillary medical staff, nor the sponsor staff and its designees were aware of which treatment (TIS vs PBO) was being administered in addition to chemotherapy. Emergency unblinding for AEs was permitted through an interactive web response system. [00558] During the neoadjuvant phase, patients received three to four cycles of TIS 200 mg or 161 4893-2664-4718.1 Atty. Dkt.
  • Postoperative radiotherapy was administered to some patients (i.e., those with positive tumor margins) before adjuvant treatment per standard medical practice; in these patients, adjuvant treatment was administered between 7 and 30 days after postoperative radiotherapy. Patients continued to receive treatment until disease recurrence or progression, unacceptable AEs, death, or until the maximum number of adjuvant cycles was complete, or either the patient and/or investigator decided to discontinue study treatment, whichever occurred first.
  • Scheduled tumor assessments were performed by computed tomography, positron emission tomography, and contrast-enhanced magnetic resonance imaging at screening, and then by computed tomography only within 14 days before cycle 3 of neoadjuvant treatment and surgery.
  • tumor assessments were performed every 3 months for the first 2 years, every 6 months from years 3–5, and then annually thereafter based on RECIST version 1 ⁇ 1. Tumor assessments continued until disease recurrence/progression was confirmed by blinded independent central review (BICR) per RECIST v1 ⁇ 1, withdrawal of consent, death, loss to follow-up, or study termination by the sponsor, whichever occurred first. Pathological response was assessed at a central laboratory in tumor tissue and lymph node tissue obtained from surgical resection. The percentage of viable tumor cells in ⁇ 1 section per centimeter of tumor and lymph node tissue resected was evaluated. [00560] Safety was assessed throughout the study by monitoring AEs (adverse events), serious AEs, and laboratory results.
  • BICR blinded independent central review
  • AEs and serious AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v5.0. Vital signs, physical examinations, change in ECOG performance status, electrocardiogram, and other examinations were also measured. Safety monitoring and review of interim efficacy data were performed by an independent data monitoring committee approximately every 6 months after the first patient was 162 4893-2664-4718.1 Atty. Dkt. No.: 138881-0953 BGB21112-01PCT Conversion of PCT/CN2023/135545 and PCT/CN2023/124264 randomized, or more frequently if indicated or requested by the medical monitor based on ongoing safety monitoring of patients on study. Safety follow-up was performed 30 days after the last dose of study treatment.
  • Immune-mediated AEs were reported for up to 90 days after the last dose of TIS or PBO, regardless of whether the patient had started a new anti-cancer therapy.
  • follow-up of patients for survival status and subsequent anti-cancer treatment was done every 3 months ( ⁇ 14 days) via in-person or phone contact.
  • the dual primary endpoints were MPR rate, assessed by blinded independent pathology review (BIPR), and EFS, assessed by BICR, in the intention-to-treat (ITT) population.
  • MPR rate was defined as the proportion of patients with ⁇ 10% residual viable tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant therapy in the ITT population.
  • EFS was defined as the time from randomization until any of the following, whichever occurred first: disease progression precluding surgery according to RECIST v1 ⁇ 1, local or distant recurrence, or death due to any cause.
  • the key secondary endpoint was BIPR-assessed pCR rate, which was defined as the proportion of patients with absence of residual tumour in the resected primary tumour and all resected lymph nodes after completion of neoadjuvant therapy.
  • MPR and pCR were compared between treatment groups using the Cochran-Mantel- Haenszel test stratified by factors as previously described at randomization.
  • the 95% confidence intervals (CIs) of MPR and pCR rates were computed using the Clopper-Pearson method.
  • the Mantel-Haenszel common risk difference for MPR and pCR was estimated along with its 95% CIs constructed by a normal approximation and Sato’s variance estimator stratified by factors as previously described at randomization.
  • the Mantel-Haenszel common odds ratio (OR) for MPR and pCR was estimated along with its 95% CI constructed by a normal approximation of log OR and the Robins, Breslow, and Greenland variance estimate stratified by factors as previously described at randomization.
  • the risk difference and its 95% CI were estimated using the same method without stratification factors.
  • Kaplan-Meier methodology was also used to estimate the median (IQR) and the rate of EFS and OS at select time points. EFS and OS were compared between treatment groups using a stratified log-rank test, with HR and 95% CI estimated using a stratified Cox regression model.
  • the 95% CIs for median EFS and OS were estimated using the Brookmeyer and Crowley method, and the 95% CIs for the EFS and OS rates were estimated using Greenwood’s formula. In the subgroup analysis of EFS, the unstratified HR and 95% CI were estimated using a Cox regression model. [00566]
  • the ITT population included all randomized patients, and the safety population for the neoadjuvant and adjuvant phases included all randomized patients who received any amount 164 4893-2664-4718.1 Atty. Dkt.
  • EFS by BICR in the ITT population significantly favoured the TIS group over the PBO group (stratified HR 0 ⁇ 56 [95% CI 0.40–0.79]; one-sided p 0 ⁇ 0003) (FIG.6A). Median EFS was not reached in either the tislelizumab (95% CI not estimable [NE]–NE) or placebo PBO (95% CI 16 ⁇ 6–NE) group. At 24 months, the EFS rate was 68 ⁇ 3% (95% CI 60.8–74.8) for the TIS group and 51.8% (95% CI 43.8–59.2) for the PBO group. The EFS benefit with TIS over PBO was generally consistent across prespecified subgroups (FIG.6B).
  • Immune-mediated AEs occurred in 90/226 (40%) patients who received TIS and 40/226 (18%) patients who received PBO.
  • Grade ⁇ 3 immune-mediated AEs were observed in 21/226 (9%) patients in the TIS group and 6/226 (3%) patients in the PBO group.
  • the most common immune-mediated AE category was skin adverse reaction (TIS, 39/226 [17%]; PBO, 24/226 [11%]).
  • the safety profile of TIS plus chemotherapy followed by surgery and adjuvant TIS was consistent with the safety profiles of the individual therapies.
  • the incidence of grade ⁇ 3 treatment-related AEs was comparable between both study groups, occurring in 72% of patients receiving TIS and in 66% of those receiving PBO. No new safety signals were identified.
  • the incidence of treatment-related AEs was similar to that in previously reported trials of chemotherapy combined with checkpoint inhibitors, and most AEs were associated with chemotherapy (anaemia, nausea, and alopecia).
  • the most common treatment-related AEs reported were decreased haematological indexes (neutrophil count, white blood cell count, and anaemia).
  • any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.
  • a range includes each individual member.

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Abstract

La divulgation vise à traiter des cancers solides, tels que le cancer du sein, du côlon et du poumon (en particulier, le cancer du poumon non à petites cellules (NSCLC)) chez des sujets humains avec un anticorps anti-PD-1 en tant que monothérapie ou en tant que polythérapie avec par exemple une chimiothérapie et/ou une chirurgie. Le traitement fourni peut être le tislelizumab en combinaison avec une chimiothérapie avant la chirurgie, avec une dose différente de tislelizumab dans la phase adjuvante après chirurgie. La posologie d'administration peut comprendre l'administration de 200 mg d'un anticorps anti-PD-1 (par exemple, le tislelizumab) (par exemple, toutes les trois semaines), suivie d'une résection tumorale, et l'administration de 400 mg de l'anticorps anti-PD-1 (par exemple, toutes les six semaines). En outre, la chimiothérapie peut être à base de platine (par exemple, le carboplatine et/ou le cisplatine), et peut en outre comprendre du pémétrexed (par exemple, pour un carcinome non squameux) ou du paclitaxel (par exemple, pour un carcinome squameux).
PCT/IB2024/059994 2023-10-12 2024-10-11 Traitement à base d'anti-pd-1 avant et après chirurgie Pending WO2025079039A1 (fr)

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