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WO2025238176A1 - Combinaisons d'inhibiteurs d'egfr/erb et de bet pour le cancer de gastrique - Google Patents

Combinaisons d'inhibiteurs d'egfr/erb et de bet pour le cancer de gastrique

Info

Publication number
WO2025238176A1
WO2025238176A1 PCT/EP2025/063447 EP2025063447W WO2025238176A1 WO 2025238176 A1 WO2025238176 A1 WO 2025238176A1 EP 2025063447 W EP2025063447 W EP 2025063447W WO 2025238176 A1 WO2025238176 A1 WO 2025238176A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
egfr
kmt2b
alobresib
gastric cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/063447
Other languages
English (en)
Inventor
Amy EMERY
Anamarija JURISIC
Daniel ZERBINO
Jose DIANES SANTOS
Grahame Mckenzie
Mathew GARNETT
Patrick Herr
Bryn Hardwick
Alex CROOKS
Antonio ROMO MORALES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mosaic Therapeutics Ltd
Genome Research Ltd
Original Assignee
Mosaic Therapeutics Ltd
Genome Research Ltd
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Filing date
Publication date
Application filed by Mosaic Therapeutics Ltd, Genome Research Ltd filed Critical Mosaic Therapeutics Ltd
Publication of WO2025238176A1 publication Critical patent/WO2025238176A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/395—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to combination therapies for the treatment of cancer.
  • Gastrointestinal (Gl) cancers represent a particularly high unmet medical need; subtypes include colorectal, gastric, oesophageal, pancreatic, and liver cancer.
  • Gastric, or stomach, cancer is the second- most common form of Gl cancer.
  • WHO World Health Organization
  • gastric cancer is the sixth most-common cancer overall and the fourth-leading cause of cancer-related deaths worldwide. It is often diagnosed late and at an advanced stage of disease, when both treatment options and clinical outcomes are poor.
  • the invention is directed to the use of therapeutic combinations of active ingredients for the treatment of gastric cancer in patients, and especially to the combination of an EGFR/ERBB2 inhibitor and a bromodomain and extra-terminal motif (BET) inhibitor, or their pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • BET bromodomain and extra-terminal motif
  • the invention provides a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for use in a method of treatment of gastric cancer in a patient.
  • the invention provides an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for use in a method of treatment of gastric cancer in a patient, wherein the EGFR/ERBB2 inhibitor is administered to a patient in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the invention provides a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for use in a method of treatment of gastric cancer in a patient, wherein the BET inhibitor is administered to a patient in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the invention provides a method of treatment of gastric cancer, wherein the method comprises the step of administering a therapeutically effective amount of a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to a patient in need thereof.
  • the invention also relates to a method of treatment of gastric cancer, wherein the method comprises the step of administering a therapeutically effective amount of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to a patient in need thereof, wherein the EGFR/ERBB2 inhibitor is administered to the patient in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the invention also relates to a method of treatment of gastric cancer, wherein the method comprises the step of administering a therapeutically effective amount of a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to a patient in need thereof, wherein the BET inhibitor is administered to the patient in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • a BET inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • the invention provides a use of a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for the manufacture of a medicament for the treatment of gastric cancer in a patient.
  • the invention provides a use of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for the manufacture of a medicament for the treatment of gastric cancer in a patient, wherein the EGFR/ERBB2 inhibitor is administered to a patient in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the invention provides a use of a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for the manufacture of a medicament for the treatment of gastric cancer in a patient, wherein the BET inhibitor is administered to a patient in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the invention provides a method of predicting whether a subject having gastric cancer is likely to respond to treatment with a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising determining the mutational status of KMT2B gene in the gastric cancer and selecting the subject for treatment if the KMT2B gene is a KMT2B mutant.
  • the invention provides a method of predicting whether a subject having gastric cancer is likely to respond to treatment with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising the step of determining the mutational status of KMT2B gene in the gastric cancer and selecting the subject for treatment if the KMT2B gene is a KMT2B mutant, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the invention provides a method of predicting whether a subject having gastric cancer is likely to respond to treatment with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising determining the mutational status of KMT2B gene in the gastric cancer and selecting the subject for treatment if the KMT2B gene is a KMT2B mutant, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • an EGFR/ERBB2 inhibitor and a BET inhibitor may provide a synergistic effect against gastric or stomach cancer cells, that is the EGFR/ERBB2 inhibitor and the BET inhibitor are more potent and promote more cell-death against gastric or stomach cancer cells than would be expected from the additive effect of combining the EGFR/ERBB2 inhibitor and BET inhibitor.
  • the inventors have identified the combination of an EGFR/ERBB2 inhibitor and a BET inhibitor as a potent combination in KMT2B mutant gastric cancer cells, the combination sensitising the mutant cells, promoting cell death and enhancing response when compared to KMT2B wild-type gastric cancer cells.
  • the KMT2B mutation in the KMT2B mutant gastric cancer is a cancer driver mutation.
  • the gastric cancer is KMT2B mutant gastric cancer.
  • the KMT2B mutation in the KMT2B mutant gastric cancer is a cancer driver mutation.
  • the KMT2B mutation in the KMT2B mutant gastric cancer comprises a nonsense, frameshift, or truncating mutation.
  • the KMT2B mutation in the KMT2B mutant gastric cancer results in a loss of the KMT2B protein. Loss is defined as a complete or partial lack of the KMT2B protein and/or a lack of functional KMT2B protein.
  • the KMT2B mutation in the KMT2B mutant gastric cancer results in a complete loss of the KMT2B protein or a partial loss of the KMT2B protein.
  • the KMT2B mutation in the KMT2B mutant gastric cancer results in no production of the KMT2B protein (that is, the KMT2B protein is not produced), or results in substantially no KMT2B production.
  • the KMT2B mutation in the KMT2B mutant gastric cancer comprises a mutation selected from: p.T176fs*8, p.W336*, p.R2587*, p.V314fs*20, and p.Q2150fs*.
  • the method of treatment comprises a step of determining the patient’s KMT2B mutational status.
  • the EGFR/ERBB2 inhibitor may be selected from the group consisting of afatinib, afatinib dimaleate, AL-6802, allitinib (AST-1306), almonertinib (aumolertinib), aumolertinib mesylate, brigatinib, CP-724714, dacomitinib, epertinib, erlotinib, gefitinib, icotinib, icotinib hydrochloride, lapatinib, lapatinib ditosylate, neratinib, olmutinib, olmutinib hydrochloride, osimertinib, osimertinib mesylate, pyrotinib, sapitinib, teseva
  • the EGFR/ERBB2 inhibitor is selected from the group consisting of afatinib, allitinib, almonertinib, erlotinib, lapatinib, and dacomitinib.
  • the BET inhibitor may be selected from the group consisting of ABBV-744, apabetalone, birabresib, molibresib, NHWD-870, trotabresib, alobresib, mivebresib, and ODM-207.
  • the BET inhibitor is selected from the group consisting of alobresib, trotabresib. mivebresib, ODM-207, NHWD-870, and birabresib.
  • an EGFR/ERBB2 inhibitor and a BET inhibitor may be selected from: afatinib and alobresib; afatinib and trotabresib; afatinib and mivebresib; afatinib and ODM-207; afatinib and NHWD-870; afatinib and birabresib; erlotinib and alobresib; erlotinib and birabresib; erlotinib and NHWD-870; lapatinib and alobresib; dacomitinib and alobresib; icotinib and alobresib; AL-6802 and alobresib; allitinib and alobresib; almonertinib and alobresib; brigatinib and alobresib;
  • the combination of an EGFR/ERBB2 inhibitor and a BET inhibitor is selected from: afatinib and alobresib; afatinib and trotabresib; afatinib and mivebresib; afatinib and ODM-207; afatinib and NHWD-870; afatinib and birabresib; erlotinib and alobresib; erlotinib and birabresib; erlotinib and NHWD-870; lapatinib and alobresib; dacomitinib and alobresib; allitinib and alobresib; and almonertinib and alobresib.
  • the combination of an EGFR/ERBB2 inhibitor and a BET inhibitor is selected from: afatinib and alobresib; afatinib and NHWD-870; afatinib and birabresib; erlotinib and alobresib; erlotinib and birabresib; erlotinib and NHWD-870; dacomitinib and alobresib; allitinib and alobresib; and almonertinib and alobresib.
  • the EGFR/ERBB2 inhibitor and the BET inhibitor may be administered together or separately and may be administered at the same time or at different times.
  • the compounds may be administered on different days as part of a treatment cycle or treatment regimen.
  • the EGFR/ERBB2 inhibitor and the BET inhibitor will be formulated separately.
  • each or either compound may be formulated for oral, parenteral, or intravenous administration.
  • the combination therapies claimed may be used both curatively and palliatively. They may lead to better patient outcomes and/or quality of life when compared to other treatment regimens and additionally or alternatively may expand the treatment options available to patients.
  • the invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • Figure 1 Correlation of KMT2B mut biomarker with synergy in response to Afatinib + Alobresib in gastric cancer cell lines.
  • Drug-drug screen Iog2 AIC50 (A) and AEmax (%) (B) are plotted against mutation status for KMT2B. Box and whisker plots show the median and interquartile range. WT: wild-type; MUT: mutant. See Example 1 .
  • Figure 2 Correlation of KMT2B mut biomarker with synergy in response to Erlotinib + Alobresib in gastric cancer cell lines.
  • Drug-drug screen Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Box and whisker plots show the median and interquartile range. WT: wildtype; MUT: mutant. See Example 1.
  • FIG. 3 Correlation of KMT2B mut biomarker with synergy in response to Afatinib + Alobresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT : wild-type; MUT: mutant. See Example 2.
  • FIG. 4 Correlation of KMT2B mut biomarker with synergy in response to Erlotinib + Alobresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT : wild-type; MUT: mutant. See Example 3.
  • FIG. 5 Correlation of KMT2B mut biomarker with synergy in response to Lapatinib + Alobresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT : wild-type; MUT: mutant. See Example 3.
  • FIG. 6 Correlation of KMT2B mut biomarker with synergy in response to Dacomitinib + Alobresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT : wild-type; MUT: mutant. See Example 3.
  • FIG. 7 Correlation of KMT2B mut biomarker with synergy in response to Afatinib + Trotabresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT : wild-type;
  • Figure 8 Correlation of KMT2B mut biomarker with synergy in response to Afatinib + Mivebresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT : wild-type; MUT: mutant. See Example 3.
  • Figure 9 Correlation of KMT2B mut biomarker with synergy in response to Afatinib + ODM-207 in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT: wild-type; MUT: mutant. See Example 3.
  • Figure 10 Correlation of KMT2B mut biomarker with synergy in response to Afatinib + NHWD-870 in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT: wild-type; MUT: mutant. See Example 3.
  • FIG 11 Correlation of KMT2B mut biomarker with synergy in response to Afatinib + Birabresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT: wild-type; MUT: mutant. See Example 3.
  • Figure 12 Correlation of KMT2B mut biomarker with synergy in response to Allitinib + Alobresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT: wild-type; MUT: mutant. See Example 3.
  • Figure 13 Correlation of KMT2B mut biomarker with synergy in response to Almonertinib + Alobresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT: wild-type; MUT: mutant. See Example 3.
  • Figure 14 Correlation of KM72B mut biomarker with synergy in response to Erlotinib + Birabresib in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT: wild-type; MUT: mutant. See Example 3.
  • Figure 15 Correlation of KMT2B mut biomarker with synergy in response to Erlotinib + NHWD-870 in gastric cancer cell lines. Verification Iog2 AIC50 (A) and %AEmax (%) (B) are plotted against mutation status for KMT2B. Plots show the median and each point represents an individual cell line. WT: wild-type; MUT: mutant. See Example 3.
  • Figure 16 Correlation of KMT2B mut biomarker with loss of KMT2B protein.
  • references to “compounds”, “inhibitors”, and “active ingredients” also include antibodies, such as EGFR/ERBB2 antibodies.
  • the epidermal growth factor receptor is a transmembrane protein and member of protein kinase superfamily encoded by the EGFR/HER1 gene locus. It is sometimes referred to as ERBB1 , ERBB-1 , or HER1 in humans. It is a receptor for members of the epidermal growth factor (EGF) family of extracellular protein ligands.
  • ERBB2 The erb-b2 receptor tyrosine kinase 2 (ERBB2) is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene.
  • ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. It is also known as ERBB-2, CD340, or HER2 in humans.
  • Both EGFR and ERBB2 are members of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4).
  • EGF ligand binding at the cell surface to EGFR promotes EGFR dimerization either as homodimers or heterodimers, such as with ERBB2/HER2.
  • Receptor dimerization leads to receptor phosphorylation and downstream signal activation.
  • Key downstream signalling pathways activated by EGFR/ERBB2 signalling include the RAS-RAF-MEK-ERK MARK (that is, the MARK downstream signalling cascade) and AKT- PI3K-mTOR pathways (that is, the PI3K/AKT downstream signalling cascade), as well as downstream signalling cascades such as JAK/STAT and PLCg1/PKC. These pathways activate many biological outputs that promote cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Dysregulated EGFR signalling through copy number alteration or activating point mutations has been described to lead to oncogenic transformation.
  • Inhibitors of EGFR and/or ERBB2 inhibit EGFR and/or ERBB2 proteins, which disrupts these downstream signalling pathways.
  • EGFR inhibitors generally target the tyrosine kinase domain of EGFR and block downstream signalling (Levantini et al., Semin. Cancer Biol., 2022, 85, p253-275). This inhibition may be useful in the treatment of cancer, such as gastric cancer.
  • Examples of EGFR/ERBB2 inhibitors for use in the combinations described herein are abivertinib maleate, ABK-3376, ABM-1381 , ABP-1130, ABSK-111 , ABSK-112, AC-480, AEE-788, afatinib, afatinib dimaleate, AL-6802, AMX-3009, ARB-085, ARRY-333786, ASK-120067, allitinib (AST-1306), almonertinib (aumolertinib), aumolertinib mesylate, AV-412, AXP-10711 , AZD-4769, B-17, BAY-2476568, BAY-2927088, BAY-846, BDTX-1535, BEBT-108, BEBT-109, befotertinib, BGB-102, BI-732, BL-7030, BLU-451, BLU-525, BLU-701 , BMS-690514, BO
  • EGFR/ERBB2 inhibitors that are EGFR/ERBB2 antibodies for use in the combinations describe herein are ALLC-2137, AM-105, amelimumab, ametumumab, amivantamab, AP-005, ATV:HER2, BC-001 , BC-3448, BCD-147, BCD-235, becotatug, BH-2922, BMX-002, BR-115, BSI-001 , CAB-051 , cetuximab, CKD-10101 , CMAB-017, CTX-023, depatuxizumab, DR-50201 , duligotuzumab, DXL-1218, DXL-702, EPS-201 , ERAS-12, erbicin, fderceptin, fidasimtamab, FS-101 , GB-235, GB-263, GC-1118A, HL-07, HLX-22, IAH-0968, IBI-3
  • the EGFR/ERBB2 inhibitors for use in the combinations described herein are selected from the group consisting of afatinib, afatinib dimaleate, AL-6802, allitinib (AST-1306), almonertinib (aumolertinib), aumolertinib mesylate, brigatinib, CP-724714, dacomitinib, epertinib, erlotinib, gefitinib, icotinib, icotinib hydrochloride, lapatinib, lapatinib ditosylate, neratinib, olmutinib, olmutinib hydrochloride, osimertinib, osimertinib mesylate, pyrotinib, sapitinib, tesevatinib, tesevatinib tosylate, vandet
  • the EGFR/ERBB2 inhibitors for use in the combinations described herein are selected from the group consisting of afatinib dimaleate, AL-6802, allitinib (AST-1306), almonertinib (aumolertinib), aumolertinib mesylate, brigatinib, CP-724714, dacomitinib, epertinib, erlotinib, gefitinib, icotinib hydrochloride, lapatinib ditosylate, neratinib, olmutinib hydrochloride, osimertinib mesylate, pyrotinib, sapitinib, tesevatinib tosylate, vandetanib, and varlitinib.
  • the EGFR/ERBB2 inhibitors for use in the combinations described herein are selected from the group consisting of afatinib, AL-6802, allitinib (AST-1306), almonertinib (aumolertinib), brigatinib, CP-724714, dacomitinib, epertinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, olmutinib, osimertinib, pyrotinib, sapitinib, tesevatinib, vandetanib, and varlitinib.
  • the EGFR/ERBB2 inhibitors are EGFR/ERBB2 antibodies for use in the combinations describe herein are selected from the group consisting of amivantamab, cetuximab, inetetamab, necitumumab, nimotuzumab, panitumumab, pertuzumab, and trastuzumab.
  • the EGFR/ERBB2 inhibitors are EGFR/ERBB2 antibodies for use in the combinations describe herein are selected from the group consisting of cetuximab and trastuzumab.
  • the EGFR/ERBB2 inhibitors for use in the combinations described herein are selected from the group consisting of afatinib, allitinib, almonertinib, erlotinib, lapatinib, and dacomitinib. More preferably, the EGFR/ERBB2 inhibitors for use in the combinations described herein are selected from the group consisting of afatinib, erlotinib, lapatinib, and dacomitinib. Even more preferably, the EGFR/ERBB2 inhibitor is afatinib, erlotinib, or dacomitinib.
  • the EGFR/ERBB2 inhibitor is afatinib or erlotinib. In some embodiments, the EGFR/ERBB2 inhibitor is afatinib. In some embodiments, the EGFR/ERBB2 inhibitor is erlotinib.
  • the EGFR/ERBB2 inhibitor is a dual EGFR and ERBB2 inhibitor. In some embodiments, the EGFR/ERBB2 inhibitor is an EGFR inhibitor. In other embodiments, the EGFR/ERBB2 inhibitor is an ERBB2 inhibitor.
  • Afatinib also referred to a BIBW 2992, is an orally active, potent and irreversible dual specificity inhibitor of ErbB family (EGFR and ERBB2).
  • EGFR and ERBB2 ErbB family
  • Afatinib has reported IC50 values of 0.5 nM, 0.4 nM, 10 nM and 14 nM against EGFR 4 , EGFR L858R , EGFR L858R/T790M and ERBB2, respectively. Its structure is:
  • Afatinib dimaleate also referred to a BIBW 2992MA2 is the dimaleate salt of afatinib.
  • Afatinib dimaleate is also an orally active, potent and irreversible dual specificity inhibitor of ErbB family (EGFR and ERBB2).
  • EGFR and ERBB2 ErbB family
  • Afatinib dimaleate also has reported IC50 values of 0.5 nM, 0.4 nM, 10 nM and 14 nM against EGFR , EGFR L858R , EGFR L858R/T790M and ERBB2, respectively. Its structure is:
  • Simotinib also known as AL-6802 or SIM-6802, is a selective, specific, and orally bioavailable EGFR tyrosine kinase inhibitor. It has an IC50 of 19.9 nM against EGFR. Its structure is:
  • Allitinib also known as AST-1306 and ALS 1306, is an orally active and irreversible EGFR and ErbB2 inhibitor with IC50S of 0.5 and 3 nM, respectively. Allitinib also inhibits ErbB4 with an IC50 of 0.8 nM. Its structure is:
  • Almonertinib also known as aumolertinib and HS-10296, is an orally available, irreversible, third- generation EGFR tyrosine kinase inhibitor with high selectivity for EGFR-sensitizing and T790M resistance mutations. It exhibits great inhibitory activity against T790M, T790M/L858R and T790M/Del19 resistance mutations in EGFR with IC50 values of 0.37, 0.29 and 0.21 nM, respectively. It is less effective against EGFR wild type with an IC50 values of 3.39 nM. Its structure is:
  • Aumolertinib mesylate also known as almonertinib mesylate and HS-10296 methanesulfonate, is the mesylate salt of aumolertinib. It is also an orally available, irreversible, third-generation EGFR tyrosine kinase inhibitor with high selectivity for EGFR-sensitizing and T790M resistance mutations.
  • Almonertinib mesylate shows the IC50 same inhibitor activity as aumolertinib against T790M, T790M/L858R and T790M/Del19 resistance mutations in EGFR and EGFR wild-type. Its structure is:
  • AP-261 13 is a highly potent, selective and orally active ALK inhibitor. It potently inhibits the in vitro kinase activity of ALK with an IC50 of 0.6 nM and inhibits both the ALK-11171 N and the ALK-G1269A mutant receptors at IC50 values of 10 and 4 nM levels, respectively. It also inhibits FLT3 and IGF-1 R with about 11 -fold lower potency (IC50 of 148-158 nM) and inhibits mutant variants of FLT3 and EGFR with 15- to 35-fold lower potency (IC50 of 211-489 nM). Its structure is:
  • CP-724714 is a potent, selective inhibitor of HER2/ErbB2 with IC50 of 10 nM.
  • CP-724714 is marked selectively against EGFR with IC50 of 6.4 pM. It is >1 ,000-fold less potent for IR, IGF-1 R, PDGFRp, VGFR2, abl. Src, c-Met c-jun NH2-terminal kinase (JNK)-2, JNK-3, ZAP-70, cyclin-dependent kinase (CDK)-2, and CDK-5. Its structure is:
  • Dacomitinib is a potent, irreversible pan-ErbB inhibitor, mostly to EGFR with IC50 of 6 nM in a cell-free assay. Dacomitinib inhibits ERBB2 and ERBB4 with IC50 of 45.7 nM and 73.7 nM, respectively.
  • Dacomitinib is effective against NSCLCs with EGFR or ERBB2 mutations (resistant to gefitinib) as well as those harboring the EGFR T790M mutation. Dacomitinib inhibits cell growth and induces apoptosis. Its structure is:
  • Epertinib also known as S-2261 1 , is a potent, orally active, reversible, and selective tyrosine kinase inhibitor of EGFR, ERBB4 and ERBB2. It has with IC50 values of 1 .48 nM, 2.49 nM and 7.15 nM, respectively against EGFR, ERBB4 and ERBB2. Epertinib shows potent antitumor activity. Its structure is:
  • Erlotinib also known as CP-358774, is a directly acting EGFR tyrosine kinase inhibitor, with an IC50 of
  • Erlotinib reduces EGFR autophosphorylation in intact tumor cells with an IC50 of
  • Gefitinib also known as ZD1839, is a potent, selective and orally active EGFR tyrosine kinase inhibitor with an IC50 of 33 nM. Gefitinib selectively inhibits EGF-stimulated tumor cell growth (IC50 of 54 nM) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. Its structure is:
  • Icotinib also known as BPI-2009, is a potent and specific EGFR inhibitor with an IC50 of 5 nM. It also inhibits mutant EGFR L858R , EGFR L858R/T790M , EGFR T790M and EGFR L861Q . Its structure is:
  • Icotinib Hydrochloride also known as BPI-2009H, is the hydrochloride salt of icontinib. It is also a potent and specific EGFR inhibitor with an IC50 of 5 nM and also inhibits mutant EGFR L858R , EGFR L858R/T790M , EGFR T790M and EGFR L861Q . Its structure is:
  • Lapatinib also known as GW572016, is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM, respectively. Its structure is:
  • Lapatinib ditosylate also known as GW572016 ditosylate, is the ditosylate salt of lapatinib. It is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM, respectively. Its structure is:
  • Neratinib also known as HKI-272, is an orally available, irreversible, highly selective ERBB2 and EGFR inhibitor with IC50 values of 59 nM and 92 nM, respectively. Its structure is:
  • Olmutinib also known as HM61713 and BI-1482694, is an orally active and irreversible third EGFR tyrosine kinase inhibitor that binds to a cysteine residue near the kinase domain. Its structure is:
  • Olmutinib hydrochloride is the hydrochloride salt of olmutinib. It has comparable activity to olmutinib. Its structure is: In IUPAC nomenclature, it may be referred to as A/-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]thieno[3,2- d]pyrimidin-4-yl]oxyphenyl]prop-2-enamide hydrochloride. Its synthesis is known in the art and the compound is commercially available.
  • Osimertinib also known as AZD9291 , AZD-9291 , and mereletinib, is a covalent, orally active, irreversible, and mutant-selective EGFR inhibitor with an apparent IC50 of 12 nM against L858R and 1 nM against
  • Osimertinib mesylate also known as AZD9291 mesylate, AZD-9291 mesylate, and mereletinib mesylate, is the mesylate salt of Osimertinib. It is also a covalent, orally active, irreversible, and mutant-selective
  • Pyrotinib also known as SHR-1258, is a potent and selective EGFR/ERBB2 dual inhibitor with IC50 values of 13 and 38 nM, respectively. Its structure is:
  • Sapitinib also known as AZD8931 and AZD-8931 , is a reversible, ATP competitive EGFR inhibitor of with
  • Tesevatinib also known as XL-647, EXEL-7647, and KD-019, is an orally available, multi-target tyrosine kinase inhibitor. It inhibits EGFR, ErbB2, KDR, Flt4 and EphB4 kinase with IC50 values of 0.3, 16, 1.5, 8.7, and 1 .4 nM. Its structure is:
  • Tesevatinib tosylate is the tosylate salt of tesevatinib. It has comparable activity to tesevatinib. Its structure is: In IUPAC nomenclature, it may be referred to as 7-[[(3aR,6aS)-2-methyl-3,3a,4,5,6,6a-hexahydro-1 /7- cyclopenta[c]pyrrol-5-yl]methoxy]-A/-(3,4-dichloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine 4- methylbenzenesulfonate. Its synthesis is known in the art and the compound is commercially available.
  • Vandetanib also known as D6474, is a potent, orally active inhibitor of VEGFR2/KDR tyrosine kinase activity, with an IC50 of 40 nM. Vandetanib also has activity versus the tyrosine kinase activity of VEGFR3/FLT4 with an IC50 of 1 10 nM, and EGFR/HER1 with an IC50 of 500 nM. Its structure is:
  • Varlitinib also known as ASLAN001 , is a potent, reversible, small molecule pan-EGFR inhibitor with IC50 values of 7, 2, and 4 nM for HER1 , HER2, and HER4, respectively. Its structure is:
  • Amivantamab is also known as JNJ-61186372, JNJ 61186372, JNJ-611 , and CNTO-4424. It is a human EGFR-MET bispecific antibody with immune anticancer activity. Amivantamab inhibits ligand binding, promotes endocytosis and degradation of receptor-antibody complexes, and induces Fc-dependent cytokinesis in macrophages and antibody-dependent cytotoxicity in natural killer cells. Its CAS number is 2171511-58-1. Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name Rybrevant®.
  • Cetuximab is also known as C225, C-225, ABP-494, BMS 564717, CMAB-009, CMAB009, IMC-225, IMC-C225, and MOAB C225. It is a human/mouse IgG 1 monoclonal antibody that competitively binds to epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor (EGF). It inhibits epidermal growth factor receptor (EGFR) with a Kd of 0.201 nM for EGFR by SPR. Cetuximab has potent antitumor activity. Its CAS number is 205923-56-4. Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name Erbitux®.
  • Inetetamab is a monoclonal antibody binding to domain IV of ERBB2 receptor. Inetetamab has antitumor activities. Inetetamab is a trastuzumab analog. It differs from trastuzumab by a two amino acid variation in its Fc domain (allotype variation) and possesses an exact F(ab’)2 of trastuzumab. Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name Cipterbin®.
  • Necitumumab, IMC 11 F8, IMC-11 F8, and IMC11 F8, is a human recombinant IgG monoclonal antibody directed against EGFR. It is an epidermal growth factor receptor (EGFR) antagonist (anti-EGFR). Its CAS number is 906805-06-9. Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name PortrazzaTM.
  • Nimotuzumab is a humanized IgG 1 monoclonal antibody targeting EGFR with a KD of 0.21 nM. It is an anti-ERBB1 / EGFR / HER1 antibody. Nimotuzumab is directed against the extracellular domain of the EGFR blocking the binding to its ligands. Nimotuzumab is a strong antitumor agent with potential antineoplastic activity and is cytolytic on target tumors by its capacity to cause antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). Its CAS number is 780758- 10-3. Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name Theraloc®.
  • Panitumumab also known as ABX-EGF, is a fully human recombinant lgG2 anti-EGFR monoclonal antibody with anti-tumor activity. It is an antineoplastic agent. Panitumumab inhibits tumor cell proliferation, survival, and angiogenesis. Its CAS number is 339177-26-3. Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name Vectibix®.
  • Pertuzumab also known as R1273 and RG-1273, is a humanized lgG1 monoclonal antibody and is a ERBB2 dimerization inhibitor (anti-HER2). It impairs the ability of ERBB2 to bind to other members of the HER family. Its CAS number is 380610-27-5. Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name Perjeta®.
  • Trastuzumab is a humanized, recombinant IgG 1 monoclonal antibody that binds to the extracellular domain of ERBB2 (anti-human ERBB2). It has been used in treating patients with invasive breast cancers that overexpress ERBB2. Its CAS number is 180288-69-1 . Its synthesis is known in the art and the antibody is commercially available. It is sold under the brand name Herceptin®. BET inhibitor
  • a bromodomain is a protein domain that recognizes acetylated lysine residues, such as those on the A/-terminal tails of histones.
  • Bromodomains are often referred to as the "readers" of lysine acetylation. They are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodelling.
  • the domain itself adopts an all-a protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.
  • Bromodomain-containing proteins can have a wide variety of functions, ranging from histone acetyltransferase activity and chromatin remodelling to transcriptional mediation and co-activation.
  • bromodomain family is the BET (Bromodomain and extraterminal domain) family.
  • BET Bromodomain and extraterminal domain
  • BRD2 BRD3, BRD4, and BRDT
  • BRD7 and BRD9 BRD7 and BRD9.
  • BRD proteins There are 4 BRD genes encoded in the human genome (BRD2, 3, 4, and T). BRD proteins contain several functional domains with the BET bromodomains functioning as epigenetic readers to recognise and bind to acetylated Histones. BRD proteins form part of the Mediator complex to regulate DNA polymerase Il-mediated gene expression at sites of acetylated histones. Oncogenic transformation can lead to hyperacetylation of enhancer regions and therefore enhanced transcriptional output of oncogenic signalling networks such as cMYC.
  • BET inhibitors are designed to bind to and occupy the BET domain to disrupt BRD-chromatin association and interfere with the aberrant transcriptional program (Shorstova et al., Br. J. Cancer, 2021 , 124, p1478- 1490). Accordingly, bromodomains are thought to be key players in cancer biology and inflammation due to their role in deregulation of the cell acetylome. Inhibitors of bromodomains are therefore thought to be useful in the treatment of cancer, such as gastric cancer.
  • BET inhibitors for use in the combinations described herein are ABBV-744, ADY-76001 , amredobresib, apabetalone, ARCC-29, ARV-763, ARV-771 , ARV-825, BAY-1238097, birabresib, CC- 95775, CFT-2718, CFT-743, CFT-8634, CG-202, CG-223, CG-250, CK-103, CN-427, CN-470, DCBD- 005, DYB-186, EP-11313, FHD-609, GNE-0011 , INCB-54329, INHAL-101 , JAB-8263, KM-601 , MA-2014, molibresib, MS-417, NEO-2734, NHWD-870, NUE-19796, NUE-20798, NUE-7770, NUV-868, OHM-581 , OPN-2853, pelabresib, PLX-
  • the BET inhibitors for use in the combinations described herein are selected from the group consisting of ABBV-744, apabetalone, birabresib, molibresib, NHWD-870, trotabresib, alobresib, mivebresib, and ODM-207.
  • the BET inhibitors for use in the combinations described herein are selected from the group consisting of birabresib, molibresib, NHWD-870, trotabresib, alobresib, mivebresib, and ODM-207.
  • the BET inhibitors for use in the combinations described herein are selected from the group consisting of alobresib, trotabresib, mivebresib, ODM-207, NHWD-870, and birabresib. Even more preferably, the BET inhibitor is alobresib, birabresib, and NHWD-870. In some embodiments, the BET inhibitor is alobresib. In some embodiments, the BET inhibitor is birabresib. In some embodiments, the BET inhibitor is NHWD-870.
  • the BET inhibitor is an inhibitor of at least one of BRD2, BRD3, BRD4, and BRDT. In some embodiments, the BET inhibitor is a BRD2 inhibitor. In some embodiments, the BET inhibitor is a BRD3 inhibitor. In some embodiments, the BET inhibitor is a BRD4 inhibitor. In some embodiments, the BET inhibitor is a BRDT inhibitor.
  • ABBV-744 is a first-in-class, orally active and selective inhibitor of the BDII domain of BET family proteins (that is, it is a BDII-selective BET bromodomain inhibitor) with IC50 values ranging from 4 to 18 nM for BRD2, BRD3, BRD4 and BRDT.
  • ABBV-744 is primarily metabolized by CYP3A4 with agent-like properties enable the investigation of its antitumor efficacy and tolerability. Its structure is:
  • Apabetalone also known as RVX-208 and RVX-000222, is an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.
  • the IC50 values are 87 pM and 0.51 pM for BD1 and BD2, respectively. Its structure is: In IUPAC nomenclature, it may be referred to as 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7- dimethoxy-3/7-quinazolin-4-one. Its synthesis is known in the art and the compound is commercially available.
  • Birabresib also known as OTX-015 and MK 8628, is a potent bromodomain (BRD2/3/4) inhibitor with IC50 values ranging from 92 to 112 nM. It also has EC50 values ranging from 10 to 19 nM for BRD2, BRD3, and BRD4 in cell-free assays. Its structure is:
  • Molibresib also known as I-BET762 and GSK525762, is a BET bromodomain inhibitor with IC50 of 32.5-
  • NHWD-870 is a potent, orally active and selective BET family bromodomain inhibitor and only binds bromodomains of BRD2, BRD3, BRD4 (IC50 of 2.7 nM), and BRDT.
  • NHWD-870 has potent tumor suppressive efficacies and suppresses cancer cell-macrophage interaction.
  • NHWD-870 increases tumor apoptosis and inhibits tumor proliferation. It also inhibits CSF1 expression through suppressing BRD4 and its target HIF1 a. Its structure is:
  • Trotabresib also known as BMS-986378 and CC-90010, is a reversible, orally active and central nervous system-penetrant inhibitor of bromodomain and extra-terminal (BET) proteins. Its structure is:
  • Alobresib also known as GS-5829, is a BET bromodomain inhibitor. It inhibits CLL cell proliferation and induces leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. It also inhibits NF-KB signaling.
  • Alobresib represents a highly effective therapeutics agent against recurrent/chemotherapy resistant uterine serous carcinoma (USC) overexpressing c-Myc. Its structure is:
  • Mivebresib also known as ABBV-075, is a potent and orally active bromodomain and extraterminal domain (BET) bromodomain inhibitor. Mivebresib binds to BRD4 with a Ki of 1 .5 nM.
  • ODM-207 also known as BET-IN-4, is a potent and selective BET bromodomain protein (BRD4) inhibitor, with an IC50 of ⁇ 1 pM. ODM-207 also shows potent antiproliferative effects in patient-derived cancer cells and in xenograft models. Its structure is:
  • the combination of an EGFR/ERBB2 inhibitor together with a BET inhibitor for use in a method of treatment described herein may be specific inhibitor combinations.
  • the combination of an EGFR/ERBB2 inhibitor together with a BET inhibitor for use in a method of treatment described herein may be wherein the EGFR/ERBB2 inhibitor is selected from afatinib, afatinib dimaleate, AL-6802, allitinib, almonertinib, aumolertinib mesylate, brigatinib, CP-724714, dacomitinib, epertinib, erlotinib, gefitinib, icotinib, icotinib hydrochloride, lapatinib, lapatinib ditosylate, neratinib, olmutinib, olmutinib hydrochloride, osimertinib, osimertinib mesylate, pyrotinib, sapitinib, tesevatinib, tesevatinib
  • the combination of an EGFR/ERBB2 inhibitor together with a BET inhibitor for use in a method of treatment described herein may be wherein the EGFR/ERBB2 inhibitor is selected from afatinib dimaleate, AL-6802, allitinib, almonertinib, aumolertinib mesylate, brigatinib, CP-724714, dacomitinib, epertinib, erlotinib, gefitinib, icotinib hydrochloride, lapatinib ditosylate, neratinib, olmutinib hydrochloride, osimertinib mesylate, pyrotinib, sapitinib, tesevatinib tosylate, vandetanib, varlitinib, amivantamab, cetuximab, inetetamab, necitumumab, n
  • the combination of an EGFR/ERBB2 inhibitor together with a BET inhibitor for use in a method of treatment described herein may be wherein the EGFR/ERBB2 inhibitor is selected from afatinib, AL-6802, allitinib, almonertinib, brigatinib, CP-724714, dacomitinib, epertinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, olmutinib, osimertinib, pyrotinib, tesevatinib, sapitinib, vandetanib, varlitinib, trastuzumab, and cetuximab; and wherein the BET inhibitor is selected from ABBV-744, alobresib, apabetalone, birabresib, mivebresib, molibresib
  • the combination of an EGFR/ERBB2 inhibitor together with a BET inhibitor for use in a method of treatment described herein may be wherein the EGFR/ERBB2 inhibitor is selected from afatinib, allitinib, almonertinib, dacomitinib, epertinib, erlotinib, lapatinib, tesevatinib, vandetanib; and wherein the BET inhibitor is selected from birabresib, NHWD-870, trotabresib, alobresib, mivebresib, and ODM-207.
  • the combination may be selected from: afatinib and ABBV-744; afatinib and alobresib; afatinib and apabetalone; afatinib and birabresib; afatinib and mivebresib; afatinib and molibresib afatinib and NHWD-870; afatinib and ODM-207; afatinib and trotabresib; afatinib dimaleate and ABBV-744; afatinib dimaleate and alobresib; afatinib dimaleate and apabetalone; afatinib dimaleate and birabresib; afatinib dimaleate and mivebresib; afatinib dimaleate and molibresib afatinib dimaleate and NHWD-870; afatinib dimaleate and
  • AL-6802 and ABBV-744 AL-6802 and alobresib; AL-6802 and apabetalone; AL-6802 and birabresib; AL- 6802 and mivebresib; AL-6802 and molibresib; AL-6802 and NHWD-870; AL-6802 and ODM-207; AL- 6802 and trotabresib; allitinib and ABBV-744; alliti nib and alobresib; allitinib and apabetalone; allitinib and birabresib; alliti nib and mivebresib; allitinib and molibresib; allitinib and NHWD-870; allitinib and ODM-207; allitinib and trotabresib; almonertinib and ABBV-744; almonertinib and alobresib; almonertinib and
  • CP-724714 and ABBV-744 CP-724714 and alobresib; CP-724714 and apabetalone; CP-724714 and birabresib; CP-724714 and mivebresib; CP-724714 and molibresib; CP-724714 and NHWD-870; CP- 724714 and ODM-207; CP-724714 and trotabresib; dacomitinib and ABBV-744; dacomitinib and alobresib; dacomitinib and apabetalone; dacomitinib and birabresib; dacomitinib and mivebresib; dacomitinib and molibresib; dacomitinib and NHWD-870; dacomitinib and ODM-207; dacomitinib and trotabresib; epertinib and ABBV
  • the combination may be selected from: afatinib and birabresib; afatinib and NHWD-870; afatinib and trotabresib; afatinib and alobresib; afatinib and mivebresib; afatinib and ODM-207; allitinib and birabresib; allitinib and NHWD-870; allitinib and trotabresib; allitinib and alobresib; allitinib and mivebresib; allitinib and ODM-207; almonertinib and birabresib; almonertinib and NHWD-870; almonertinib and trotabresib; almonertinib and alobresib; almonertinib and mivebresib; almonertinib and mivebre
  • the combination may be selected from: afatinib and alobresib; afatinib and trotabresib; afatinib and mivebresib; afatinib and ABBV-744; afatinib and ODM-207; afatinib and molibresib; afatinib and NHWD-870; afatinib and birabresib; afatinib and apabetalone; afatinib and BAY1238097; afatinib and ZL- 0580; erlotinib and alobresib; lapatinib and alobresib; dacomitinib and alobresib; sapitinib and alobresib; gefitinib and alobresib; vandetanib and alobresib; icotinib and a
  • the combination may be selected from: afatinib and alobresib; afatinib and trotabresib; afatinib and mivebresib; afatinib and ODM-207; afatinib and NHWD-870; afatinib and birabresib; erlotinib and alobresib; lapatinib and alobresib; dacomitinib and alobresib; icotinib and alobresib; AL-6802 and alobresib; allitinib and alobresib; almonertinib and alobresib; brigatinib and alobresib; CP-724714 and alobresib; epertinib and alobresib; neratinib and alobresi
  • the combination may be selected from: afatinib and alobresib; afatinib and trotabresib; afatinib and mivebresib; afatinib and ODM-207; afatinib and NHWD-870; afatinib and birabresib; erlotinib and alobresib; erlotinib and trotabresib; erlotinib and mivebresib; erlotinib and ODM-207; erlotinib and NHWD-870; erlotinib and birabresib; dacomitinib and alobresib; dacomitinib and trotabresib; dacomitinib and mivebresib; dacomitinib and ODM-207; dacomitinib and NHWD-870; and dacomitinib and birabres
  • the combination may be selected from: afatinib and alobresib; afatinib and trotabresib; afatinib and mivebresib; afatinib and ODM-207; afatinib and NHWD-870; afatinib and birabresib; erlotinib and alobresib; lapatinib and alobresib; and dacomitinib and alobresib.
  • the combination may be selected from: afatinib and alobresib; erlotinib and alobresib; afatinib and trotabresib; and afatinib and mivebresib.
  • any compound for example, an EGFR/ERBB2 inhibitor or a BET inhibitor
  • a pharmaceutically acceptable salt for example, an EGFR/ERBB2 inhibitor or a BET inhibitor
  • Suitable pharmaceutically acceptable salts are known in the art and are described in, for example, in Berge et al., J Pharm Sci, 1977, 66(1), p1.
  • any EGFR/ERBB2 inhibitor or BET inhibitor described herein may be provided as a pharmaceutically acceptable salt, such as a dimaleate salt, a mesylate salt, a hydrochloride salt, a ditosylate salt, or a tosylate salt.
  • the pharmaceutically acceptable salts may also be a hydrate or solvate thereof. Any reference to an EGFR/ERBB2 inhibitor or a BET inhibitor encompasses their pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • afatinib may be provided as the dimaleate salt (that is, afatinib dimaleate).
  • Almonertinib (aumolertinib) may be provided as the mesylate salt (that is, aumolertinib mesylate).
  • Icotinib may be provided as the hydrochloride salt (that is, icotinib hydrochloride).
  • Lapatinib may be provided as the distosylate salt (that is, lapatinib ditosylate).
  • Olmutinib may be provided as the hydrochloride salt (that is, olmutinib hydrochloride).
  • Osimertinib may be provided as the mesylate salt (that is, osimertinib mesylate).
  • Tesevatinib may be provided as the tosylate salt (that is, tesevatinib tosylate).
  • Compounds used in the methods of the invention may be administered by any suitable route, including oral and intravenous routes. It will be understood that oral administration may be preferred.
  • the compounds may be provided in pharmaceutical compositions comprising the compound and one or more pharmaceutically acceptable excipients.
  • Formulation for oral administration may be in the form of a tablet or a capsule comprising a powder or liquid.
  • small molecules that is, compounds with a low molecular weight ( ⁇ 1000 daltons) - for example, afatinib or alobresib
  • Antibodies may be administered intravenously.
  • Administration is preferably in a “therapeutically effective amount” or an “effective amount” (used interchangeably), this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s Pharmaceutical Sciences, 20 th Edition, 2000, pub. Lippincott, Williams & Wilkins.
  • afatinib an EGFR/ERBB2 inhibitor
  • afatinib an EGFR/ERBB2 inhibitor
  • 20 mg, 30 mg, and 40 mg tablets with the recommended daily dose being 40 mg.
  • Alobresib a BET inhibitor
  • the active ingredients described herein may be administered in dosages of about 0.1 mg to about 1000 mg, such as about 0.1 mg to about 500 mg, such as about 0.1 mg to about 100 mg.
  • the EGFR/ERBB2 inhibitor may be administered in a dosage of about 1 mg to about 1000 mg, such as about 5 mg to about 500 mg, such as about 10 mg to about 100 mg.
  • the BET inhibitor may be administered in a dosage of about 0.1 mg to about 100 mg, such as about 0.1 mg to about 50 mg, such as about 0.1 mg to about 10 mg.
  • the active ingredients described herein may be administered orally, parenterally, or intravenously. In some embodiments, the active ingredients described herein may be administered orally or parenterally. In some embodiments, the active ingredients described herein may be administered orally. In some embodiments, the active ingredients described herein may be administered parenterally. In some embodiments, the active ingredients described herein may be administered intravenously. Each active ingredient may be administered via a different route of administration to the other active ingredient.
  • the active ingredients described herein may be administered simultaneously, separately or sequentially/consecutively, or at different times within a prescribed dosing cycle.
  • the active ingredients described herein may be administered daily, such as once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID), or on a less frequent or intermittent schedule.
  • the patient or subject may be a human patient or subject.
  • “Patient” and “subject” are used interchangeably throughout.
  • Stomach cancer also known as gastric cancer, is when abnormal cells in the stomach start to grow and divide in an uncontrolled way. This cancer usually starts in the cells lining the stomach.
  • the stomach is part of the digestive system. It is in the upper left side of the abdomen.
  • the top of the stomach joins the bottom of the oesophagus and the other end is joined to the bowel.
  • It is a muscular bag that has three main parts. They are the top (fundus), middle (body), and bottom (antrum or pylorus).
  • valves At each end of the stomach there is a valve called a sphincter. These valves control the movement of food through the digestive system.
  • the valves are the cardiac sphincter (at the top joining the oesophagus to the stomach) and the pyloric sphincter (at the bottom joining the stomach to the bowel).
  • the stomach wall is made up of a number of layers: the outer lining, the muscle layer, the supportive tissue, and the inner lining.
  • Stomach (gastric) cancer can start in any part of the stomach wall.
  • stomach cancers start in the gland cells in the inner stomach lining. These are called adenocarcinomas. Some stomach cancers can start in the cells that help food move through the digestive system. These are called gastrointestinal stromal tumours (GIST) and are a type of soft tissue sarcoma. Stomach neuroendocrine tumours (NETs) start in the hormone cells in the stomach.
  • GIST gastrointestinal stromal tumours
  • NETs Stomach neuroendocrine tumours
  • the invention relates to methods for the treatment of cancer in patients, and in particular the treatment of stomach (gastric) cancer.
  • the cancer is gastric cancer.
  • the invention relates to a combination of an EGFR/ERBB2 inhibitor and a BET inhibitor for use in a method of treatment of gastric cancer in a patient.
  • the invention also relates to use of an EGFR/ERBB2 inhibitor for use in a method of treatment of gastric cancer in a patient, wherein the EGFR/ERBB2 inhibitor is administered to a patient in combination with a BET inhibitor.
  • the invention also relates to use of a BET inhibitor for use in a method of treatment of gastric cancer in a patient, wherein the BET inhibitor is administered to a patient in combination with an EGFR/ERBB2 inhibitor.
  • the invention also relates to a method of treatment of gastric cancer, wherein the method comprises the step of administering a therapeutically effective amount of a combination of an EGFR/ERBB2 inhibitor and a BET inhibitor to a patient in need thereof.
  • the invention also relates to a method of treatment of gastric cancer, wherein the method comprises the step of administering a therapeutically effective amount of an EGFR/ERBB2 inhibitor to a patient in need thereof, wherein the EGFR/ERBB2 inhibitor is administered to the patient in combination with a BET inhibitor.
  • the invention also relates to a method of treatment of gastric cancer, wherein the method comprises the step of administering a therapeutically effective amount of a BET inhibitor to a patient in need thereof, wherein the BET inhibitor is administered to the patient in combination with an EGFR/ERBB2 inhibitor.
  • the invention also relates to the use of a combination of an EGFR/ERBB2 inhibitor and a BET inhibitor for the manufacture of a medicament for the treatment of gastric cancer in a patient.
  • the invention also relates to the use of an EGFR/ERBB2 inhibitor for the manufacture of a medicament for the treatment of gastric cancer in a patient, wherein the EGFR/ERBB2 inhibitor is administered to a patient in combination with a BET inhibitor.
  • the invention also relates to the use of a BET inhibitor for the manufacture of a medicament for the treatment of gastric cancer in a patient, wherein the BET inhibitor is administered to a patient in combination with an EGFR/ERBB2 inhibitor.
  • the gastric cancer may be a KMT2B mutant gastric cancer.
  • the KMT2B (Lysine Methyltransferase 2B) gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain.
  • the SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues and is also amplified in solid tumor cell lines and may be involved in human cancer. Two alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene.
  • Histone methyltransferase catalyse the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the Lysine 4 of histone H3 (H3K4) to generate H3K4Me2 and H3K4Me3.
  • SAM S-adenosyl-L-methionine
  • H3K4Me3 histone H3
  • KMT2B fulfils this function as part of the COMPASS (Complex Proteins Associated with Set1) chromatin remodelling complex to mark active chromatin sites where transcription and DNA repair take place.
  • KMT2 genes There are multiple KMT2 genes, namely KMT2A, KMT2C, KMT2D, KMT2F and KMT2G, all of which are defined by the presence of the C-terminal SET domain. Only KMT2A and KMT2B complex with the same partner proteins while KMT2C, KMT2D, KMT2F and KMT2G have different complex partners (Poreba et al., Int. J. Mol. Sci., 2020, 21 , p9340).
  • the KMT2B gene is the gene identified by Gene ID: 9757 (https://www.ncbi.nlm.nih.gov/gene/9757) in the GenBank.
  • the nucleic acid sequence (5'-3') of the wild-type KMT2B gene is SEQ ID NO: 1 : GCTGTCTGGGCTCTTACCTGTGGGCCGCCCCGCCGGGCCTCGCAACCTCCTGGTTTCTCCAGGG CCCCAGTTTCTCTTGGCATCTCAGGTAGAGTGGTGGAGGGCTTCCTCTTGGGGCTCGGGTTGAAC AGG AGTGG G ATG AAG GCCG G G ACTG GG CACTCTAG CAG GTCAG AG CTC AG CTCAG G ATTTCTCC CCCAGCCTTTCAGAACAGGCAGGAAGGTGTGGGTTGCGTTGCCCTGGACGGTTAATAACAACCT GAGAGCTCGCAGTGGAGCCTGTACGAAAGCCATCTGATGCCCTCCGCCCCTTCACTTGCGGG CCCC
  • the main transcript sequence (5'-3') of the wild-type KMT2B gene is SEQ ID NO: 2: agtgtgacaaaatagaggctcggaagatggaacgactggctaaaaaggccggacgatagtgaagacgctgttgccctgggattccgatga atctcctgaggcctccctggtcctccaggcccacgccggggggcgggagctggggggggcccgggaggaggtggtggcccacccagggcc cgaggagcaggactccctctgcagcgcaagtcagctcggcgctgcgtcaaacagcgaccctcctatgatatcttcgaggattcggatgactcg gagcccgggggccccctgctgctgctg
  • the corresponding KMT2B protein encoded by the wild-type KMT2B gene is identified by UniProt ID
  • KMT2B protein is SEQ ID NO: 3:
  • the inventors have observed that mutations in KMT2B in gastric cancer cell lines sensitises the cancer cells to the combination of an EGFR/ERBB2 inhibitor and a BET inhibitor as compared to KMT2B wildtype gastric cancer cells. That is, the gastric cancer is preferably a KMT2B mutant gastric cancer. Preferably, the KMT2B mutant gastric cancer is a cancer driver mutation.
  • a cancer driver mutation is a mutation that provides a selective growth advantage, and thus promotes cancer development. Cancer driver mutations can be: (i) proto-oncogenes, which requires a gain-of-function mutation to become tumorigenic; or (ii) tumour suppressor genes, which require inactivation of both alleles to become tumorigenic.
  • the cancer driver mutations may overlap the genomic coordinates of a mutation with the same effect in the library of mutations.
  • the mutation may be: missense (a mutation that changes the coded amino acid), nonsense (a mutation that causes a shift in the reading frame or the formation of a premature stop codon which forms a truncated protein upon translation), inframe (a mutation occurring within the protein-coding region of a gene which results in a retention of the reading frame such that the protein production machinery can continue to read the DNA sequence after the mutation), or silent (a mutation that has no effect on the coded amino acid sequence).
  • the cancer driver mutation may be in a LoF (loss-of-fu notion) or an ambiguous gene (that is, a gene with evidence of both activating and loss-of-function events), and the mutation has a loss of function effect.
  • the mutation may be: frameshift (an insertion or deletion of nucleotide bases in numbers that are not multiples of three), nonsense (a mutation that causes a protein to terminate or end its translation earlier than expected), ess_splice (exonic splicing silencer), start ost (a mutation that affects the initiation codon), or stopjost (a mutation that affects the final codon).
  • the cancer driver mutation does not need to result in the total loss of the production of the coded protein, such as the KMT2B protein.
  • the KMT2B mutation in the KMT2B mutant gastric cancer is a cancer driver mutation.
  • the KMT2B mutation in the KMT2B mutant gastric cancer comprises a nonsense, frameshift, or truncating mutation.
  • the KMT2B mutation in the KMT2B mutant gastric cancer results in a loss of KMT2B protein. Loss is defined as a complete or partial lack of KMT2B protein and/or a lack of functional KMT2B protein.
  • the KMT2B mutation in the KMT2B mutant gastric cancer results in a complete loss of KMT2B protein or a partial loss of KMT2B protein.
  • the KMT2B mutation in the KMT2B mutant gastric cancer results in no production of the KMT2B protein (that is, the KMT2B protein is not produced), or results in substantially no KMT2B production.
  • the method of treatment comprises a step of determining the patient’s KMT2B mutational status.
  • CellModelPassports https://cellmodelpassports.sanger.ac.uk/; see also Van der Meer etal., Nucleic Acids Research, 2019, Volume 47, Issue D1 , pD923-D929) to identify and determine the mutation status of cancer cell lines.
  • CellModelPassports uses the OncodriveFML methodology (Mularoni etal., Genome Biol, 2016, 17, 128, https://doi.org/10.1186/s13059-016-0994-0) to identify the mutational status of various cancer cell lines described in the database.
  • OncodriveFML methodology can be used to identify the mutational status of other cancer cell lines, such as identifying the KMT2B mutational status of such cancer cell lines.
  • the inventors have identified 5 frameshift and nonsense mutations in the KMT2B gene in sensitive gastric cancer cell lines tested:
  • the KMT2B mutation in the KMT2B mutant gastric cancer comprises a mutation selected from: p.T176fs*8, p.W336*, p.R2587*, p.V314fs*20, and p.Q2150fs*.
  • KMT2B truncating and T176Dfs*8 (KMT2B frameshift) mutations above were also identified by the inventors in the sensitive gastric cancer cell lines tested. These KMT2B frameshift and truncating mutations may also be cancer driver mutations that sensitise the gastric cancer to the combinations described herein.
  • a patient For a patient to be eligible for treatment with a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), a patient would first need to receive a clinical diagnosis of gastric cancer.
  • a patient would also need to undergo diagnostic testing to determine the mutational status of KMT2B in a suitable tumor sample, which may include a tissue biopsy, liquid biopsy, or other suitable biological sample.
  • the mutational status of KMT2B may be confirmed via any approved companion diagnostic test that is able to analyse variations in the sequence, structure, or expression of human nucleic acids. Examples of such nucleic-acid-based tests include but are not limited to: Foundation Medicine’s FoundationOne® CDx and FoundationOneOLiquid CDx, Guardant Health’s Guardant360® TissueNext and Guardant360® CDx, and Illumina’s TruSight Oncology Comprehensive.
  • the method comprises the step of selecting a subject having or determined to have KMT2B mutant gastric cancer for treatment with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising determining the mutational status of KMT2B gene in the gastric cancer and selecting the subject for treatment if the KMT2B gene is a KMT2B mutant, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the method comprises the step of selecting a subject having or determined to have KMT2B mutant gastric cancer for treatment with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising determining the mutational status of KMT2B gene in the gastric cancer and selecting the subject for treatment if the KMT2B gene is a KMT2B mutant, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • Also provided herein is a method of predicting whether a subject having gastric cancer is likely to respond to treatment with a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising determining the mutational status of KMT2B gene in the gastric cancer and selecting the subject for treatment if the KMT2B gene is a KMT2B mutant.
  • Also described herein is a method for identifying a subject with KMT2B mutant gastric cancer who is likely to respond to treatment with a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising obtaining a biopsy sample from the subject and determining the mutational status of KMT2B gene in the gastric cancer in said biopsy sample, wherein the subject is likely to respond to treatment with a combination of an EGFR/ERBB2 inhibitor and a BET inhibitor if the KMT2B gene is a KMT2B mutant.
  • Also described herein is a method for identifying a subject with KMT2B mutant gastric cancer who is likely to respond to treatment with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising obtaining a biopsy sample from the subject and determining the mutational status of KMT2B gene in the gastric cancer in said biopsy sample, wherein the subject is likely to respond to treatment with the EGFR/ERBB2 inhibitor, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • Also described herein is a method for identifying a subject with KMT2B mutant gastric cancer who is likely to respond to treatment with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof), the method comprising obtaining a biopsy sample from the subject and determining the mutational status of KMT2B gene in the gastric cancer in said biopsy sample, wherein the subject is likely to respond to treatment with the BET inhibitor, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • Also provided herein is a method of treating or preventing gastric cancer in a subject in whom the gastric cancer is KMT2B mutant gastric cancer, wherein the method comprises administering a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject.
  • an EGFR/ERBB2 inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • BET inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • Also provided herein is a method of treating or preventing gastric cancer in a subject in whom the gastric cancer is KMT2B mutant gastric cancer, wherein the method comprises administering an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • an EGFR/ERBB2 inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • Also provided herein is a method of treating or preventing gastric cancer in a subject in whom the gastric cancer is KMT2B mutant gastric cancer, wherein the method comprises administering a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • a BET inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • Also provided herein is a method of treating or preventing KMT2B mutant gastric cancer in a subject, wherein the method comprises: determining the mutational status of KMT2B gene in the gastric cancer and administering a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to a subject having or determined to have KMT2B mutant gastric cancer.
  • Also provided herein is a method of treating or preventing KMT2B mutant gastric cancer in a subject, wherein the method comprises: determining the mutational status of KMT2B gene in the gastric cancer and administering an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to a subject having or determined to have KMT2B mutant gastric cancer, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • Also provided herein is a method of treating or preventing KMT2B mutant gastric cancer in a subject, wherein the method comprises: determining the mutational status of KMT2B gene in the gastric cancer and administering a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to a subject having or determined to have KMT2B mutant gastric cancer, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • a BET inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • Also provided herein is a method of treating or preventing gastric cancer in a subject, the method comprising administering a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject, wherein the subject has been selected for treatment with a combination of an EGFR/ERBB2 inhibitor and a BET inhibitor on the basis of whether the gastric cancer is KMT2B mutant gastric cancer.
  • Also provided herein is a method of treating or preventing gastric cancer in a subject, the method comprising administering an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject, wherein the subject has been selected for treatment with an EGFR/ERBB2 inhibitor on the basis of whether the gastric cancer is KMT2B mutant gastric cancer, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • an EGFR/ERBB2 inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • a method of treating or preventing gastric cancer in a subject comprising administering a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject, wherein the subject has been selected for treatment with a BET inhibitor on the basis of whether the gastric cancer is KMT2B mutant gastric cancer, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • Also described herein is a method of identifying and treating a subject suitable for treatment of KMT2B mutant gastric cancer, the method comprising: a) obtaining a biopsy sample from the subject; b) determining the mutational status of KMT2B gene in the gastric cancer in said biopsy sample; c) identifying the subject as being suitable for treatment of KMT2B mutant gastric cancer when the KMT2B gene is a KMT2B mutant; and d) administering an effective amount of a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject.
  • an EGFR/ERBB2 inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • BET inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • Also described herein is a method of identifying and treating a subject suitable for treatment of KMT2B mutant gastric cancer, the method comprising: a) obtaining a biopsy sample from the subject; b) determining the mutational status of KMT2B gene in the gastric cancer in said biopsy sample; c) identifying the subject as being suitable for treatment of KMT2B mutant gastric cancer when the KMT2B gene is a KMT2B mutant; and d) administering an effective amount of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • an EGFR/ERBB2 inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • Also described herein is a method of identifying and treating a subject suitable for treatment of KMT2B mutant gastric cancer, the method comprising: a) obtaining a biopsy sample from the subject; b) determining the mutational status of KMT2B gene in the gastric cancer in said biopsy sample; c) identifying the subject as being suitable for treatment of KMT2B mutant gastric cancer when the KMT2B gene is a KMT2B mutant; and d) administering an effective amount of a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) to the subject, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • a BET inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • Also described herein is a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for use in a method of treating or preventing gastric cancer in a subject having or determined to have KMT2B mutant gastric cancer in a biopsy sample compared to a KMT2B wild-type gastric cancer.
  • an EGFR/ERBB2 inhibitor for use in a method of treating or preventing gastric cancer in a subject having or determined to have KMT2B mutant gastric cancer in a biopsy sample compared to a KMT2B wild-type gastric cancer, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • a BET inhibitor for use in a method of treating or preventing gastric cancer in a subject having or determined to have KMT2B mutant gastric cancer in a biopsy sample compared to a KMT2B wild-type gastric cancer, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • Also provided herein is a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for use in a method of treating or preventing KMT2B mutant gastric cancer in a subject, the method comprising: determining the mutational status of KMT2B gene in the gastric cancer.
  • an EGFR/ERBB2 inhibitor for use in a method of treating or preventing KMT2B mutant gastric cancer in a subject, the method comprising: determining the mutational status of KMT2B gene in the gastric cancer, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • a BET inhibitor for use in a method of treating or preventing KMT2B mutant gastric cancer in a subject, the method comprising: determining the mutational status of KMT2B gene in the gastric cancer, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • Also provided herein is a combination of an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) and a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof) for use in a method of treating or preventing KMT2B mutant gastric cancer, the method comprising administering the combination of an EGFR/ERBB2 inhibitor and a BET inhibitor to a subject having or determined to have KMT2B mutant gastric cancer.
  • an EGFR/ERBB2 inhibitor for use in a method of treating or preventing KMT2B mutant gastric cancer, the method comprising administering the EGFR/ERBB2 inhibitor to a subject having or determined to have KMT2B mutant gastric cancer, wherein the EGFR/ERBB2 inhibitor is administered to the subject in combination with a BET inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • a BET inhibitor for use in a method of treating or preventing KMT2B mutant gastric cancer, the method comprising administering the BET inhibitor to a subject having or determined to have KMT2B mutant gastric cancer, wherein the BET inhibitor is administered to the subject in combination with an EGFR/ERBB2 inhibitor (or a pharmaceutically acceptable salt, hydrate, or solvate thereof).
  • the inventors compared the observed combination response of cells to the Bliss independence-predicted response based on monotherapy activity, and classified drug combinations based on shifts beyond Bliss independence (Bliss, Annals of Applied Biology, 1939, 26(3), p585-615).
  • Two key synergy metrics were used: Iog2 AIC50, (an indication of increased sensitivity) and AEmax, (an indication of reduced cell viability).
  • Iog2 AIC50 an indication of increased sensitivity
  • AEmax an indication of reduced cell viability
  • the combination-cell line pairs were classified as synergistic if, at any anchor concentration, combination IC50 or Emax was reduced 8-fold (a Iog2 AIC50 of 3) or 20% over Bliss, respectively.
  • Synergistic combinations were identified as those with 3 or more synergistic cell lines and a statistically significant difference between biomarker positive and biomarker negative populations.
  • Afatinib or Erlotinib were screened in combination with Alobresib (BET inhibitor) in 26 gastric cancer cell lines.
  • BET inhibitor Alobresib
  • To screen efficiently we used a 3x7 concentration matrix, or “anchored” approach.
  • the inventors screened each anchor compound at three optimised concentrations and a discontinuous 1 ,000-fold (7-point) dose-response curve of the library compound. Viability was read out after 72 h of drug treatment using CellTiter-Glo and drug responses for single agent and combination responses were fitted.
  • Single-agent and combination viability measurements were fitted per cell line and multiple parameters derived including: 1) anchor viability effect, 2) library and combination viability effect at the highest-used library concentration (library Emax and combo Emax), and 3) the estimated library drug concentration producing a 50% viability reduction (IC50) for the library and combination.
  • Afatinib + Alobresib was screened in 6 gastric cancer cell lines (NUGC-4, SNU-5, SNU-16, IM95, KATOIII, NUGC-3). For verification screening we used a larger 8x8 concentration matrix. The inventors screened each compound combination at a discontinuous 1 ,000-fold (7-point) dose-response curve.
  • Viability was read out after 72 h of drug treatment using CellTiter-Glo and drug responses for single agent and combination responses were fitted. Single-agent and combination viability measurements were fitted per cell line and multiple parameters derived including: 1) anchor viability effect, 2) library and combination viability effect at the highest-used library concentration (library Emax and combo Emax), and 3) the estimated library drug concentration producing a 50% viability reduction (IC50) for the library and combination.
  • Additional EGFR/ERBB2 inhibitors were screened in combination with BET inhibitors in 4 gastric cancer cell lines (SNU-16, IM95, KATOIII, NUGC-3) in Figures 4-12 and 6 gastric cancer cell lines (SNU-16, NUGC-4, SNU-5, IM95, KATOIII, NUGC-3) in Figures 13-15.
  • the additional EGFR/ERBB2 inhibitors are Erlotinib, Lapatinib, Dacomitinib, Allitinib, and Almonertinib; and the additional BET inhibitors are Trotabresib, Mivebresib, ODM-207, NHWD-870, and Birabresib.
  • For verification screening we used a larger 8x8 concentration matrix.
  • a shift in potency (log2AIC5o) and in efficacy (AEmax(%)) is observed in KMT2B mutant cell lines compared with KMT2B wild-type cells (see Figures 4-12).
  • a shift in potency (log2AIC5o) and in efficacy (AEmax(%)) is observed in KMT2B mutant cell lines compared with KMT2B wild-type cells (see Figures 13-15).
  • Sensitivity towards the combinations of EGFR/ERBB2 and BET inhibitors correlates with KMT2B mul and absence of KMT2B protein.
  • the inventors observe synergistic activity of a combination of EGFR/ERBB2 and BET inhibitors in gastric cancer cell lines). Furthermore, an increased sensitivity (drug-drug synergy) of gastric cancer cells harbouring deleterious mutations in the KMT2B gene to the combined treatment with EGFR/ERBB2 and BET inhibitors was observed in contrast to gastric cancer cells without KMT2B mutations (see Examples 1-3).
  • the inventors observe sensitisation in KMT2B mutant gastric cancer cells to the combination of an EGFR/ERBB2 inhibitor and a BET inhibitor.
  • the use of the combinations described herein may be useful in the treatment of gastric cancer, such as KMT2B mutant gastric cancer, in patients, which may provide better patient outcomes than treatment of the gastric cancer using either inhibitor alone.
  • the use of the combination may also be useful in the treatment of gastric cancer that exhibits resistance to either one of the EGFR/ERBB2 or BET inhibitors alone.
  • the combination may also reduce side effects in the patient as compared to use of either one of the EGFR/ERBB2 or BET inhibitors alone.

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Abstract

La présente invention concerne des polythérapies d'un inhibiteur d'EGFR/ERBB2 et d'un inhibiteur de BET, ou leurs sels, hydrates ou solvates pharmaceutiquement acceptables, et leur utilisation dans le traitement du cancer, en particulier du cancer gastrique, y compris le cancer gastrique mutant KMT2B. L'invention concerne également des méthodes de traitement et des procédés permettant de prévoir si un sujet atteint d'un cancer gastrique est susceptible de répondre à un traitement.
PCT/EP2025/063447 2024-05-17 2025-05-15 Combinaisons d'inhibiteurs d'egfr/erb et de bet pour le cancer de gastrique Pending WO2025238176A1 (fr)

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Citations (1)

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