WO2025159982A1

WO2025159982A1 - Treatment of non-small cell lung cancer using sacituzumab govitecan

Info

Publication number: WO2025159982A1
Application number: PCT/US2025/012019
Authority: WO
Inventors: Sabeen F. MEKAN
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2024-01-22
Filing date: 2025-01-17
Publication date: 2025-07-31
Anticipated expiration: 2026-07-22

Abstract

The present disclosure relates to methods of treating an advanced or metastatic NSCLC in a patient in need thereof, comprising administering sacituzumab govitecan (SG).

Description

TREATMENT OF NON-SMALL CELL LUNG CANCER USING SACITUZUMAB

GOVITECAN

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/623,635, filed January 22, 2024, and to U.S. Provisional Application No. 63/651,086, filed May 23, 2024, each of which is incorporated herein in its entirety for all purposes.

FIELD

[0002] The present disclosure relates to methods of treatment of non-small cell lung cancer using sacituzumab govitecan (“SG”).

BACKGROUND

[0003] Lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women in the U.S. (not counting skin cancer). About 10-15% of all lung cancers are small cell and about 80-85% of all lung cancers are non-small cell (www.cancer.org). Worldwide, more than two million people were diagnosed with lung cancer in 2020. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for up to 85% of diagnoses. About half of NSCLC cases are diagnosed at the metastatic stage (57%), when treatment is especially difficult. Even in patients whose disease is caught early, half will eventually progress to the metastatic stage within five years. Newly diagnosed patients have several treatment options including platinum-based therapy, checkpoint inhibitors and targeted therapies. Programmed death (ligand) 1 (PD-[L] 1) inhibitor-based regimens are the standard of care in first-line metastatic non-small cell lung cancer (“NSCLC”); however, additional therapies are needed to further improve outcomes. However, there are limited treatment options once patients with metastatic NSCLC progress on or after platinum-based chemotherapy and checkpoint inhibitors.

[0004] Sacituzumab govitecan (“SG”) is an antibody-drug-conjugate (“ADC”) comprised of a (a) a humanized monoclonal antibody (“hRS7”) that binds to the cell-surface receptor, Trop 2, (b) a payload (“SN-38”) that is a topoisomerase I inhibitor, and (c) a linker (“CL2A”), that couples the antibody to the pay load. There is a high expression of Trop 2 in non-small cell lung cancers. [0005] The high expression of Trop 2 in non-small cell lung cancers, coupled to the high unmet need, led to the design of a phase 3, open-label, multi-cohort, Ph 3 EVOKE-01 study (NCT05089734) evaluating SG versus docetaxel in patients with advanced or metastatic NSCLC with progression on after platinum-based chemotherapy and anti-PD-l/PD-Ll immunotherapy.

[0006] SG is marketed under the name TRODELVY and is indicated for (1) adult patients with unresectable locally advanced or metastatic HR+/HER2- breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting; (2) adult patients with unresectable locally advanced or mTNBC who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease; and (3) adult patients with locally advanced or mUC who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor (accelerated approval only).

SUMMARY

[0007] In certain embodiments, disclosed herein are methods of treating an advanced or metastatic NSCLC in a patient in need thereof is provided. The method comprises administering: (a) 10 mg/kg of an antibody-drug conjugate (ADC) comprising an anti-Trop-2 antibody or an antigen-binding fragment thereof as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, wherein the anti-Trop-2 antibody or the antigen binding fragment thereof comprises light chain complementarity determining regions (CDRs) comprising a sequence of amino acids as set forth in SEQ ID NOs: 22, 23 and 24 and heavy chain CDRs comprising a sequence of amino acids as set forth in SEQ ID NOs: 19, 20 and 21, and wherein the ADC has a formula MAb-CL2A-SN-38, with the formula represented by:

[0008] In certain embodiments, the anti-Trop-2 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising SEQ ID NO: 25, and a light chain variable region comprising SEQ ID NO: 26.

[0009] In certain embodiments, the anti-Trop-2 antibody comprises a heavy chain comprising SEQ ID NO: 1, and a light chain comprising SEQ ID NO: 2. [0010] In certain embodiments, the anti-Trop-2 antibody is Sacituzumab or “hRS7.” [0011] In certain further embodiments, the ADC is sacituzumab govitecan (SG).

[0012] In certain embodiments, disclosed herein is a method of treating an advanced or metastatic NSCLC in a patient in need thereof that is statistically significantly superior to a standard of care, wherein the patient has not responded to a prior therapy containing either a PD- 1 or a PD-L1 inhibitor. The method comprises administering to the patient in need thereof a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, wherein when the method is used to treat advanced or metastatic NSCLC in a population of patients in need thereof, wherein the population of patients has not responded to a prior therapy containing either a PD-1 or a PD-L1 inhibitor, the population of patients treated with SG achieves a statistically significantly greater OS compared to a control group of patients treated with the standard of care. In certain embodiments, the standard of care is docetaxel.

[0013] In certain embodiments, disclosed herein is a method of treating advanced or metastatic NSCLC in a population of patients in need thereof that is statistically significantly superior to a standard of care. The method comprises administering to the population of patients SG, wherein the population of patients have not responded to prior therapy containing a PD-1 or PD-L1 inhibitor, wherein a dosage of 10 mg/kg of SG is administered as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, and wherein the method achieves a statistically significantly greater OS compared to OS of a control group of patients treated with the standard of care. In certain embodiments, the standard of care is docetaxel.

[0014] In certain embodiments, disclosed herein is a method of increasing median overall survival (OS) in a population of patients having advanced or metastatic NSCLC compared to median OS of a control group of patients treated with a standard of care, wherein the population of patients did not respond to last prior therapy containing a PD-1 or PD-L1 inhibitor. The method comprises administering a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles to the population of patients in need thereof, and wherein overall survival is increased by a median of at least about 3 months, compared to median OS in the control group of patients treated with the standard of care. In certain embodiments, the standard of care is docetaxel.

[0015] In certain embodiments, disclosed herein is a method of treating an advanced or metastatic NSCLC in a patient in need thereof that increases overall survival of the patient by at least about 3 months compared to treatment with a standard of care, wherein the patient did not respond to last prior therapy containing a PD-1 or a PD-L1 inhibitor. The method comprises administering to the patient a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles. In certain embodiments, the standard of care is docetaxel.

[0016] In certain embodiments, disclosed herein is a method of treating an advanced or metastatic NSCLC in a patient in need thereof, wherein the patient did not respond to last prior therapy containing a PD-1 or a PD-L1 inhibitor. The method comprises administering to the patient a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, wherein the method improves OS in the patient compared to treatment with a standard of care. In certain embodiments, the standard of care is docetaxel.

[0017] In certain embodiments, a method of improving median overall survival (OS) in a population of patients having advanced or metastatic NSCLC, wherein the population of patients did not respond to last prior therapy containing a PD-1 or a PD-L1 inhibitor, is provided. The method comprises administering to the population of patients in need thereof a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, wherein median OS is improved by at least about 3 months, compared to median OS in a control group of patients treated with a standard of care. In certain embodiments, the standard of care is docetaxel.

[0018] In certain embodiments, a method of statistically significant treatment of advanced or metastatic NSCLC in a population of patients in need thereof, wherein the population of patients did not respond to prior therapy containing a PD-1 or a PD-L1 inhibitor, is provided. The method comprises administering to the population of patients 10 mg/kg of SG on day 1 and day 8 of one or more 21 -day treatment cycles, wherein said treatment achieves a statistically significant OS compared to OS of a control group of patients treated with a standard of care. [0019] In certain embodiments, disclosed herein is a method of improving clinical efficacy compared to a standard of care in a population of patients having advanced or metastatic non- squamous or squamous NSCLC, wherein the population of patients did not respond to last prior therapy containing a PD-1 or a PD-L1 inhibitor, without concomitant administration of a chemotherapy and/or an anti-cancer agent, comprising administering to the population of patients in need thereof 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles. In certain embodiments, the standard of care is docetaxel.

[0020] In certain embodiments, the patients and/or population of patients treated with the methods disclosed herein progressed after receipt of prior therapy containing a PD-1 or a PD-L1 inhibitor. In certain embodiments, the patients and/or population of patients treated with the methods disclosed herein did not respond to prior therapy containing a PD-1 or a PD-L1 inhibitor. In certain embodiments, the patients and/or the population of patients treated with the methods disclosed herein had a best response of stable disease (“SD”) after receipt of prior therapy containing a PD-1 or a PD-L1 inhibitor. In certain embodiments, the patients and/or the population of patients treated with the methods disclosed herein had a best response of progressive disease (“PD”) after receipt of prior therapy containing a PD-1 or a PD-L1 inhibitor. [0021] In certain embodiments, the patient and/or population of patients treated with the methods disclosed herein has received prior therapy containing a platinum-based chemotherapy. In certain embodiments, the patient and/or population of patients has progressed after receipt of prior therapy containing a platinum-based chemotherapy. In certain embodiments, the patient and/or population of patients did not respond to prior therapy containing a platinum-based chemotherapy.

[0022] In certain embodiments, the method does not comprise administration of a second antitumor agent or anti-cancer agent. In certain embodiments, the NSCLC is advanced. In certain embodiments, the NSCLC is metastatic. In certain embodiments, the advanced or metastatic NSCLC is squamous NSCLC. In certain embodiments, the advanced or metastatic NSCLC is non- squamous.

[0023] In certain embodiments, the method does not comprise concomitant administration of chemotherapy. In certain embodiments, the method does not comprise concomitant administration of platinum-based chemotherapy. In certain embodiments, the method does not comprise concomitant administration of an anti-TGIT antibody. In certain embodiments, the method does not comprise concomitant administration of an anti PD-1 or PD-L1 antibody. In certain embodiments, the method does not include concomitant administration of an additional targeted oncology drug. In certain embodiments, the method does not comprise administration of a second anti-cancer agent. In certain embodiments, the method does not comprise concomitant administration of an additional and/or a third anti-cancer agent. In certain embodiments, the treatment disclosed herein is a monotherapy.

[0024] In certain embodiments, a method of numerically improving median overall survival (OS) in a population of patients having advanced or metastatic NSCLC compared to treatment in a control group treated with a standard of care, wherein the population of patients have received prior therapy containing a PD-1 or a PD-L1 inhibitor, the method comprising administering to the population of patients a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, wherein median OS is numerically improved compared to median OS in the control group treated with the standard of care. In certain embodiments, the standard of care is docetaxel. [0025] In certain embodiments, the method comprises administering SG for at least about (5) 21-day treatment cycles. In certain embodiments, the method comprises administering 10 mg/kg SG for at least about (5) 21-day treatment cycles.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 shows the design of an open-label, global, multicenter, randomized, Phase 3 clinical trial (NCT05089734) for evaluating sacituzumab govitecan (SG) versus docetaxel in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in patients with progression on or after platinum-based chemotherapy and PD-1/PD-L1 immunotherapy received either in combination or sequentially. The clinical trial is referred to as “EVOKE-01.” As used in the figure, ALK, anaplastic lymphoma kinase; CR, complete response; D, day; DOR, duration of response; DCR, disease control rate; EGFR, epidermal growth factor receptor; IO, immunooncology, mNSCLC, metastatic non-small cell lung cancer; non-sq, non-squamous; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progression free survival; PR, partial response; PRO, patient-reported outcomes; q3wk, every 3 weeks; SD, stable disease; SOC, standard of care; s/p, status post; sq squamous; vs, versus.

[0027] FIGS. 2A-2B show the sequences of the heavy (FIG. 2a) and the light (FIG. 2b) chains of the antibody (hRS7) in SG.

[0028] FIG. 3 shows Study Procedures for EVOKE-01. As used in the figure: ADA, antidrug antibody; AEK, anaplastic lymphoma kinas; C, cycle; CR, complete response; CT, computed tomography; D, day; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EOT, end of treatment; FDG, fluorodeoxy glucose (18F); FFPE, formalin-fixed paraffin-embedded; FSH, follicle-stimulating hormone; INR international normalized ratio; IV, intravenous; LDH, lactate dehydrogenase; PT, prothrombin time; PTT, partial thromboplastin time; QOL, quality of life; SAE, serious adverse event; SG, Sacituzumab govitecan.

[0029] FIG. 4 shows the Study Design for EVOKE-01.

[0030] FIG. 5A disposition of study patient population at data cutoff (November 2023) and FIG. 5B shows treatment exposure at data cutoff.

[0031] FIG. 6 shows Patient Baseline Characteristics in the ITT (“intent to treat”) patient population.

[0032] FIG. 7 shows the primary endpoint (overall survival) in the ITT patient population. [0033] FIG. 8A shows the secondary endpoint (PFS ) and FIG. 8B shows ORR in the ITT patient population.

[0034] FIG. 9 shows a subgroup analysis for overall survival for the EVOKE-01 clinical trial.

[0035] FIGS. 10A and 10B show efficacy results for EVOKE-01 for patients that responded to prior treatment with a PD-(L)-1 containing regimen (FIG. 10A) and for patients that did not respond to prior treatment with a PD-(L)-1 containing regimen (FIG. 10B).

[0036] FIGS. 11A and 11B show efficacy results for EVOKE-01 for patients with non- squamous NSCLC (FIG. 11 A) and for patients with squamous NSCLC (FIG. 11B).

[0037] FIGS. 12A and 12B show secondary endpoint (TTD in shortness of breath domain - FIG. 12A) and secondary endpoint (TTD in NSCLC-SAQ total score.

DETAILED DESCRIPTION

Anti-TROP2 ADC: Sacituz.umab govitecan (“SG”)

[0038] SG is a pharmaceutical composition comprising an antibody-drug conjugate (“ADC”) comprised of (1) a drug (“SN-38”), a topoisomerase 1 inhibitor that is an active metabolite of irinotecan; (2) a linker (“CL2A”); and (3) a humanized monoclonal antibody (“hRS7 IgGk” or “sacituzumab”). CL2A couples SN-38 to hRS7, which binds to Trop-2.

[0039] In certain embodiments, hRS7 is described, e.g., in W02003074566, Figures 3 and 4, incorporated by reference in its entirety.

[0040] In certain embodiments, SG is represented by Formula I as shown below. [0041] In certain embodiments, ADC comprises drug molecules linked to the antibody moieties in various stoichiometric molar ratios depending on the configuration of the antibody and, at least in part, the method used to effect configuration. In certain embodiments, the drug-antibody ratio (“DAR”) is about 7.6. In certain embodiments, the DAR is about 7.0 to about 8.0.

[0042] In certain embodiments, the hRS7 antibody in SG comprises the heavy chain as shown in SEQ ID NO.: 1 and light chain as shown in SEQ ID NO.: 2 (as shown in Table 1 and in FIGS. 2A-2B). In certain embodiments, the hRS7 antibody in SG comprises two heavy chains each having the sequence as shown in SEQ ID NO.: 1, and two light chains each having the sequence as shown in SEQ ID NO.: 2.

Table 1. Amino Acid Sequences of hRS7 antibody [0043] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described, for example, in U.S. Patent No. 7,999,083 and U.S. Patent No. 9,028,833, which are hereby incorporated herein by reference in their entireties.

Definitions

[0044] The singular forms “a,” “an,” and “the” include the plural referents unless the context dictates otherwise.

[0045] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 L” means “about 5 L” and also “5 pL.” Generally, the term “about” includes an amount that would be expected to be within experimental error, such as, for example, within 15%, 10%, or 5%.

[0046] “Actionable genomic alteration(s),” is known in the art, i.e., a gene is actionable if it has an established biologic role in cancer and there is a clinically available drug to which the gene confers sensitivity or resistance, where actionability can be applicable to all or select alteration or tumor types.

[0047] “Advanced disease” refers to stage III disease which has not spread or cancers that are unlikely to be cured or controlled long-term with treatment, as they have spread to distant locations.

[0048] “Anti-cancer agent” refers to an approved or investigational agent(s) for use, or that are being evaluated in, cancer. It can refer to systemic and targeted therapy.

[0049] “Control group” as is known in the art, is the group of patients treated with the standard of care in a double arm clinical trial, i.e., a clinical trial wherein response rate is compared between a new treatment (i.e., SG) and a standard of care (i.e., docetaxel) via randomization.

[0050] “Metastatic cancer or disease” is a sub-category of advanced disease. It refers to Stage IV disease and/or cancers that are unlikely to be cured or controlled long-term with treatment, as they have spread to distant locations.

[0051] “Locally advanced disease,” as used herein, refers to a disease state in which cancer cells have begun to spread out from the initial site of origin but have not yet spread to other parts of the body.

[0052] “Antibody-drug conjugate” or “ADC” generally refers to a compound comprising an antibody targeting a tumor antigen and an anticancer agent drug or payload, optionally connected by a linker. In certain embodiments, the ADC is SG. In certain embodiments, the ADC is an ADC that is approved for NSCLC, or in the clinic being evaluated for NSCLC. In certain embodiments, the ADC comprises a Trop2-targeting antibody. In certain embodiments, “ADC” refers to the compound of Formula I, which has an anti-Trop-2 antibody (sacituzumab) linked to the drug or payload SN38.

[0053] “Baseline” as used herein, is the time within approximately 28 days prior to initiation of therapy, i.e., within approximately 28 days prior to day 1 of cycle 1. In certain embodiments, baseline refers to approximately day -28 to day -1 prior to day 1 of cycle 1. In certain embodiments, the baseline is the time within approximately 28 days +/- 7 days prior to the initiation of therapy. In certain embodiments, baseline is the time from one measurement to another, i.e., baseline can refer to an initial time point when a measurement, i.e., a measurement of a lesion, is compared between two time points. The initial time point, in this instance, does not necessarily correspond with the initiation of treatment.

[0054] “Blinded Independent Central Review” (“BICR”) refers to the process by which radiologic exams and selected clinical data, performed as part of a clinical trial protocol, are submitted to a central location for independent review.

[0055] “Chemotherapy-naive,” as used herein, refers to not having received chemotherapy, i.e., not having received chemotherapy for advanced or metastatic NSCLC.

[0056] “Clinical efficacy” or “clinical activity” refers to clinical efficacy or activity in human patient(s). In certain embodiments, clinical activity or clinical efficacy refers to a partial or complete response. In certain embodiments, clinical efficacy or clinical activity, when used in the context of a population of patients, comprises ORR, DOR, and/or DCR. In certain embodiments, improvement of clinical efficacy or clinical activity, when used in the context of a comparison between two or more agents, can be used to describe a clinically meaningful benefit to the human patient of one agent compared to the other. As used herein “clinically meaningful benefit” (or grammatical variations thereof) refers to results/findings that improve medical care resulting in improvement in the individual’s physical function, his/her mental status, and/or ability to engage in social life. The term improvement of quality of life in medical care deals with both subjective and objective terms. Objective terms may be duration of remission of disease, etc. Subjective terms may be improvement in the quality of life.

[0057] “Complete Response” (“CR”) refers to disappearance of all target lesions.

[0058] ‘ ‘CDR” or “CDRs” as used herein means complementarity determining region(s) in an immunoglobulin variable region, defined using the Kabat numbering system, unless otherwise indicated.

[0059] “Concomitant administration” or “concurrent administration,” can be used interchangeably, and refer to administration of two or more drugs or therapies during the same dosing cycle. Each of the drugs can be approved or investigational for the indication-of-interest. [0060] “Disease Control Rate” (“DCR”) is defined as the proportion of patients who achieve a CR, PR or SD (stable disease) as assessed by IRC per RECIST Version 1.1 and/or by investigator assessment.

[0061] “Duration of response” (“DOR”) refers to the time from the first documentation of CR or PR to the earlier of the first documentation of progressive disease (PD) or death from any cause (whichever comes first) as assessed by the investigator per RECIST Version 1.1.

[0062] “First line treatment” as is known in the art refers to the initial therapy for a particular disease.

[0063] “NSCLC histology” as used herein, refers to whether the NSCLC is squamous or non- squamous.

[0064] “Non-responder(s)” refers to a patient or a population of patients for which the intervention had no clinical benefit. As used herein, “did not respond” and/or grammatical variations thereof, refers to a patient or a population of patients in need of treatment for a disease for which the intervention had no benefit. In certain embodiments, the patient or population of patients that did not respond had stable disease (SD) and/or progressive disease (PD) after treatment with the intervention. In certain embodiments, the patient or the population of patients that did not respond had SD after treatment with the intervention. In certain embodiments, the patient or population of patients had PD after treatment with the intervention. In certain embodiments, “non-responder(s)” refers to a patient or a population of patients for which the best response on the intervention or treatment was SD or PD. In certain embodiments, “did not respond” [after the intervention or treatment] is interchangeable with “progressed” [after the intervention or treatment].

[0065] “Objective Responsive Rate” (“ORR”) refers to the proportion of subjects who achieve a complete response (CR) or partial response (PR) that is confirmed at least 4 weeks later as assessed by the investigator per RECIST Version 1.1.

[0066] “Partial Response” (“PR”), refers to a > 30% decrease in the sum of the longest diameter (“LD”) of target lesions, taking as reference the baseline sum LD. In certain embodiments, lesions are measured by computed tomography or MRI scans with IV contrast (unless contrast use is medically contraindicated). Lesions in the chest, abdomen, pelvis, and any other involved disease sites are measured in all patients according to the study procedures (as shown in FIG. 3) at baseline and every 6 weeks after initiation of study treatment for the first 12 months and then every 9 weeks until initiation of subsequent anticancer therapy or termination of study by sponsor, whichever occurs first. For patients with evidence of CR or PR, a confirmatory scan is performed at least 4 weeks after initial documentation of response. In certain embodiments, tumor response and progression are determined using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1. 1 by IRC. In certain embodiments, PR refers to a 50% or greater size in the measurable tumor(s).

[0067] “Patient” or “subject,” as used herein, refers to a human having a particular disease. In certain embodiments, the patient is an adult patient in need of treatment for the disease. As used herein, “patient” may refer to a “population of patients.”

[0068] “Progression Free Survival” (“PFS”) refers to the time from the date of randomization until the date of objective disease progression or death (whichever occurs first) as assessed by the investigator using RECIST VERSION 1.1.

[0069] “Refractory” is used to describe when the disease does not respond to treatment or when the response to treatment does not last very long.

[0070] “Relapsed” refers to a disease that reappears or grows again after a period of remission. [0071] “Standard of care,” as used herein refers to a preferred treatment regimen for a particular disease or indication, such as a treatment that a governmental regulatory agency has approved for the disease or indication.

[0072] “Statistically significant” or “statistically significantly superior” (and grammatical variations thereof) refers, in certain embodiments, to meeting primary and secondary endpoints of the clinical trial. In certain embodiments, the term refers to whether there is any mathematical significance to the carried analysis of the results or not.

[0073] “Targeted therapie(s)” refers to small molecule inhibitors, monoclonal antibodies, tumor agnostic treatments, and the like, in cancer treatment.

[0074] “Therapeutically effective amount” or “effective amount” is defined as an amount of compound/drug to treat the disease or disorders and achieve clinical efficacy.

[0075] “Treatment” (or grammatical variations thereof), refers to medical care that results in clinically meaningful benefit or clinically meaningful improvement in human patient(s) or human subject(s). In certain embodiments, “treatment” refers to medical care that results in a clinically meaningful improvement compared to a standard-of-care, i.e., compared to docetaxel. In certain embodiments, “treatment” refers to medical care that results in a clinically meaningful improvement in OS and/or PFS.

[0076] “Treatment emergent adverse effects” (“TEAEs”), as used herein, refers to adverse effects reported in patients who have received at least one dose of a treatment.

[0077] “Treatment-naive,” as used herein, refers to not having received treatment, i.e., not having received treatment for advanced or metastatic NSCLC. Recommended Dosing Regimen

[0078] In certain embodiments, SG is administered as an intravenous infusion at a dosage of 10 mg/kg once weekly on days 1 and 8 of continuous 21 -day treatment cycles. In certain embodiments, SG is administered until disease progression or unacceptable toxicity.

[0079] In certain embodiments, docetaxel is administered only on day 1 of the 21 -day cycles. In certain embodiments, in the patients administered docetaxel, corticosteroids are administered 3 days prior to administration of docetaxel.

[0080] In certain embodiments, and as shown in FIG. 5B, SG is administered as an intravenous infusion for about 3.5 months or at least about 3.5 months. In certain embodiments, SG is administered for about (5) 21-day cycles or at least about (5) 21-day cycles.

[0081] In certain embodiments, SG is administered for about (6) 21-day cycles; about (7) 21- day cycles; about (8) 21-day cycles; about (9) 21-day cycles; about (10) 21-day cycles; about (11) 21-day cycles; about (12) 21-day cycles; about (13) 21-day cycles; about (14) 21-day cycles; about (15) 21-day cycles; about (16) 21-day cycles; about (17) 21-day cycles; about (18) 21-day cycles; about (19) 21-day cycles; about (20) 21-day cycles; about (21) 21-day cycles; about (22) 21-day cycles; about (23) 21-day cycles; about (24) 21-day cycles; about (25) 21-day cycles; about (26) 21-day cycles; about (27) 21-day cycles; or about (28) 21-day cycles.

[0082] In certain embodiments, SG is administered for at least about (6) 21-day cycles; at least about (7) 21-day cycles; at least about (8) 21-day cycles; at least about (9) 21-day cycles; at least about (10) 21-day cycles; at least about (11) 21-day cycles; at least about (12) 21-day cycles; at least about (13) 21-day cycles; at least about (14) 21-day cycles; at least about (15) 21-day cycles; at least about (16) 21-day cycles; at least about (17) 21-day cycles; at least about (18) 21-day cycles; at least about (19) 21-day cycles; at least about (20) 21-day cycles; at least about (21) 21- day cycles; at least about (22) 21-day cycles; at least about (23) 21-day cycles; at least about (24) 21-day cycles; at least about (25) 21-day cycles; at least about (26) 21-day cycles; at least about (27) 21-day cycles; or at least about (28) 21-day cycles.

Dose Modifications for Adverse Reactions

[0083] In certain embodiments, the dosage of 10 mg/kg of SG is withheld, modified, or discontinued to manage adverse reactions as described in Tables 3 and 4. In certain embodiments, the dosage of SG is not re-escalated after a dose reduction for an adverse reaction has been made. Table 2: Dose Modifications for Adverse Reactions (Severe Neutropenia)

Table 3. Dose Modifications for Adverse Reactions (Severe Non-Neutropenic Toxicity)

Patient Populations

[0084] In certain embodiments, patients (and/or population of patients) treated with the methods disclosed herein have NSCLC. In certain embodiments, the NSCLC is advanced. In certain embodiments, the NSCLC is metastatic. In certain embodiments, the NSCLC is advanced or metastatic. In certain embodiments, the NSCLC is relapsed. In certain embodiments, the NSCLC is refractory. In certain embodiments, the NSCLC is relapsed from, or refractory to, prior therapy containing a PD-1 or PD-L1 inhibitor. In certain embodiments, the methods disclosed herein are used to treat relapsed and/or refractory NSCLC.

[0085] In certain embodiments, patients (and/or population of patients) treated with the methods disclosed herein have had prior therapy containing a PD-1 or PD-L1 inhibitor. In certain embodiments, the patients have progressed after prior therapy containing a PD-1 or PD-L1 inhibitor. In certain embodiments, the patients did not respond to prior therapy containing a PD- 1 or PD-L1 inhibitor. In certain embodiments, the patients did not respond to the last prior therapy containing a PD-1 or PD-L1 inhibitor. In certain embodiments, the patients had SD after treatment with/receipt of prior therapy containing a PD-1 or a PD-L1 inhibitor. In certain embodiments, the patients had PD after treatment with/receipt of prior therapy containing a PD-1 or a PD-L1 inhibitor. In certain embodiments, the prior therapy containing a PD-1 or PD-L1 inhibitor was pembrolizumab. In certain embodiments, the last prior therapy containing PD-1 or PD-L1 inhibitor was pembrolizumab. In certain embodiments, patients treated with the methods disclosed herein have received prior platinum-based chemotherapy. In certain embodiments, the patients had progressed after receipt of platinum-based chemotherapy. In certain embodiments, the patients did not respond after receipt of platinum-based chemotherapy.

[0086] In certain embodiments, to be considered to have progressed during or after prior treatment with platinum-based chemotherapy, patients should have either received prior platinumbased chemotherapy in the recurrent metastatic setting or have experienced disease progression within 6 months of last dose of platinum-based chemotherapy administered as part of concurrent chemoradiation for stage 3 disease or as neoadjuvant or adjuvant therapy. In certain embodiments, the patients have progressed after prior therapy containing a PD-1 or PD-L1 inhibitor and have progressed after platinum-based chemotherapy (in either order and sequentially or together). In certain embodiments, to be considered to have progressed during or after prior treatment with an anti-PD-l/PD-Ll antibody, patients should have either received this therapy in the recurrent/metastatic setting or have experienced disease progression during “maintenance” treatment following concurrent chemoradiation for stage 3 disease.

[0087] In certain embodiments, patients treated with the methods disclosed herein do not have genomic alterations in EGFR. In certain embodiments, the patients do not have genomic alterations in ALK. In certain embodiments, the patients do not have actionable genomic alterations in EFGR. In certain embodiments, the patients do not have actionable genomic alterations in ALK. In certain embodiments, the patients do not have actionable genomic alterations in EGFR and ALK. In certain embodiments, if patient status is not known, testing is required. In certain embodiment, if patient status is not known, testing is required for genomic alterations in EGFR, ALK, and PD-(L)1. In certain embodiments, if patient status is not known, testing is not required.

[0088] In certain embodiments, patients treated with the methods disclosed herein do not have a mixed small cell lung cancer (“SCLC”)/NSCLC histology.

[0089] In certain embodiments, patients treated with the methods disclosed herein have squamous NSCLC. In certain embodiments, patients treated with the methods disclosed herein have non-squamous NSCLC. In certain embodiments, patients treated with the methods disclosed herein have both squamous and non-squamous NSCLC.

[0090] In certain embodiments, the methods disclosed herein do not comprise administering an anti-TIGIT antibody to the patient. In certain embodiments, the patient does not receive an anti- TIGIT antibody during the one or more 21 -day treatment cycles. In certain embodiments, the method does not comprise concomitant administration of an anti-TGIT antibody.

[0091] In certain embodiments, the methods disclosed herein do not comprise administration of a second anti-cancer agent and/or anti-tumor agent. In certain embodiments, the methods disclosed herein do not comprise administration of chemotherapy. In certain embodiments, the methods disclosed herein do not comprise administration of a platinum-based chemotherapy. In certain embodiments, the methods disclosed herein do not comprise concomitant administration of a pemetrexed. In certain embodiments, the methods disclosed herein do not comprise administration of pemetrexed and platinum-based chemotherapy. In certain embodiments, the methods disclosed herein do not comprise administration of carboplatin. In certain embodiments, the methods disclosed herein do not comprise administration of paclitaxel/paclitaxel proteinbound. In certain embodiments, the methods disclosed herein do not comprise administration of carboplatin and paclitaxel/paclitaxel protein-bound. In certain embodiments, the methods disclosed herein do not comprise administration of pemetrexed, platinum-based chemotherapy, carboplatin, and paclitaxel/paclitaxel protein-bound. EXAMPLES

EXAMPLE 1

Ph 1/2 IMMU-132-01 Basket Trial (NCT01631552)

[0092] SG (as a monotherapy) was evaluated in metastatic NSCLC in a single-arm clinical trial with either 8 mg/kg or 10 mg/kg on days 1 of 8 of 21-day cycles: IMMU-132-01 (completed, 54 patients enrolled). The ORR based on local response assessment was 16.7% for the NSCLC population; all responses were PRs. The median duration of response (DOR) by local assessment was 6.0 months. The median progression free survival was 5.2 months, and the median overall survival was 9.5 months.

[0093] Table 4 shows the key efficacy results for patients having NSCLC in the IMM-132-01 basket trial.

Table 4. Summary of Responses for Assessable Patients With an Intention-to-Treat Analysis for PFS and OS

Response No. (%)

All patients

Best overall response (n = 47)

PR 9 (19)

SD 23 (49)

PD 15 (32)

Objective response duration, months

Median (95% CI) 6.0 (4.8 to 8.3)

Clinical benefit (PR + SD > 4 months) 20 (43)

PFS (n = 54), months

Median (95% CI) 5.2 (3.2 to 7.1)

OS (n = 54), months

Median (95% CI) 9.5 (5.9 to 16.7)

Patients with prior CPI therapy (n = 14)

Best overall response

PR 2 (14)

SD 7 (50)

PD 5 (36)

Clinical benefit (PR + SD > 4 months) 5 (36)

PFS, months

Median (95% CI) 5.2 (2.0 to 5.5)

OS, months

Median (95% CI) 14.6 (5.9 to 14.6)

Abbreviations: OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response SD, stable disease. EXAMPLE 2

Phase 3 Clinical Trial - EVOKE-Ol (NCT05089734)

[0094] As shown in FIGS. 1 and 3, EVOKE-Ol was an open-label, global, multi-center, randomized Phase 3 study to compare the efficacy and safety of SG versus docetaxel in patients with advanced or metastatic NSCLC with progression on or after platinum-based chemotherapy and anti-PD-l/PD-Ll immunotherapy received either in combination or sequentially. Patients with actionable genomic alterations were included if they received prior treatment with an appropriate TKI (targeted kinase).

[0095] Approximately 603 eligible patients were randomly assigned in a 1:1 ratio to receive either SG (Investigational Arm A) or docetaxel (Control Arm B). Randomization was stratified based on histology (squamous versus nonsquamous), response to last prior immune therapy received (best response PD/SD versus CR/PR on immune therapy), and if they received prior therapy for actionable genomic alteration. The primary endpoint of the study was OS. Secondary efficacy endpoints were PFS, ORR, DOR, and DCR as assessed by the investigator per RECIST Version 1.1.

[0096] SG was administered at 10 mg/kg via IV infusion on Days 1 and 8 of a 21 -day cycle. Docetaxel was administered at 75 mg/m2 via infusion on Day 1 of a 21 -day cycle. Patients received study drug until PD, death, unacceptable toxicity, or if another treatment discontinuation criterion was met.

Inclusion Criteria.

[0097] Patients met all of the inclusion criteria outlined below at screening/Day -1 were eligible for participation in this study, with no waivers for patient eligibility offered or permitted:

[0098] The patients were 18 years of age or older and able to understand and give written informed consent.

[0099] The patients had a life expectancy > 3 months.

[0100] The patients had pathologically documented NSCLC. The pathologically documented NSCLC was by way of stage IV NSCLC at the time of enrollment based on the American Joint Committee on Cancer, Eighth Edition; EGFR, ALK, and PD-1 results are required prior to enrollment. For patients with squamous cell carcinoma, EGFR and ALK testing is optional; must have progressed after platinum-based chemotherapy in combination with anti-PD-l/PD-Ll antibody OR platinum-based chemotherapy and anti-PD-l/PD-Ll antibody (in either order) sequentially. This includes patients who received prior platinum-based chemoradiotherapy (with or without maintenance anti-PD-l/PD-Ll antibody) for Stage 3 disease.

[0101] To be considered to have progressed during or after prior treatment with platinum-based chemotherapy, patients should have either received prior platinum-based chemotherapy in the recurrent/metastatic setting or have experienced disease progression within 6 months of the last dose of platinum-based chemotherapy administered as part of concurrent chemoradiation for Stage 3 disease or as neoadjuvant or adjuvant therapy. To be considered to have progressed during or after treatment with an anti-PD-l/PD-Ll antibody, patients should have either received this therapy in the recurrent/metastatic setting or have experienced disease progression during the “maintenance” treatment following concurrent chemoradiation for Stage 3 disease. No additional treatments were allowed in the recurrent/metastatic setting for patients with no actionable genomic alterations.

[0102] Patients with EGFR, ALK, or any other known actionable genomic alterations must have also received treatment with at least 1 locally approved and available TKI appropriate to the genomic alteration. Patients must also have had documented radiologic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.

[0103] The patients had measurable disease by CT or magnetic resonance imaging (MRI) as per RECIST Version 1.1 criteria by investigator. Tumor lesions situated in a previously irradiated area were considered measurable if progression had been demonstrated in such lesions. Historical images within 28 days of the screening visit were accepted as a screening image if deemed acceptable in the opinion of the investigator.

[0104] The patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 before randomization.

Clinical Results

[0105] Clinical results for the Evoke-01 clinical trial are shown in FIGS. 5A-12B. As shown in FIG. 10A, patients who did not respond (SD/PD) to last treatment with a PD-(L)-1 containing regimen and treated with SG showed about a median of 3.5 OS improvement over standard of care in the same patient population. As shown in FIGS. 11A and 11B, patients who did not respond (SD/PD) to last treatment with a PD-(L)-1 containing regimen and treated with SG showed about a median 3-3.5 month improvement over standard of care in both the non-squamous (FIG. 11 A) and the squamous (FIG. 1 IB) subsets of this patient population. Randomization

[0106] Patients who met randomized criteria were randomized in a 1 : 1 ratio to receive either SG or docetaxel starting on day 1. Randomization was stratified by the following: (1) Histology (squamous vs. nonsquamous); (2) response to last prior immune therapy received (best PD/SD vs. CR/PR on immune therapy and (3) received prior therapy for actionable genomic alteration.

EXAMPLE 3

Press Release Dated January 22, 2024

Gilead Provides Update on Phase 3 EVQKE-01 Study (Results')

[0107] On January 24, 2024, Gilead announced that a more than three-month difference in median OS favoring SG was observed in a sub-group of patients non-responsive to last prior anti- PD-(L)1 therapy, representing over 60% of the trial population. This analysis was pre-specified in the protocol, but not alpha-controlled for formal statistical testing. This magnitude of difference was not observed in the sub-group of patients with response to last prior anti-PD-(L)l therapy. Additionally, a numerical improvement in OS favoring SG was observed in the study overall, including in patients with both squamous and non-squamous histology.

[0108] The EVOKE-01 study, however, did not meet its primary endpoint of overall survival (OS) in previously treated metastatic NSCLC [when considering all sub-groups together].

[0109] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A method of increasing median overall survival (OS) in a population of patients having advanced or metastatic NSCLC compared to treatment of a control group with a standard of care, wherein the population of patients have not responded to last prior therapy containing a PD-1 or PD-L1 inhibitor, the method comprising administering to the population of patients in need thereof a dosage of 10 mg/kg of SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, and wherein median OS is increased by about at least 3 months compared to median OS of the control group of patients treated with the standard of care.

2. A method of improving median overall survival (OS) in a population of patients having advanced or metastatic NSCLC compared to treatment of a control group with a standard of care, wherein the population of patients have not responded to last prior therapy containing a PD-1 or a PD-L1 inhibitor, the method comprising administering to the population of patients in need thereof a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, and wherein median OS is improved by at least about 3 months compared to median OS of the control group of patients treated with the standard of care.

3. A method of improving clinical efficacy compared to a standard of care in a population of patients having advanced metastatic non-squamous or squamous NSCLC, wherein the population of patients have not responded to last prior therapy containing a PD- 1 or a PD-L1 inhibitor, without concomitant administration of a chemotherapy, comprising administering to the population of patients in need thereof 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles.

4. A method of numerically improving median overall survival (OS) in a population of patients having advanced or metastatic NSCLC compared to treatment in a control group treated with a standard of care, wherein the population of patients have received prior therapy containing a PD-1 or a PD-L1 inhibitor, the method comprising administering to the population of patients a dosage of 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles, wherein the median OS is numerically improved compared to median OS of the control group treated with the standard of care.

5. The method of claims 1-4, wherein the standard of care is docetaxel.

6. The method of claims 1-5, wherein the population of patients have received prior therapy containing a platinum-based chemotherapy.

7. The method of claims 1-6, wherein the population of patients have not responded to prior therapy containing a platinum-based chemotherapy.

8. The method of claims 1-7, wherein the method does not comprise the administration of a second anti-cancer agent.

9. The method of claims 1-8, wherein the advanced or metastatic NSCLC is non- squamous.

10. The method of claims 1-8, wherein the advanced or metastatic NSCLC is squamous.

11. The method of claims 1-10, wherein the population of patients has Stage 3 NSCLC.

12. A method of treating an advanced or metastatic NSCLC in a patient in need thereof that increases overall survival of the patient by at least about 3 months compared to treatment with a standard of care, wherein the patient has not responded to last prior therapy containing a PD-1 or a PD-L1 inhibitor, the method comprising administering to the patient 10 mg/kg SG as an intravenous infusion on day 1 and day 8 of one or more 21 -day treatment cycles.

13. The method of claim 12, wherein the standard of care is docetaxel.

14. The method of claims 12-13, wherein the patient has received prior therapy containing a platinum-based chemotherapy.

15. The method of claim 14, wherein the patient has not responded to prior therapy containing a platinum-based chemotherapy.

16. The method of claims 12-13, wherein the method does not comprise the administration of a second anti-cancer agent.

17. The method of claims 12-16, wherein the advanced or metastatic NSCLC is non- squamous.

18. The method of claims 12-16, wherein the advanced or metastatic NSCLC is squamous.

19. The method of claims 12-18, wherein the patient has Stage 3 NSCLC.

20. The method of claims 1-19, comprising administering SG for at least about (5) 21 -day treatment cycles.