Combination of ras inhibitor and PD-1 or PD-l1 inhibitor, and use thereof

Abstract

The present invention relates to a combination of a RAS inhibitor and a PD-1 / PD-L1 inhibitor, and a use thereof. Specifically, the present invention relates to a combination of a RAS inhibitor and a PD-1 / PD-L1 inhibitor, and a use thereof for treating tumors, wherein the RAS inhibitor is a compound 1 or a pharmaceutically acceptable salt thereof.

Description

Combinations and uses of RAS inhibitors and PD-1 or PD-L1 inhibitors

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese Patent Application No. 202411621009.4, filed on November 13, 2024; Chinese Patent Application No. 202511620840.2, filed on November 6, 2025; and U.S. Patent Application No. 63 / 721078, filed on November 15, 2024. The full text of the aforementioned two Chinese patent applications is incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of biomedicine and specifically relates to a combination of a RAS inhibitor and a PD-1 / PD-L1 inhibitor and their uses. Background Technology

[0004] Currently, cancer remains a major public health problem worldwide. With a deeper understanding of tumor biology, the biological characteristics of tumors are gradually being elucidated, such as acquiring proliferative signals, escaping the regulation of growth inhibitors, persistent activation of replication checkpoints, reprogramming cell metabolism, and activating invasion and metastasis. Targeting these biological characteristics of tumors, traditional chemotherapy, radiotherapy, and targeted drug therapy have achieved good clinical treatment results in various types of cancer.

[0005] Programmed death 1 (PD-1) is a transmembrane protein expressed on the surface of T cells, while programmed death-ligand 1 (PD-L1) is a ligand molecule of PD-1 expressed on the surface of tumor cells, APCs, and T cells. When PD-L1 binds to PD-1, it can reduce T cell responses by inhibiting downstream signaling pathways activated by the TCR. Antibodies targeting these immune checkpoints differ from traditional cancer treatments; instead, they work by enhancing the body's own immune system to kill tumor cells. Currently, antibodies targeting PD-1 and PD-L1, such as nivolumab, atezolizumab, pembrolizumab, durvalumab, and toripalimab, have shown promising results in the immunotherapy of various malignant tumors.

[0006] RAS (including KRAS, NRAS, and HRAS) are downstream of growth factor receptors such as EGFR. They are small GTPases that act as molecular switches, serving as key nodes in the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways, regulating events such as cell proliferation and survival. Mutations in RAS can disrupt GTP hydrolysis, leading to functional activation of the protein. Under normal physiological conditions, RAS typically exists in its inactive form (OFF) bound to GDP; however, in RAS-mutated tumor cells, it primarily exists in its activated form (ON) bound to GTP. Approximately 30% of cancer patients have RAS mutations, with KRAS mutations being the most common, including various types such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, and KRAS G13C. Because RAS mutations are a significant factor in cancer development and progression, mutant RAS has become an important therapeutic target for cancer. Patent publication numbers WO2024067857A1, WO2024153208A1, WO2024060966A1, and WO2024169914A1 disclose a series of RAS inhibitors with macrocyclic structures. Summary of the Invention

[0007] This disclosure aims to provide a combination of a RAS inhibitor and a PD-1 / PD-L1 inhibitor and its use.

[0008] This disclosure provides a pharmaceutical combination product comprising a RAS inhibitor and a PD-1 / PD-L1 inhibitor;

[0009] The RAS inhibitor is either compound 1 or compound 2, or a pharmaceutically acceptable salt thereof;

[0010] In some implementations, the drug combination product includes:

[0011] (i) a first pharmaceutical composition comprising the RAS inhibitor; and

[0012] (ii) A second pharmaceutical composition comprising the PD-1 / PD-L1 inhibitor.

[0013] This disclosure also provides the use of the above-described pharmaceutical combination product in the preparation of a medicament for treating tumors.

[0014] This disclosure also provides the use of a combination of a RAS inhibitor and a PD-1 / PD-L1 inhibitor in the preparation of a medicament for treating tumors, wherein the RAS inhibitor is as defined herein.

[0015] This disclosure also provides the use of a RAS inhibitor in the preparation of a medicament for the treatment of tumors in combination with a PD-1 / PD-L1 inhibitor, wherein the RAS inhibitor is as defined herein.

[0016] This disclosure also provides the use of a PD-1 / PD-L1 inhibitor in the preparation of a medicament for the treatment of tumors in combination with a RAS inhibitor, wherein the RAS inhibitor is as defined herein.

[0017] This disclosure also provides a method for treating a tumor in a subject, the method comprising administering to the subject a therapeutically effective amount of a RAS inhibitor and a PD-1 / PD-L1 inhibitor, wherein the RAS inhibitor is as defined herein.

[0018] This disclosure also provides a method for inhibiting tumor cell growth under in vitro, in vivo, or ex vivo conditions, comprising contacting the tumor cells with a therapeutically effective amount of a RAS inhibitor and a PD-1 / PD-L1 inhibitor.

[0019] This disclosure also provides a pharmaceutical combination product or kit, comprising:

[0020] (i) a pharmaceutical composition comprising a RAS inhibitor, wherein the RAS inhibitor is as defined herein; and

[0021] (ii) Instructions for the combined use of the RAS inhibitor with PD-1 / PD-L1 inhibitors and optional other oncology agents.

[0022] This disclosure also provides a pharmaceutical combination product or kit, comprising:

[0023] (i) a pharmaceutical composition comprising a RAS inhibitor, wherein the RAS inhibitor is as defined herein; and

[0024] (ii) Instructions for using the RAS inhibitor in combination with a PD-1 / PD-L1 inhibitor.

[0025] In some embodiments, the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof;

[0026] In some embodiments, the RAS inhibitor is compound 2 or a pharmaceutically acceptable salt thereof;

[0027] In some embodiments, the PD-1 / PD-L1 inhibitor is a PD-1 / PD-L1 antibody or its antigen-binding fragment. In some embodiments, the PD-1 / PD-L1 antibody is a PD-1 antibody, such as a PD-1 monospecific antibody. In some embodiments, the PD-1 / PD-L1 antibody is a PD-L1 antibody, such as a PD-L1 monospecific antibody. In some embodiments, the PD-1 / PD-L1 antibody is a PD-1 and VEGF bispecific antibody. In some embodiments, the PD-1 / PD-L1 antibody is camrelizumab, pembrolizumab, adebrelimab, toripalimab, tislelizumab, sintilimab, penpulimab, catonililimab, Ivonescimab, serplulimab, pucotenlimab, zimberelimab, nivolumab, bemmelstobart, sugemalimab, or socazolimab. Envafolimab, Atezolizumab, Durvalumab, Geptanolimab, Lipustobart, Cemiplimab, Prolgolimab, Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, Iparomlimab, Spartalizumab, Retifanlimab, Sasanlimab, Rulonilimab, Enlonstobart, or Avelumab.

[0028] In some embodiments, the PD-1 / PD-L1 inhibitor is camrelizumab or its antigen-binding fragment.

[0029] In some embodiments, the PD-1 / PD-L1 inhibitor is pembrolizumab or its antigen-binding fragment.

[0030] In some embodiments, the PD-1 / PD-L1 inhibitor is adebelimab or its antigen-binding fragment.

[0031] In some embodiments, the PD-1 / PD-L1 inhibitor is toripalimab or its antigen-binding fragment.

[0032] In some embodiments, the PD-1 / PD-L1 inhibitor is tislelizumab or its antigen-binding fragment.

[0033] In some embodiments, the PD-1 / PD-L1 inhibitor is sintilimab or its antigen-binding fragment.

[0034] In some embodiments, the PD-1 / PD-L1 inhibitor is penaplimab or its antigen-binding fragment.

[0035] In some embodiments, the PD-1 / PD-L1 inhibitor is cantulimumab or its antigen-binding fragment.

[0036] In some embodiments, the PD-1 / PD-L1 inhibitor is evosimib or its antigen-binding fragment.

[0037] In some embodiments, the PD-1 / PD-L1 inhibitor is slulimab or its antigen-binding fragment.

[0038] In some embodiments, the PD-1 / PD-L1 inhibitor is putelimab or its antigen-binding fragment.

[0039] In some embodiments, the PD-1 / PD-L1 inhibitor is serpalimab or its antigen-binding fragment.

[0040] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab or its antigen-binding fragment.

[0041] In some embodiments, the PD-1 / PD-L1 inhibitor is bemosubalimab or its antigen-binding fragment.

[0042] In some embodiments, the PD-1 / PD-L1 inhibitor is sugemalimab or its antigen-binding fragment.

[0043] In some embodiments, the PD-1 / PD-L1 inhibitor is socalzolimab or its antigen-binding fragment.

[0044] In some embodiments, the PD-1 / PD-L1 inhibitor is envorimab or its antigen-binding fragment.

[0045] In some embodiments, the PD-1 / PD-L1 inhibitor is atezolizumab or its antigen-binding fragment.

[0046] In some embodiments, the PD-1 / PD-L1 inhibitor is durvalumab or its antigen-binding fragment.

[0047] In some embodiments, the combination or pharmaceutical combination product further comprises one or more additional oncology therapeutic agents. In some embodiments, the one or more additional oncology therapeutic agents may be one or more chemotherapy drugs and optionally, adjuvant chemotherapy drugs. In some embodiments, the one or more additional oncology therapeutic agents are pemetrexed and platinum-based chemotherapy drugs (e.g., cisplatin or carboplatin). In some embodiments, the one or more additional oncology therapeutic agents are pemetrexed and cisplatin. In some embodiments, the one or more additional oncology therapeutic agents are pemetrexed and carboplatin.

[0048] In some embodiments, the combination or pharmaceutical combination product is a combination or pharmaceutical combination product of the RAS inhibitor, the PD-1 / PD-L1 inhibitor, pemetrexed and platinum-based chemotherapy drugs (e.g., cisplatin or carboplatin).

[0049] In some embodiments, the combination or pharmaceutical combination product does not include other oncology therapeutics besides the RAS inhibitor and the PD-1 / PD-L1 inhibitor.

[0050] In some implementations, the tumor is a hematologic malignancy or a solid tumor.

[0051] In some implementations, the tumor is brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer (e.g., non-small cell lung cancer, including but not limited to lung adenocarcinoma, lung squamous cell carcinoma, lung large cell carcinoma, lung adenosquamous carcinoma, lung carcinoid; small cell lung cancer), liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colon cancer, rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, or bladder cancer. Anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia (e.g., acute myeloid leukemia, including but not limited to acute promyelocytic leukemia, acute monocytic leukemia, acute myelomonocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia; acute lymphoblastic leukemia, including but not limited to precursor B-cell acute lymphoblastic leukemia, precursor T-cell acute lymphoblastic leukemia, etc.). Acute lymphoblastic leukemia, Burkitt cell leukemia; chronic myeloid leukemia, including but not limited to chronic myeloid leukemia, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, and chronic neutrophilic leukemia; chronic lymphocytic leukemia; acute mixed cell leukemia); lymphoma (e.g., Hodgkin's lymphoma); B-cell lymphoma, including but not limited to diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and B-lymphoblastic lymphoma; T-cell lymphoma, including but not limited to peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and T-lymphoblastic lymphoma; NK-cell lymphoma); myeloma (e.g., multiple myeloma); skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma (e.g., neuroblastoma of the brain), glioblastoma, and neuroendocrine tumors, one or more of these.

[0052] In some implementations, the tumor is a solid tumor.

[0053] In some embodiments, the tumor is lung cancer. In some embodiments, the tumor is non-small cell lung cancer.

[0054] In some implementations, the tumor is colon cancer and / or rectal cancer (which may also be collectively referred to as colorectal cancer).

[0055] In some implementations, the tumor is pancreatic cancer.

[0056] In some implementations, the tumor is cholangiocarcinoma.

[0057] In some implementations, the tumor contains RAS mutations.

[0058] In some embodiments, the tumor contains one or a combination of two or more of the following: KRAS mutation, NRAS mutation, and HRAS mutation. In some embodiments, the tumor contains a KRAS mutation. In some embodiments, the tumor contains an NRAS mutation. In some embodiments, the tumor contains an HRAS mutation.

[0059] In some embodiments, the tumor contains one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H. In some embodiments, the tumor contains a KRAS G12A mutation. In some embodiments, the tumor contains a KRAS G12C mutation. In some embodiments, the tumor contains a KRAS G12D mutation. In some embodiments, the tumor contains a KRAS G12V mutation. In some embodiments, the tumor contains a KRAS G12R mutation. In some embodiments, the tumor contains a KRAS G12S mutation. In some embodiments, the tumor contains a KRAS G13C mutation. In some embodiments, the tumor contains a KRAS G13D mutation. The tumor contains a KRAS Q61R mutation. In some embodiments, the tumor contains a KRAS Q61K mutation. In some embodiments, the tumor contains a KRAS Q61H mutation. In some embodiments, the tumor contains an NRAS G12D mutation. In some embodiments, the tumor contains an NRAS Q61K mutation. In some embodiments, the tumor contains an NRAS Q61L mutation. In some embodiments, the tumor contains an HRAS Q61H mutation.

[0060] In some implementations, the tumor does not contain RAS mutations.

[0061] In some embodiments, the tumor is pancreatic cancer, the pancreatic cancer comprising one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H. In some embodiments, the tumor is pancreatic cancer, the pancreatic cancer comprising a KRAS G12C mutation. In some embodiments, the tumor is pancreatic cancer, the pancreatic cancer comprising a KRAS G12D mutation. In some embodiments, the tumor is pancreatic cancer, the pancreatic cancer comprising a KRAS G12V mutation. In some embodiments, the tumor is pancreatic cancer, the pancreatic cancer comprising a KRAS G13D mutation. In some embodiments, the tumor is pancreatic cancer containing a KRAS G13C mutation. In some embodiments, the tumor is pancreatic cancer containing a KRAS Q61H mutation.

[0062] In some embodiments, the tumor is colon cancer and / or rectal cancer, which contains one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H. In some embodiments, the tumor is colon cancer and / or rectal cancer, which contains a KRAS G12C mutation. In some embodiments, the tumor is colon cancer and / or rectal cancer, which contains a KRAS G12D mutation. In some embodiments, the tumor is colon cancer and / or rectal cancer containing a KRAS G12V mutation. In some embodiments, the tumor is colon cancer and / or rectal cancer containing a KRAS G13D mutation. In some embodiments, the tumor is colon cancer and / or rectal cancer containing a KRAS G13C mutation. In some embodiments, the tumor is colon cancer and / or rectal cancer containing a KRAS Q61H mutation.

[0063] In some embodiments, the tumor is non-small cell lung cancer (NSCLC) comprising one or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H. In some embodiments, the tumor is NSCLC comprising a KRAS G12C mutation. In some embodiments, the tumor is NSCLC comprising a KRAS G12D mutation. In some embodiments, the tumor is NSCLC comprising a KRAS G12V mutation. In some embodiments, the tumor is non-small cell lung cancer (NSCLC) containing a KRAS G13D mutation. In some embodiments, the tumor is NSCLC containing a KRAS G13C mutation. In some embodiments, the tumor is NSCLC containing a KRAS Q61H mutation.

[0064] In some embodiments, this disclosure provides the use of a combination of a RAS inhibitor, evosimab, pemetrexed, and a platinum-based chemotherapy agent (e.g., cisplatin or carboplatin) in the preparation of a medicament for treating RAS-mutant non-small cell lung cancer, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, this disclosure provides the use of a RAS inhibitor in the preparation of a medicament for use in combination with evosimab, pemetrexed, and platinum-based chemotherapy agents (e.g., cisplatin or carboplatin) for the treatment of RAS-mutant non-small cell lung cancer, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, this disclosure provides a method for treating RAS-mutant non-small cell lung cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a RAS inhibitor, evosimab, pemetrexed, and a platinum-based chemotherapy agent (e.g., cisplatin or carboplatin), wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, this disclosure provides a pharmaceutical combination product or kit comprising: a pharmaceutical composition containing a RAS inhibitor; and instructions for using the RAS inhibitor in combination with evokimab, pemetrexed, and a platinum-based chemotherapy agent (e.g., cisplatin or carboplatin), wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0068] In some implementations, the pancreatic cancer, when it occurs anywhere, can be pancreatic ductal adenocarcinoma.

[0069] In some implementations, the non-small cell lung cancer, when present in any location, can be adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma, or carcinoid carcinoma.

[0070] In some implementations, the colon cancer and / or rectal cancer, when present in either location, may be adenocarcinoma.

[0071] In some embodiments, the RAS mutation, occurring at any location, can be one or a combination of two or more of the following: KRAS mutation, NRAS mutation, and HRAS mutation. In some embodiments, the mutation site of the RAS mutation can be G12, G13, and / or Q61. In some embodiments, the RAS mutation can be a RAS G12 mutation, such as G12A, G12C, G12D, G12V, G12R, or G12S mutation. In some embodiments, the RAS mutation can be a RAS G13 mutation, such as G13C or G13D mutation. In some embodiments, the RAS mutation can be a RAS Q61 mutation, such as Q61R, Q61K, Q61H, Q61K, or Q61L mutation. In some embodiments, the RAS mutation, when present at any location, can be a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, or HRAS Q61H mutation. In some embodiments, the RAS mutation, when present at any location, can be a KRAS mutation. In some embodiments, the RAS mutation, when present at any location, can be a KRAS G12C mutation. In some embodiments, the RAS mutation, when present at any location, can be a KRAS G12D mutation. In some embodiments, the RAS mutation, when present at any location, can be a KRAS G12V mutation. In some embodiments, the RAS mutation, when present at any location, may be a KRAS G13D mutation. In some embodiments, the RAS mutation, when present at any location, may be a KRAS G13C mutation.

[0072] In some implementations, all types of tumors described in this disclosure may be advanced, locally advanced, recurrent, or metastatic.

[0073] In some embodiments, the subject has not received systemic antitumor therapy for advanced tumors prior to administration of the combination of this disclosure.

[0074] In some embodiments, the subject is resistant to first-line systemic antitumor therapy for advanced tumors. In some embodiments, the subject had previously received first-line systemic antitumor therapy for advanced tumors and developed resistance prior to administration of the combination of this disclosure.

[0075] In some implementations, all types of tumors described in this disclosure are PD-L1 positive.

[0076] In some embodiments, all types of tumors described in this disclosure contain EGFR mutations. In some embodiments, all types of tumors described in this disclosure do not contain EGFR mutations. [0076.1][Cited in Article (20.6) 13.01.2026] This document also discloses a method for treating cancer in a subject with this need, the method comprising administering a therapeutically effective amount to the subject requiring treatment. [0076.2][Reference to (Detailed Rule 20.6) 13.01.2026](i) Compound 1: or its pharmaceutically acceptable salt; and [0076.3][Reference to (Details 20.6) 13.01.2026](ii) PD-1 or PD-L1 inhibitors. [0076.4] [Incorporated (Details 20.6) 13.01.2026] In some embodiments, the PD-1 inhibitor is an anti-PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is acrixolimab, AMP-224, camrelizumab, cemiplimab, dostarlimab, MEDI0680, nivolumab, pembrolizumab, retifanlimab, sintilimab, spartalizumab, tislelizumab, toripalimab, or vopratelimab. [0076.5][Reference to Rule 20.6 (2026) 13.01.2026] In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is atezolizumab, AUNP12, avelumab, BMS-986189, CA-170, cosibelimab (CK-301), durvalumab, or KN035. [0076.6][Cited in (Details 20.6) 13.01.2026] This document also discloses a compound in a method for treating a subject suffering from cancer, which is compound 1 or a pharmaceutically acceptable salt thereof: [0076.7][Reference to (Details 20.6) 13.01.2026] The method comprises administering to the subject a therapeutically effective amount of the compound 1 or a salt thereof in combination with a PD-1 or PD-L1 inhibitor. [0076.8][Cited in Article (20.6) 13.01.2026] This document also discloses a method for treating a subject with non-small cell lung cancer (NSCLC) in need, the method comprising: administering to the subject in need a therapeutically effective dose of... [0076.9][Cited to (Details 20.6) 13.01.2026](i) Compound 1: Or its pharmaceutically acceptable salt; [0076.10][Incorporated (Rules 20.6) 13.01.2026](ii) PD-1 or PD-L1 inhibitors; and [0076.11][Reference to (Detail 20.6) 13.01.2026](iii) Additional therapeutic agents. [0076.12][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having EGFR exon 19 deletion or exon 21 L858R mutation, and the additional therapeutic agent is afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib. [0076.13][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional therapeutic agent is osimertinib plus pemetrexed. [0076.14][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR exon 19 deletion or an exon 21L858R mutation, and the additional therapeutic agent is osimertinib + pemetrexed + cisplatin or carboplatin. [0076.15][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional therapeutic agent is erlotinib plus ramucirumab. [0076.16][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional therapeutic agent is erlotinib plus bevacizumab. [0076.17][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed. [0076.18] [Cited in (Rules 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having EGFR S768I, L861Q and / or G719X mutations, and the additional therapeutic agent is afatinib, erlotinib, dacomitinib, gefitinib or osimertinib. [0076.19][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having EGFR S768I, L861Q and / or G719X mutations, and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed. [0076.20][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR exon 20 insertion mutation, and the additional therapeutic agent is amivantamab-vmjw. [0076.21][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having an EGFR exon 20 insertion mutation, and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed. [0076.22][Cited in (Rules 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a KRAS G12C mutation, and the additional therapeutic agent is (adagrasib, divarasib, garsorasib, glecirasib, olomorasib, RMC-6291, or sotorasib) + / - anti-EGFR monoclonal antibody. [0076.23][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a BRAF V600E mutation, and the additional therapeutic agent is (dabrafenib + trametinib, encorafenib + binimetinib, dabrafenib, or vemurafenib) + / - anti-EGFR monoclonal antibody. [0076.24][Cited in (Details 20.6) 13.01.2026] In some embodiments of a method for treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a MET exon 14 skipping mutation or high-level MET amplification, and the additional therapeutic agent is (capmatinib, crizotinib, or tepotinib) + / - anti-EGFR monoclonal antibody. [0076.25][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the cancer has been identified as having a HER2 mutation, and the additional therapeutic agent is (fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine)) + / - anti-EGFR monoclonal antibody. [0076.26][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histology, and the additional treatment agent is (pembrolizumab or cimipril (cemiplimab-rwlc)) + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR monoclonal antibody. [0076.27][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is pembrolizumab + pemetrexed + / - anti-EGFR monoclonal antibody. [0076.28] [Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is atezolizumab + bevacizumab + carboplatin + paclitaxel + / - anti-EGFR monoclonal antibody. [0076.29][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is atezolizumab + bevacizumab + / - anti-EGFR monoclonal antibody. [0076.30][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is atezolizumab + carboplatin + albumin-bound paclitaxel + / - anti-EGFR monoclonal antibody. [0076.31][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is nivolumab + ipilimumab + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR monoclonal antibody. [0076.32][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is cimiprilmab (cemiplimab-rwlc) + pemetrexed + (carboplatin / cisplatin) + / - anti-EGFR monoclonal antibody. [0076.33][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is cimiprilmab (cemiplimab-rwlc) + pemetrexed + / - anti-EGFR monoclonal antibody. [0076.34][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is tremelimumab-actl + durvalumab + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR monoclonal antibody. [0076.35][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is durvalumab + pemetrexed + / - anti-EGFR monoclonal antibody. [0076.36][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is carboplatin + pemetrexed + / - anti-EGFR monoclonal antibody. [0076.37][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is cisplatin + pemetrexed + / - anti-EGFR monoclonal antibody. [0076.38][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is bevacizumab + carboplatin + (paclitaxel or pemetrexed) + / - anti-EGFR monoclonal antibody. [0076.39][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is bevacizumab + cisplatin + pemetrexed + / - anti-EGFR monoclonal antibody. [0076.40][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is bevacizumab + / - anti-EGFR monoclonal antibody. [0076.41] [Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is bevacizumab + pemetrexed + / - anti-EGFR monoclonal antibody. [0076.42][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having non-squamous histological features, and the additional therapeutic agent is pemetrexed + / - anti-EGFR monoclonal antibody. [0076.43][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having squamous histology, and the additional therapeutic agent is pembrolizumab + carboplatin + (paclitaxel or albumin-bound paclitaxel) + / - anti-EGFR monoclonal antibody. [0076.44][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having squamous histological features, and the additional therapeutic agent is nivolumab + ipilimumab + paclitaxel + carboplatin + / - anti-EGFR monoclonal antibody. [0076.45][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the subject in need has been identified as having squamous histological features, and the additional therapeutic agent is tremelimumab-actl + durvalumab + gemcitabine + (carboplatin or cisplatin) + / - anti-EGFR monoclonal antibody. [0076.46][Reference to (Detailed Rule 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is (pembrolizumab or atezolizumab or cimiprizumab (cemiplimab-rwlc) or nivolumab or durvalumab or nivolumab + ipilimumab or tremelimumab-actl + durvalumab) + / - anti-EGFR monoclonal antibody. [0076.47][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is trastuzumab + / - anti-EGFR monoclonal antibody. [0076.48] [Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is ramoximab + docetaxel + / - anti-EGFR monoclonal antibody. [0076.49][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is gemcitabine + docetaxel + / - anti-EGFR monoclonal antibody. [0076.50][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is gemcitabine + vinorelbine + / - anti-EGFR monoclonal antibody. [0076.51] [Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is (albumin-bound paclitaxel or docetaxel or gemcitabine or paclitaxel) + / - anti-EGFR monoclonal antibody. [0076.52][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is cimiprilmab (cemiplimab-rwlc) + paclitaxel + (carboplatin or cisplatin) + / - anti-EGFR monoclonal antibody. [0076.53][Reference to (Details 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is tremelimumab-actl + durvalumab + carboplatin + albumin-bound paclitaxel + / - anti-EGFR monoclonal antibody. [0076.54][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is carboplatin + (albumin-bound paclitaxel or docetaxel or etoposide or gemcitabine or paclitaxel) + / - anti-EGFR monoclonal antibody. [0076.55][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating non-small cell lung cancer (NSCLC), the additional therapeutic agent is cisplatin + (docetaxel or etoposide or gemcitabine or paclitaxel) + / - anti-EGFR monoclonal antibody. [0076.56][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method for treating non-small cell lung cancer (NSCLC), the anti-EGFR monoclonal antibody is cetixumab or panitumuab. [0076.57][Cited in (Details 20.6) 13.01.2026] This document also discloses a method for treating colorectal cancer (CRC) in a subject requiring treatment, the method comprising administering a therapeutically effective dose to the subject requiring treatment. [0076.58][Cited in (Details 20.6) 13.01.2026](i) Compound 1: Or its pharmaceutically acceptable salt; [0076.59][Incorporated (Rules 20.6) 13.01.2026](ii) PD-1 or PD-L1 inhibitors; and [0076.60][Reference to Article 20.6 (13.01.2026)](iii) Additional therapeutic agents. [0076.61] [Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having a dMMR / MSI-H mutation, and the additional therapeutic agent is an anti-EGFR monoclonal antibody + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly)). [0076.62][Reference to (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having a POLE / POLD1 mutation, and the additional therapeutic agent is an anti-EGFR monoclonal antibody + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly)). [0076.63][Reference to (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having a BRAF WT mutation, and the additional therapeutic agent is an anti-EGFR monoclonal antibody + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly)). [0076.64][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having any RAS mutation, and the additional therapeutic agent is an anti-EGFR monoclonal antibody + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly)). [0076.65][Reference to (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having any KRAS mutation, and the additional therapeutic agent is an anti-EGFR monoclonal antibody + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly)). [0076.66][Reference to (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having any HER2 mutation, and the additional therapeutic agent is an anti-EGFR monoclonal antibody + (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly)). [0076.67][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the additional therapeutic agent is an anti-EGFR monoclonal antibody plus chemotherapy. [0076.68][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the additional therapeutic agent is anti-VEGFR monoclonal antibody + anti-EGFR monoclonal antibody + chemotherapy. [0076.69][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the additional therapeutic agent is an anti-EGFR monoclonal antibody plus (fruquintinib or regorafenib). [0076.70][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the additional therapeutic agent is an anti-EGFR monoclonal antibody. [0076.71][Reference to Article (20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having a BRAF V600E mutation, and the additional therapeutic agent is an encorafenib + / - anti-EGFR monoclonal antibody. [0076.72][Reference to Article (20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having a BRAF V600E mutation, and the additional therapeutic agent is naprafenib + / - anti-EGFR monoclonal antibody. [0076.73][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating colorectal cancer (CRC), the cancer has been identified as having HER2 amplification or being IHC 3+, and the additional therapeutic agent is trastuzumab + (pertuzumab or lapatinib or tucatinib) + / - anti-EGFR monoclonal antibody. [0076.74][Reference to Article (20.6) 13.01.2026] In some embodiments of a method for treating colorectal cancer (CRC), the cancer has been identified as having HER2 amplification or being IHC 3+, and the additional therapeutic agent is trastuzumab + / - anti-EGFR monoclonal antibody. [0076.75][Cited in (Details 20.6) 13.01.2026] In some embodiments of a method for treating colorectal cancer (CRC), the cancer has been identified as having a KRAS G12C mutation, and the additional therapeutic agent is an anti-EGFR monoclonal antibody plus (adagrasib or sotorasib or olomorasib or divarasib or glecirasib or garsorasib or RMC-6291). [0076.76][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method for treating colorectal cancer (CRC), the anti-EGFR monoclonal antibody is cetixumab or panitumuab. [0076.77][Cited in (Details 20.6) 13.01.2026] In some embodiments of methods for treating colorectal cancer (CRC), the anti-VEGFR monoclonal antibody is bevacizumab, raucirumab, or zivaflibercept. [0076.78][Cited in Article (20.6) 13.01.2026] In some embodiments of the method for treating colorectal cancer (CRC), the chemotherapy is (5-FU or capecitabine), (5-FU or capecitabine) + oxaliplatin, (5-FU or capecitabine) + irinotecan, (5-FU or capecitabine) + oxaliplatin + irinotecan, irinotecan, or trifluridine + tiparacil. In some embodiments, the 5-FU combination also includes leucovorin. [0076.79][Cited in Article (20.6) 13.01.2026] This document also discloses a method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject requiring treatment, the method comprising administering a therapeutically effective dose to the subject requiring treatment. [0076.80][Reference to (Details 20.6) 13.01.2026](i) Compound 1: Or its pharmaceutically acceptable salt; [0076.81][Referencing (Rules 20.6) 13.01.2026](ii) PD-1 or PD-L1 inhibitors; and [0076.82][Reference to Article 20.6 (13.01.2026)](iii) Additional therapeutic agents. [0076.83][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a dMMR / MSI-H mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly)) + / - anti-EGFR monoclonal antibody. [0076.84][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRAF WT mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dotalimab) + / - anti-EGFR monoclonal antibody. [0076.85][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having any RAS mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dotalimab) + / - anti-EGFR monoclonal antibody. [0076.86][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having any HER2 mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dotalimab) + / - anti-EGFR monoclonal antibody. [0076.87][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having any BRCA1 / 2 mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dotalimab) + / - anti-EGFR monoclonal antibody. [0076.88][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dotalimab) + / - anti-EGFR monoclonal antibody. [0076.89][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the additional therapeutic agent is chemotherapy plus / - anti-EGFR monoclonal antibody. [0076.90][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the additional therapeutic agent is an anti-EGFR monoclonal antibody. [0076.91] [Cited in Article (20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRAF V600E mutation, and the additional therapeutic agent is dabrafenib + (trametinib or binimetinib) + / - anti-EGFR monoclonal antibody. [0076.92][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRAF V600E mutation, and the additional therapeutic agent is naprafenib + (trametinib or bemettinib) + / - anti-EGFR monoclonal antibody. [0076.93][Reference to Article (20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a HER2-positive mutation or being IHC 3+, and the additional therapeutic agent is trastuzumab + / - anti-EGFR monoclonal antibody. [0076.94][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a KRAS G12C mutation, and the additional therapeutic agent is (adarecec or sotorexec or oloresec or devarexec or gleresec or gersoresec or RMC-6291) + / - anti-EGFR monoclonal antibody. [0076.95][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRCA1 / 2 mutation, and the additional therapeutic agent is gemcitabine + cisplatin + / - anti-EGFR monoclonal antibody. [0076.96][Reference to Article (20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRCA1 / 2 mutation, and the additional therapeutic agent is a rucaparib + / - anti-EGFR monoclonal antibody. [0076.97][Reference to Article (20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a BRCA1 / 2 mutation, and the additional therapeutic agent is olaparib (BRCA1 / 2 only) + / - anti-EGFR monoclonal antibody. [0076.98][Reference to (Detail 20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation, and the additional therapeutic agent is gemcitabine + cisplatin + / - anti-EGFR monoclonal antibody. [0076.99][Reference to Article (20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation, and the additional therapeutic agent is a rucaparib + / - anti-EGFR monoclonal antibody. [0076.100][Reference to Article (20.6) 13.01.2026] In some embodiments of the method of treating pancreatic ductal adenocarcinoma (PDAC), the cancer has been identified as having a PALB2 mutation, and the additional therapeutic agent is olaparib (BRCA1 / 2 only) + / - anti-EGFR monoclonal antibody. [0076.101] [Cited in Article (20.6) 13.01.2026] In some embodiments of the method for treating pancreatic ductal adenocarcinoma (PDAC), the anti-EGFR monoclonal antibody is cetuximab or pertuximab. [0076.102][Cited in (Details 20.6) 13.01.2026] In some embodiments of the method for treating pancreatic ductal adenocarcinoma (PDAC), the anti-VEGFR monoclonal antibody is bevacizumab, ramoximab, or aflibercept. [0076.103][Incorporated (Details 20.6) 13.01.2026] In some embodiments of the treatment of pancreatic ductal adenocarcinoma (PDAC), chemotherapy is (5-FU or capecitabine), (5-FU or capecitabine) + oxaliplatin, (5-FU or capecitabine) + irinotecan, (5-FU or capecitabine) + oxaliplatin + irinotecan, gemcitabine, gemcitabine + albumin-bound paclitaxel, gemcitabine + capecitabine, (5-FU or capecitabine) + liposomal irinotecan + oxaliplatin, (5-FU or capecitabine) + liposomal irinotecan, gemcitabine + albumin-bound paclitaxel + cisplatin, gemcitabine + docetaxel + capecitabine, or gemcitabine + erlotinib. In some embodiments, the combination of 5-FU also includes leucovorin. [0076.104][Referencing (Details 20.6) 13.01.2026] Cancer [0076.105][Cited in (Details 20.6) 13.01.2026] This article discloses a method for treating cancer using the combination disclosed herein. [0076.106][Incorporated (Details 20.6) 13.01.2026] “Cancer” means all types of cancer, neoplasm, or malignant tumors found in mammals (e.g., humans), including but not limited to leukemia, lymphoma, myeloma, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer (such as pancreatic adenocarcinoma, PDAC), medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's disease, and non-Hodgkin's lymphoma. Exemplary cancers that can be treated with the compounds or methods provided herein include cancers of the blood, thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Other examples include thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, skin melanoma, colonic adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocytosis, primary globulinemia, primary brain tumor, malignant insulinoma, malignant carcinoid tumor, bladder cancer, malignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer. [0076.107][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer carries at least one of KRAS, NRAS or HRAS mutations. [0076.108][Reference to Rule 20.6 (13.01.2026)] In some embodiments, the cancer is KRAS-driven, HRAS-driven, or NRAS-driven. [0076.109][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has at least one RAS mutation. [0076.110][Reference to (Details 20.6) 13.01.2026] In some embodiments, the RAS mutation is a mutation at the G12, G13 and / or Q61 positions of the RAS protein. [0076.111][Reference to Rule 20.6 (2026) 13.01.2026] In some embodiments, the cancer has a G12C RAS ​​mutation. In some embodiments, the cancer has a G12D RAS mutation. In some embodiments, the cancer has a G12R RAS mutation. In some embodiments, the cancer has a G12S RAS mutation. In some embodiments, the cancer has a G12V RAS mutation. In some embodiments, the cancer has a G12W RAS mutation. In some embodiments, the cancer has a G13D RAS mutation. In some embodiments, the cancer has an H95D RAS mutation. In some embodiments, the cancer has an H95Q RAS mutation. In some embodiments, the cancer has an H95R RAS mutation. In some embodiments, the cancer has a Q61H RAS mutation. In some embodiments, the cancer has a Q61K RAS mutation. In some embodiments, the cancer has a Q61R RAS mutation. In some embodiments, the cancer has an R68S RAS mutation. [0076.112][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a BRCA1 / 2 mutation. [0076.113][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a PALB2 mutation. [0076.114][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a BRAF mutation. [0076.115][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a BRAF V600E mutation. [0076.116][Reference to (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a HER2 mutation. [0076.117][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having an MSI mutation. [0076.118][Reference to (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having the BRAF V600E mutation. [0076.119][Reference to (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a HER2 mutation. [0076.120][Reference to (Detail 20.6) 13.01.2026] In some embodiments, cancer has been identified as having high levels of MET amplification. [0076.121][Cited in (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a MET exon 14 skipping mutation. [0076.122][Cited in (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having EGFR exon 19 deletion or exon 21L858R mutation. [0076.123][Cited in (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having EGFR S768I, L861Q and / or G719X mutations. [0076.124][Cited in (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having an EGFR exon 20 insertion mutation. [0076.125][Reference to (Detail 20.6) 13.01.2026] In some embodiments, cancer has been identified as having MET amplification. [0076.1] [Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a MET exon 14 skipping mutation. [0076.2][Reference to (Detail 20.6) 13.01.2026] In some embodiments, cancer has been identified as having NTRK 1 / 2 / 3 gene fusions. [0076.3][Reference to (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having ALK (Anaplastic lymphoma kinase) gene rearrangement. [0076.4][Reference to (Detail 20.6) 13.01.2026] In some embodiments, cancer has been identified as having RET (Rearranged during transfection) rearrangements. [0076.5][Reference to (Detail 20.6) 13.01.2026] In some embodiments, cancer has been identified as having ROS1 rearrangement. [0076.6][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has ≥50% PD-L1 level. [0076.7][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has a PD-L1 level of ≥1%-49%. [0076.8][Reference to (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as non-squamous cell carcinoma. [0076.9][Reference to (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as squamous cell carcinoma. [0076.10][Reference to (Details 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a dMMR mutation. [0076.11][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a dMMR / MSI-H mutation. [0076.12][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer has been identified as having a POLE / POLD1 mutation. [0076.13][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer is a liquid tumor, which is leukemia. In some embodiments, the cancer is leukemia, which is acute myeloid leukemia (AML). [0076.14][Incorporated (Details 20.6) 13.01.2026] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or metastatic solid tumor. [0076.15][Reference to (Details 20.6) 13.01.2026] In some embodiments, cancer is breast cancer, esophageal cancer, gastrointestinal cancer, head and neck cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, salivary gland tumor, thyroid cancer, or uterine cancer. [0076.16][Reference to (Detail 20.6) 13.01.2026] In some embodiments, pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). [0076.17][Reference to (Details 20.6) 13.01.2026] In some embodiments, pancreatic ductal adenocarcinoma (PDAC) has been identified as having RAS mutations. [0076.18][Reference to (Details 20.6) 13.01.2026] In some embodiments, pancreatic ductal adenocarcinoma (PDAC) has been identified as having BRCA1 / 2 mutations. [0076.19][Reference to (Details 20.6) 13.01.2026] In some embodiments, pancreatic ductal adenocarcinoma (PDAC) has been identified as having a PALB2 mutation. [0076.20][Reference to (Details 20.6) 13.01.2026] In some embodiments, pancreatic ductal adenocarcinoma (PDAC) has been identified as having a BRAF mutation. [0076.21][Reference to (Details 20.6) 13.01.2026] In some embodiments, pancreatic ductal adenocarcinoma (PDAC) has been identified as having a HER2 mutation. [0076.22][Cited in (Details 20.6) 13.01.2026] In some embodiments, pancreatic ductal adenocarcinoma (PDAC) has been identified as having an MSI mutation. [0076.23][Cited in (Details 20.6) 13.01.2026] In some embodiments, pancreatic ductal adenocarcinoma (PDAC) has been identified as having dMMR mutations. [0076.24][Reference to (Details 20.6) 13.01.2026] In some embodiments, gastrointestinal cancer is anal cancer, appendix cancer, bile duct cancer, cholangiocarcinoma, colon cancer, colorectal cancer (CRC), gallbladder cancer, rectal cancer, small bowel cancer, or stomach cancer. [0076.25][Reference to (Details 20.6) 13.01.2026] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). [0076.26][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having RAS mutations. [0076.27][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having the BRAF V600E mutation. [0076.28][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having a HER2 mutation. [0076.29][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having high levels of MET amplification. [0076.30][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having a MET exon 14 skipping mutation. [0076.31][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having EGFR exon 19 deletion or exon 21L858R mutation. [0076.32][Reference to (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having EGFR S768I, L861Q and / or G719X mutations. [0076.33][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having an EGFR exon 20 insertion mutation. [0076.34][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having the BRAF V600E mutation. [0076.35][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having a HER2 mutation. [0076.36][Reference to (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having MET amplification. [0076.37][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having a MET exon 14 skipping mutation. [0076.38][Reference to (Detail 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having NTRK 1 / 2 / 3 gene fusions. [0076.39][Cited in (Details 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having ALK (Anaplastic lymphoma kinase) gene rearrangement. [0076.40][Reference to Rule 20.6 (13.01.2026)] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having RET (Rearranged during transfection) rearrangements. [0076.41][Reference to (Detail 20.6) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as having ROS1 rearrangement. [0076.42][Reference to (Detail 20.6) 13.01.2026] In some embodiments, the PD-L1 level in non-small cell lung cancer (NSCLC) is ≥50%. [0076.43][Reference to (Details 20.6) 13.01.2026] In some embodiments, the PD-L1 level in non-small cell lung cancer (NSCLC) is ≥1%-49%. [0076.44][Reference to Rule 20.6 (2026) 13.01.2026] In some embodiments, non-small cell lung cancer (NSCLC) has been identified as non-squamous cell carcinoma. In some embodiments, non-small cell lung cancer (NSCLC) has been identified as squamous cell carcinoma. [0076.45][Reference to (Details 20.6) 13.01.2026] In some embodiments, gastrointestinal cancer is colorectal cancer (CRC). [0076.46][Cited in (Details 20.6) 13.01.2026] In some embodiments, colorectal cancer (CRC) has been identified as having RAS mutations. [0076.47][Cited in (Details 20.6) 13.01.2026] In some embodiments, colorectal cancer (CRC) has been identified as having a BRAF mutation. [0076.48][Cited in (Details 20.6) 13.01.2026] In some embodiments, colorectal cancer (CRC) has been identified as having HER2 amplification. [0076.49][Cited in (Details 20.6) 13.01.2026] In some embodiments, colorectal cancer (CRC) has been identified as having dMMR / MSI-H mutations. [0076.50][Reference to (Details 20.6) 13.01.2026] In some embodiments, colorectal cancer (CRC) has been identified as having a POLE / POLD1 mutation.

[0077] In some embodiments, all types of tumors described in this disclosure contain ALK mutations. In some embodiments, all types of tumors described in this disclosure do not contain ALK mutations.

[0078] In some implementations, the RAS inhibitor, PD-1 / PD-L1 inhibitor, and other therapeutic agents (when present) may be administered simultaneously or sequentially.

[0079] In this disclosure, the RAS inhibitors, PD-1 / PD-L1 inhibitors, and other therapeutic agents (when present) can be administered by any suitable method, such as oral, intravenous, intramuscular, subcutaneous, or intravenous infusion. Depending on the administration method, the RAS inhibitors, PD-1 / PD-L1 inhibitors, and other therapeutic agents (when present) can be formulated into various conventional dosage forms, such as, but not limited to, tablets, capsules, granules, syrups, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, and injections. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof can be formulated as a conventional tablet.

[0080] In some implementations, the RAS inhibitor is administered orally.

[0081] The RAS inhibitor can be administered at a fixed dose or based on the individual's weight or body surface area.

[0082] In some embodiments, the single-dose administration of the RAS inhibitor is from 0.01 mg to 1000 mg, for example 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg.

[0083] In some embodiments, the single-dose administration of the RAS inhibitor is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg. The dosages are 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, and 100 mg / kg, based on the individual's body weight. In some embodiments, the single-dose administration of the RAS inhibitor is from 0.1 mg / kg to 20 mg / kg.

[0084] In some embodiments, the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) may be administered once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), every other day, once weekly (QW), twice weekly (BIW), three times weekly (TIW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, the RAS inhibitor is administered once daily. In some embodiments, the RAS inhibitor is administered twice daily. In some embodiments, the RAS inhibitor is administered three times daily.

[0085] In some embodiments, a single dose of said compound 1 or a pharmaceutically acceptable salt thereof is 8–48 mg (in the free form of compound 1), for example 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, 32 mg, 40 mg or 48 mg (in the free form of compound 1), administered orally, and each dose may be administered once daily, twice daily, three times daily or every other day.

[0086] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) administered orally once daily.

[0087] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) administered orally once daily.

[0088] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) administered orally once daily.

[0089] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) administered orally once daily.

[0090] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) administered orally once daily.

[0091] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) administered orally once daily.

[0092] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) administered orally once daily.

[0093] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) administered orally once daily.

[0094] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) administered orally twice daily.

[0095] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) administered orally twice daily.

[0096] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) administered orally twice daily.

[0097] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) administered orally twice daily.

[0098] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) administered orally twice daily.

[0099] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) administered orally twice daily.

[0100] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) administered orally twice daily.

[0101] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) administered orally twice daily.

[0102] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) administered orally three times daily.

[0103] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) administered orally three times daily.

[0104] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) administered orally three times daily.

[0105] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) administered orally three times daily.

[0106] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) administered orally three times daily.

[0107] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) administered orally three times daily.

[0108] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) administered orally three times daily.

[0109] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) administered orally three times daily.

[0110] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) administered orally every other day.

[0111] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) administered orally every other day.

[0112] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) administered orally every other day.

[0113] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) administered orally every other day.

[0114] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) administered orally every other day.

[0115] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) administered orally every other day.

[0116] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) administered orally every other day.

[0117] In some embodiments, a single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) administered orally every other day.

[0118] In some embodiments, the PD-1 / PD-L1 inhibitor (e.g., a PD-1 / PD-L1 antibody or its antigen-binding fragment) is administered via intravenous injection, intramuscular injection, subcutaneous injection, or intravenous infusion. In some embodiments, the PD-1 / PD-L1 inhibitor is administered via intravenous injection or intravenous infusion.

[0119] The PD-1 / PD-L1 inhibitor (e.g., PD-1 / PD-L1 antibody or its antigen-binding fragment) can be administered at a fixed dose or based on the individual's weight or body surface area.

[0120] In some embodiments, the single-dose administration of the PD-1 / PD-L1 inhibitor (e.g., PD-1 / PD-L1 antibody or its antigen-binding fragment) is from 0.01 mg to 1000 mg, for example, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg. 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg. In some embodiments, the single dose of the PD-1 / PD-L1 inhibitor is 100 mg to 500 mg.

[0121] In some embodiments, the single-dose administration of the PD-1 / PD-L1 inhibitor (e.g., PD-1 / PD-L1 antibody or its antigen-binding fragment) is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg. The dosages are 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, and 100 mg / kg, based on the individual's body weight. In some embodiments, the single-dose administration of the PD-1 / PD-L1 inhibitor is from 0.1 mg / kg to 10 mg / kg.

[0122] In some embodiments, the single-dose administration of the PD-1 / PD-L1 inhibitor (e.g., a PD-1 / PD-L1 antibody or its antigen-binding fragment) is 0.01 mg / m². 2 Up to 1000 mg / m 2 For example, 0.01 mg / m³ 2 0.02 mg / m 2 0.03 mg / m 2 0.04 mg / m 2 0.05mg / m 2 0.06 mg / m 2 0.07 mg / m 2 0.08 mg / m 2 0.09 mg / m 2 0.1 mg / m 2 0.2 mg / m 2 0.3 mg / m 2 0.4 mg / m 2 0.5 mg / m 2 0.6 mg / m 2 0.7 mg / m 2、0.8mg / m 2 、0.9mg / m 2 、1mg / m 2 、2mg / m 2 、3mg / m 2 、4mg / m 2 、5mg / m 2 、6mg / m 2 、7mg / m 2 、8mg / m 2 、9mg / m 2 、10mg / m 2 、15mg / m 2 、20mg / m 2 、25mg / m 2 、30mg / m 2 、35mg / m 2 、40mg / m 2 、45mg / m 2 、50mg / m 2 、55mg / m 2 、60mg / m 2 、65mg / m 2 、70mg / m 2 、75mg / m 2 、80mg / m 2 、85mg / m 2 、90mg / m 2 、95mg / m 2 、100mg / m 2 、125mg / m 2 、150mg / m 2 、175mg / m 2 、200mg / m 2 、225mg / m 2 、250mg / m 2 、275mg / m 2 、300mg / m 2 、325mg / m 2 、350mg / m 2 、375mg / m 2 、400mg / m 2 、425mg / m 2 、450mg / m 2 、475mg / m 2 、500mg / m 2 、525mg / m 2 、550mg / m 2 、575mg / m 2 、600mg / m2 625mg / m 2 650mg / m 2 675mg / m 2 700mg / m 2 725mg / m 2 750mg / m 2 775mg / m 2 800mg / m 2 825mg / m 2 850mg / m 2 875mg / m 2 900mg / m 2 925mg / m 2 950mg / m 2 975mg / m 2 Or 1000mg / m 2 Based on the body surface area of ​​the individual to whom the drug is administered. In some embodiments, the single dose of the PD-1 / PD-L1 inhibitor is 10 mg / m². 2 Up to 500mg / m 2 .

[0123] In some embodiments, the PD-1 / PD-L1 inhibitor (e.g., a PD-1 / PD-L1 antibody or its antigen-binding fragment) may be administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the PD-1 / PD-L1 inhibitor may be administered twice weekly. In some embodiments, the PD-1 / PD-L1 inhibitor may be administered once weekly. In some embodiments, the PD-1 / PD-L1 inhibitor may be administered once every two weeks. In some embodiments, the PD-1 / PD-L1 inhibitor may be administered once every three weeks.

[0124] In some implementations, the PD-1 / PD-L1 inhibitor (e.g., PD-1 / PD-L1 antibody or its antigen-binding fragment) is administered at the standard dose and frequency when the PD-1 / PD-L1 inhibitor is used alone, such as the recommended dose and frequency in the drug information leaflet of the PD-1 / PD-L1 inhibitor (e.g., the recommended dose of toripalimab is 3 mg / kg every two weeks, or 240 mg intravenously every three weeks; the recommended dose of pembrolizumab is 2 mg / kg every three weeks, 200 mg every three weeks, or 400 mg every six weeks; the recommended dose of canducilimab is 6 mg / kg every two weeks, or 10 mg / kg every three weeks). In some embodiments, the PD-1 / PD-L1 inhibitor (e.g., PD-1 / PD-L1 antibody or its antigen-binding fragment) may be administered at 5% to 95% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) of the standard dose when the PD-1 / PD-L1 inhibitor is used alone.

[0125] In some implementations, the evosimib is administered at a single dose of 20 mg / kg (by body weight) intravenously every three weeks.

[0126] In some embodiments, other oncology therapeutic agents, including but not limited to chemotherapy drugs and chemotherapy adjuvants, when included in the combination disclosed herein, such as pemetrexed, cisplatin, carboplatin, etc., may be administered at the recommended dose and frequency in the drug label of the therapeutic agent.

[0127] In some embodiments, the pemetrexed may be in the form of pemetrexed disodium. In some embodiments, the single-dose administration of the pemetrexed (e.g., in the form of pemetrexed disodium) is 500 mg / m². 2 (Based on body surface area in free form of pemetrexed), administered intravenously once every three weeks.

[0128] In some embodiments, the single dose of cisplatin is 75 mg / m². 2 (Based on body surface area), administered intravenously once every three weeks.

[0129] In some embodiments, the single dose of carboplatin is equivalent to an AUC of 5–6, administered intravenously once every three weeks.

[0130] The combination of RAS inhibitors, PD-1 / PD-L1 inhibitors, and optional other therapeutic agents disclosed herein can be administered for one or more cycles, wherein each cycle can be longer than one week, such as one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months, one year, two years, or longer; optionally, the duration of each cycle can be the same or different, and the interval between each cycle can be the same or different. Within any treatment cycle, the dosage and frequency of administration of the RAS inhibitors, PD-1 / PD-L1 inhibitors, and optional other therapeutic agents can be adjusted as needed; for example, after using an initial dose, subsequent doses can be 10% to 300% of the initial dose, such as 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%. In some embodiments, the combination of RAS inhibitors, PD-1 / PD-L1 inhibitors, and optional other therapeutic agents disclosed herein can be administered for one or more cycles, wherein each cycle can be three weeks. In some implementations, the RAS inhibitor, PD-1 / PD-L1 inhibitor, and optional other therapeutic agents in the combination disclosed herein may be administered from day 1 of each cycle, and thereafter at their respective frequencies.

[0131] In some implementations, the combination of the RAS inhibitor, PD-1 / PD-L1 inhibitor, and optional other therapeutic agents achieves a synergistic effect.

[0132] In some embodiments, administration of the drug combination of this disclosure to a subject with a tumor results in complete tumor remission. In some embodiments, administration of the drug combination of this disclosure to a subject with a tumor results in a reduction of tumor volume by 30% or more, such as 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more. The reduction in tumor volume can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytological, histological, or molecular genetic analysis.

[0133] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0134] The terms "drug combination product" or "combination" can refer to a fixed combination of products administered in a single dosage unit (e.g., a single dosage form containing all active pharmaceutical ingredients) or a kit, or a combination of a drug and a package insert indicating that the drug can be used in combination with one or more other drugs. For example, in some embodiments, the drug combination product of this disclosure may include: a pharmaceutical composition containing a RAS inhibitor; and a package insert indicating that the RAS inhibitor is for use in combination with a PD-1 / PD-L1 inhibitor (e.g., for the treatment of cancer). In other embodiments, the drug combination product of this disclosure may include: a pharmaceutical composition containing a PD-1 / PD-L1 inhibitor; and a package insert indicating that the PD-1 / PD-L1 inhibitor is for use in combination with a RAS inhibitor (e.g., for the treatment of cancer). In some embodiments, the drug combination product of this disclosure may include: (i) a first pharmaceutical composition containing a RAS inhibitor; and (ii) a second pharmaceutical composition containing a PD-1 / PD-L1 inhibitor (defined as a second pharmaceutical composition to indicate another pharmaceutical composition independent of the first pharmaceutical composition). In other embodiments, the pharmaceutical combination products disclosed herein may include: a single pharmaceutical composition comprising a RAS inhibitor and a PD-1 / PD-L1 inhibitor (i.e., a unit dosage form comprising both a RAS inhibitor and a PD-1 / PD-L1 inhibitor).

[0135] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for exposure to mammalian (especially human) tissues within the limits of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions, and other problematic complications, and with a reasonable benefit / risk ratio.

[0136] The term "treatment" refers to the application of one or more pharmaceutical substances to a person suffering from or having symptoms of a disease in order to cure, alleviate, reduce, alter, treat, improve, enhance, or affect the disease or its symptoms.

[0137] The term "therapeutic effective amount" refers to the amount of medicine that is sufficient to effectively treat a disease or condition when administered to a subject. The therapeutic effective amount of medicine administered to a subject will depend on various factors, such as the given drug or compound, the drug formulation, the route of administration, the type of disease, the condition, the age and condition of the subject being treated, etc., but can still be routinely determined by those skilled in the art.

[0138] The term "subject" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and so on. Examples of non-mammals include, but are not limited to, birds. The term "subject" is not limited to a specific age or sex. In some implementations, the subject is a human.

[0139] The term "simultaneous or sequential administration" refers to the simultaneous or sequential administration of two or more drugs within a single dosing cycle (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours) at specific time intervals (e.g., 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week) so that they can work together to achieve the desired therapeutic effect. The manner of administration for each drug can be the same or different, and the frequency / cycle of administration can be the same or different.

[0140] The term "antigen-binding fragment" refers to a portion or segment of a complete antibody with fewer amino acid residues than the complete antibody itself, capable of binding to an antigen or competing with the complete antibody (i.e., the complete antibody from which the antigen-binding fragment originates) for antigen binding. Antigen-binding fragments can be prepared using recombinant DNA technology or by enzymatic or chemical cleavage of complete antibodies. Antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, single-chain Fv, diabody antibodies, and single-domain antibodies (sdAb).

[0141] The term "synergistic effect" refers to an effect achieved by using the drug combination of this disclosure that is greater than the sum of the effects of using them individually. As an example, the synergistic effect of the drug combination can be evaluated by the method described in Clarke R. Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models[J]. Breast Cancer Research & Treatment, 1997, 46(2-3):255-278 (the full text of which is incorporated herein by reference): Synergistic score = ((A / C)×(B / C)) / (AB / C); where A is the RTV value of drug A; B is the RTV value of drug B; C is the RTV value of the control group; AB is the RTV value of the combination treatment of A and B; a synergistic score > 1 indicates that the two drugs have a synergistic effect; the larger the synergistic score, the stronger the synergistic effect. In some embodiments, the synergy score of the drug combination disclosed herein is greater than 1.1, for example, greater than 2.0, greater than 3.0, greater than 4.0, greater than 5.0, greater than 6.0, greater than 7.0, greater than 8.0, greater than 9.0, greater than 10.0, greater than 11.0, greater than 12.0, greater than 13.0, greater than 14.0, greater than 15.0, greater than 16.0, greater than 17.0, greater than 18.0, greater than 19.0, greater than 20.0, and greater than 21.0.

[0142] The term "drug resistance" refers to the tolerance of cancer patients or cancer cells to the effects of a drug. For example, once cancer cells develop resistance to a particular drug, the therapeutic effect of that drug significantly decreases. Cancer cells may acquire resistance through a series of mechanisms, including mutations or overexpression of the drug target, drug inactivation, or elimination of the drug from the cells. Drug resistance can be classified into primary resistance and acquired resistance based on its cause. Primary resistance refers to cancer cells being insensitive to the drug at the start of treatment, while acquired resistance refers to cancer cells that were initially sensitive to the drug but became insensitive after repeated exposure during treatment.

[0143] Unless otherwise stated, the drug names listed in this disclosure include both the free form of the active ingredient and its salts or other pharmaceutical forms. For example, pemetrexed is intended to include the free pemetrexed compound, pemetrexed disodium (commonly used in clinical practice), etc.

[0144] The compounds mentioned in this disclosure also include their isotopic derivatives. All forms of the compounds, isotopic derivatives, and pharmaceutically acceptable salts of this disclosure, including various solid forms and mixtures thereof, such as crystalline, amorphous, solvates (e.g., hydrates), or any mixtures thereof, are included within the scope of this disclosure.

[0145] The names of PD-1 / PD-L1 antibodies mentioned in this disclosure include their biosimilars.

[0146] Without violating common sense in the field, the various implementation schemes and preferred conditions described herein can be combined arbitrarily to obtain various preferred examples of this disclosure.

[0147] The positive and progressive effect of this disclosure is that it provides a combination of a RAS inhibitor and a PD-1 / PD-L1 inhibitor, along with optional other therapeutic agents, which exhibits a synergistic effect in the treatment of tumors. Detailed Implementation

[0148] The present disclosure is further illustrated below by way of embodiments, but these embodiments are not intended to limit the scope of the present disclosure. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected in accordance with the product instructions.

[0149] In the following examples, the raw materials and reagents used are commercially available, or can be prepared by those skilled in the art by referring to known methods or by conventional modifications based on known methods.

[0150] Example 1:

[0151] Objective: To evaluate the antitumor effect of a RAS inhibitor combined with an anti-PD-1 antibody in a KPC mouse subcutaneous xenograft model of pancreatic cancer. Compound 1 or compound 2 (MRTX-1133) was used as an exemplary RAS inhibitor.

[0152] Experimental materials:

[0153] Compound 1:

[0154] Compound 2:

[0155] anti-PD-1 antibody: Manufacturer: BIOXCELL; Batch number: BP0146.

[0156] Cells: KPC mouse pancreatic cancer cells (KRAS G12D mutation), obtained from Fosun Pharma Biopharmaceutical Co., Ltd., catalog number FNC0071, maintained and passaged by Shanghai WuXi AppTec Co., Ltd.

[0157] Animals: C57BL / 6J mice, female, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0158] Experimental methods:

[0159] 1. Preparation of test sample

[0160] Compound 1: 0.5 mg / mL and 0.2 mg / mL solutions, in a solvent of 5% DMSO / 10% solubilol / 85% water.

[0161] Compound 2: 1 mg / mL solution, 10% SBE-β-CD in 50 mM citrate acid solution, pH 5.0.

[0162] Anti-PD-1: 1 mg / mL and 0.5 mg / mL solutions, with DPBS (CORNING, 21-031-CVC) as the solvent.

[0163] 2. Construction of KPC tumor model and grouping for drug administration

[0164] One hundred female C57BL / 6J mice were subcutaneously inoculated with KPC cells in the right axilla at a dose of 3 × 10⁻⁶ cells. 6 / 0.2mL (mixed with Matrigel at a 1:1 ratio). Forty-two animals were selected for grouping and administered the drug. The mean tumor volume of these 42 animals was 94.43±2.69mm. 3 Animals were randomly divided into 6 groups of 7 animals each, based on tumor volume and body weight. On the day of grouping (D1), each group of animals was administered the prescribed dose. The grouping and administration regimens are shown in Table 1 below.

[0165] Table 1: Grouping and Dosing Regimens

[0166] 3. Tumor volume and animal weight measurement

[0167] Tumor volume

[0168] Tumor volume was measured three times a week, and the tumor inhibition rate (TGI) was calculated (%).

[0169] The formula for calculating tumor volume (TV) is: TV = 1 / 2 × a × b 2 , where a and b represent the long and short diameters of the tumor mass, respectively.

[0170] Tumor inhibition rate (TGI) (%) = [1 – (mean tumor volume at the end of treatment group administration - mean tumor volume at the beginning of treatment group administration) / (mean tumor volume at the end of treatment group administration - mean tumor volume at the beginning of treatment group administration)] × 100%.

[0171] Formula for calculating relative tumor volume (RTV): RTV = TV n / TV1×100%; where TV1 is the tumor volume on the day of administration, and TV n To measure the tumor volume on that day.

[0172] The formula for calculating relative tumor proliferation rate (T / C%) is: T / C% = RTV t / RTV c ×100%; of which RTV t RTV represents the average relative tumor volume in the treatment group. c The average relative tumor volume is the solvent control group.

[0173] CR stands for complete remission, which refers to the complete disappearance of tumor volume in animals.

[0174] animal weight

[0175] Measure the animal's weight three times a week and calculate the rate of change in body weight (BWC) using the following formula:

[0176] BWC = (BW n -BW1) / BW1×100%; where BW1 is the body weight on the day of administration for each group, and BW1 is the body weight on the day of administration. n This represents the weight at the time of each measurement.

[0177] 4. Data processing and statistical analysis

[0178] All data are presented as mean ± SEM. Statistical analysis was performed using GraphPad Prism 8.4.3 software on the grouped D26 data. One-way ANOVA was used for inter-group comparisons. If variances were homogeneous, Turkey analysis was used; if variances were unequal, Tamhane T2 or Dunnett T3 analysis was used.

[0179] The interaction between two drugs was evaluated using the following formula described in Clarke R. Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models. Breast Cancer Res Treat. 1997, 46(2-3):255-78. Synergy score = ((A / C) × (B / C)) / (AB / C); where A is the RTV value of drug A; B is the RTV value of drug B; C is the RTV value of the control group; and AB is the RTV value of the combination therapy of A and B. A synergy score > 1 indicates a synergistic effect between the two drugs; a synergy score = 1 indicates an additive effect; and a synergy score < 1 indicates an antagonistic effect.

[0180] 5. Experimental Results

[0181] The average tumor volume of each group of animals during the administration period is shown in Table 2 below.

[0182] Table 2: Average tumor volume of animals in each group during drug administration

[0183] On day 26 of drug administration, the tumor-suppressing effects of each group are shown in Table 3 below, and the p-values ​​for tumor volume comparison are shown in Table 4 (tumor volume was obtained by one-way ANOVA analysis, and the Dunnett T3 method was used for comparison between groups).

[0184] Table 3: Antitumor effects of drugs in each group on day 26 of administration

[0185] Table 4: p-values ​​for comparing tumor volume in different groups of animals on day 26 after drug administration. Note: ns indicates no statistical difference.

[0186] On day 26 of drug administration, the mean tumor volume in the solvent control group reached 1160.2 ± 146.93 mm. 3 The mean tumor volume in the compound 2 monotherapy group was 164.27 ± 70.33 mm. 3 The TGI was 93.45%, the T / C ratio was 16.03%, and the tumor volume was significantly different from the solvent control group (p = 0.0022). One animal (1 / 7) achieved complete remission (CR). The mean tumor volume in the compound 2 combined with anti-PD-1 antibody group was 53.41 ± 47.32 mm. 3The TGI was 103.85%, the T / C ratio was 3.72%, and the tumor volume was significantly different from the solvent control group (p = 0.0021). Five animals achieved complete remission (CR) (5 / 7). The synergistic score of compound 2 combined with the anti-PD-1 antibody was 4.10, indicating a synergistic effect between the two drugs. The mean tumor volume of compound 1 monotherapy group was 130.98 ± 70.42 mm. 3 The TGI was 96.57%, the T / C ratio was 12.97%, and the tumor volume was significantly different from the solvent control group (p = 0.0018). One animal achieved complete remission (CR) (1 / 7). The mean tumor volume in the compound 1 combined with anti-PD-1 antibody group was 6.21 ± 3.4 mm. 3 The TGI was 108.27%, the T / C ratio was 0.55%, and the tumor volume was significantly different from the solvent control group (p = 0.0024). Furthermore, four animals in this group achieved complete remission (CR) (4 / 7). The synergistic score of compound 1 combined with the anti-PD-1 antibody was 21.83, indicating a strong synergistic effect between the two drugs. In addition, the efficacy of compound 1 alone and in combination with the anti-PD-1 antibody was superior to that of compound 2.

[0187] After 26 days of drug administration, the experiment was terminated in the solvent group, the anti-PD-1 antibody monotherapy group, and the compound 1 monotherapy group. In the compound 2 monotherapy group, drug administration was discontinued to observe tumor growth. In the compound 2 combined with anti-PD-1 antibody group and the compound 1 combined with anti-PD-1 antibody group, drug administration continued until day 38, when all drugs were discontinued. Tumor growth in each group was observed until day 75. On day 75, it was observed that 5 out of 7 animals in the compound 2 combined with anti-PD-1 antibody group achieved complete remission (CR), and all 7 animals in the compound 1 combined with anti-PD-1 antibody group achieved CR.

[0188] During the experiment, one animal in the compound 2 combined with anti-PD-1 antibody group died on day 32, while the remaining animals had normal weight and good tolerance.

[0189] Example 2

[0190] Experimental objective: To determine whether the animals that achieved complete remission (CR) in Example 1 acquired adaptive anti-tumor immunity, a Re-challenge experiment was conducted. KPC cells were re-inoculated into the animals that achieved CR, and the growth of the tumor was observed to determine whether compound 1 or compound 2 combined with anti-PD-1 antibody produced a durable anti-tumor immune effect.

[0191] Experimental Methods: Mice that achieved complete remission (CR) at the experimental endpoint in Example 1 were used, specifically five mice from the compound 2 combined with anti-PD-1 antibody group (G4) and seven mice from the compound 1 combined with anti-PD-1 antibody group (G6). A control group of five wild-type female C57BL / 6J mice was also included. KPC cells were subcutaneously inoculated into the left axilla of these 17 female C57BL / 6J mice at a dose of 3 × 10⁻⁶ cells. 6 / 0.2mL (mix Matrigel at a 1:1 ratio). Measure tumor volume and animal weight twice a week.

[0192] Experimental results

[0193] The average tumor volume at different time points after grouping of the animals is shown in Table 5 below.

[0194] Table 5: Average tumor volume at different time points in each group of animals

[0195] During a 63-day observation period, tumors in the control group animals grew normally, while those treated with compound 1 combined with anti-PD-1 antibody showed normal growth.

[0196] Mice that achieved complete remission (CR) after treatment remained completely resistant to tumor growth even after a re-challenge test. This indicates that compound 1 enhances the therapeutic effect of anti-PD-1 antibodies, and this combination produces durable adaptive anti-tumor immunity.

[0197] During this experiment, on day 56 after cell inoculation, one animal in the compound 2 combined with anti-PD-1 antibody group died, while the remaining animals had normal weight and good tolerance.

[0198] Example 3: Clinical Trial

[0199] The safety, tolerability, and efficacy of compound 1 combination therapy in patients with solid tumors were studied in two phases: Phase Ib and Phase II.

[0200] (1) Stage Ib: Compound 1 in combination with evokimab for the treatment of patients with solid tumors.

[0201] Patients with advanced, unresectable locally advanced, recurrent, or metastatic solid tumors (including RAS-mutated and RAS-non-mutated patients) who have failed at least one line of systemic antitumor therapy, including but not limited to non-small cell lung cancer, colorectal cancer, and pancreatic cancer (including pancreatic ductal adenocarcinoma), will be enrolled. In addition, patients with advanced first-line NSCLC who carry RAS mutations but are negative for driver genes (EGFR / ALK, etc.) and positive for PD-L1 expression may also be considered for enrollment after evaluation.

[0202] Test drug: Compound 1, evokimab.

[0203] Dosage regimen: Each treatment cycle is 21 days. The dosing regimen for compound 1 and edoximab is as follows:

[0204] Compound 1 tablets are administered orally once daily (QD), starting with a dose of 16 mg, and then escalating to 2–3 dose groups of 16 mg, 24 mg, or 32 mg.

[0205] Evoximab is administered intravenously at a dose of 20 mg / kg on day 1 of each cycle.

[0206] (2) Phase II (Extended Study)

[0207] The process is divided into two queues.

[0208] Cohort 1: Compound 1 in combination with evokimab ± AP chemotherapy regimen (pemetrexed + cisplatin); Compound 1 in combination with evokimab ± AP chemotherapy regimen (pemetrexed + carboplatin) was used to treat patients with RAS-mutant non-small cell lung cancer.

[0209] Investigational drugs: Compound 1, evokimab, pemetrexed disodium, cisplatin, carboplatin.

[0210] Patients with advanced, locally advanced, and incurable non-small cell lung cancer (NSCLC) that are RAS-mutant and driver gene-negative (EGFR / ALK, etc.) and have undergone no prior systemic anti-tumor therapy for advanced disease were enrolled.

[0211] Dosage regimen:

[0212] Compound 1 in combination with evokimab: Each treatment cycle is 21 days, and the dosing regimen for compound 1 and evokimab is selected from the dosing regimen of phase Ib.

[0213] Compound 1 in combination with evoximab + AP chemotherapy (pemetrexed + cisplatin): Each treatment cycle is 21 days. The dosing regimen for Compound 1 and evoximab is selected from the Phase Ib regimen. Cisplatin is administered intravenously at a dose of 75 mg / m². 2 Administer on day 1 of each cycle. Pemetrexed disodium is administered intravenously at a dose of 500 mg / m². 2 (Based on pemetrexed), administer on day 1 of each cycle.

[0214] Compound 1 in combination with evokimab + AP chemotherapy (pemetrexed + carboplatin): Each treatment cycle is 21 days. The dosing regimen for Compound 1 and evokimab is selected from the phase Ib regimen. Carboplatin is administered intravenously at a dose of AUC = 5–6 on day 1 of each cycle. Pemetrexed disodium is administered intravenously at a dose of 500 mg / m². 2 (Based on pemetrexed), administer on day 1 of each cycle.

[0215] Cohort 2: Compound 1 in combination with evokinemab for the treatment of patients with solid tumors.

[0216] Test drug: Compound 1, evokimab.

[0217] Patients with advanced, unresectable locally advanced, recurrent, or metastatic solid tumors (including RAS-mutated and RAS-non-mutated patients) who have failed at least one line of systemic antitumor therapy, including but not limited to non-small cell lung cancer, colorectal cancer, and pancreatic cancer (including pancreatic ductal adenocarcinoma), will be enrolled. In addition, patients with advanced non-small cell lung cancer who have received first-line treatment and are carrying RAS mutations may also be considered for enrollment after evaluation.

[0218] Dosing regimen: Each treatment cycle is 21 days. The dosing regimen for compound 1 and evokimab is selected from the dosing regimen of phase Ib.

[0219] During Phase Ib and II studies, the dosage of compound 1 may be adjusted based on obtained clinical outcome data or patient treatment status (e.g., using higher doses of 40 mg, 48 mg, etc., or intermediate doses such as 20 mg, or lower doses such as 12 mg or 8 mg), or different dosing frequencies (e.g., compound 1 administered twice daily, three times daily, or every other day), or the specific dosing regimen of other combination drugs may be adjusted (e.g., the starting dose and dosing frequency of AP chemotherapy drugs, evosimib, etc.). Considering the different sensitivities of different tumor types and patient tolerability, different dosages may be selected for different cohorts / tumor types.

[0220] Subjects received treatment according to the above dosing regimen and continued dosing until disease progression, intolerable adverse events, or other circumstances requiring discontinuation of treatment occurred.

[0221] During the study, efficacy was assessed according to RECIST 1.1 criteria, including the following indicators.

[0222] Objective response rate (ORR): defined as the proportion of subjects who achieve complete remission (CR) or partial remission (PR) after treatment.

[0223] Disease control rate (DCR): defined as the proportion of subjects who achieve complete remission (CR), partial remission (PR), or stable disease (SD) after treatment.

[0224] Clinical benefit rate (CBR): defined as the proportion of patients who achieve complete remission (CR), partial remission (PR), or stable disease (SD) lasting ≥24 weeks after treatment.

[0225] Duration of Response (DOR): Defined as the time from the start of recording to objective response to the first radiographic progression of the tumor and / or death from any cause.

[0226] Time to Response (TTR): Defined as the time from the start of study treatment to the first recorded objective response.

[0227] Progression-free survival (PFS): defined as the time from the start of investigational treatment to the onset of radiographic progression of the tumor and / or death from any cause.

[0228] Overall survival (OS): defined as the time from the start of research treatment to death from any cause.

[0229] In addition, safety was assessed through adverse events (AEs), treatment-related adverse events (TEAEs), treatment-related adverse events (TRAEs), serious adverse events (SAEs), as well as vital signs, physical examination, laboratory tests, ECOG score, and 12-lead electrocardiogram. The severity of adverse events was determined according to the NCI CTCAEv5.0 criteria.

[0230] Based on the clinical trial results, further expansion of the study may be considered: replacing evokinemab in Phase II with pembrolizumab, cantulimumab, or toripalimab. Pembrolizumab, cantulimumab, and toripalimab can be administered according to the regimen recommended in the drug instructions, and the dosing regimen for compound 1 can be selected from the dosing regimen in Phase Ib.

[0231] While specific embodiments of this disclosure have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of this disclosure. Therefore, the scope of protection of this disclosure is defined by the appended claims.

Claims

1. Use of a combination of a RAS inhibitor and a PD-1 / PD-L1 inhibitor in the manufacture of a medicament for the treatment of a tumor, wherein the RAS inhibitor is Compound 1 or a pharmaceutically acceptable salt thereof; 2. Use according to claim 1, characterized in that, The PD-1 / PD-L1 inhibitor is a PD-1 / PD-L1 antibody or its antigen-binding fragment.

3. Use according to claim 2, characterized in that, The PD-1 / PD-L1 antibodies mentioned are Camrelizumab, Pembrolizumab, Adebrelimab, Toripalimab, Tislelizumab, Sintilimab, Penpulimab, Cadonilimab, Ivonescimab, Serplulimab, Pucotenlimab, Zimberelimab, Nivolumab, Benmelstobart, Sugemalimab, Socazolimab, and Envorin. Monoclonal antibodies (Envafolimab), Atezolizumab, Durvalumab, Geptanolimab, Lipustobart, Cemiplimab, Prolgolimab, Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, Iparomlimab, Spartalizumab, Retifanlimab, Sasanlimab, Rulonilimab, Enlonstobart, or Avelumab.

4. The use according to claim 1, characterized in that, The PD-1 / PD-L1 inhibitor is evosimib or its antigen-binding fragment.

5. The use according to claim 1, characterized in that, The PD-1 / PD-L1 inhibitor is pembrolizumab or its antigen-binding fragment.

6. The use according to claim 1, characterized in that, The PD-1 / PD-L1 inhibitor is cantulimumab or its antigen-binding fragment.

7. The use according to claim 1, characterized in that, The PD-1 / PD-L1 inhibitor is toripalimab or its antigen-binding fragment.

8. Use according to any one of claims 1 - 7, characterized in that, The combination does not include other oncology therapeutics besides the RAS inhibitor and the PD-1 / PD-L1 inhibitor; or the combination or pharmaceutical combination product further includes one or more additional oncology therapeutics.

9. Use according to claim 8, characterized in that, The one or more additional tumor treatment agents are pemetrexed and platinum-based chemotherapy drugs.

10. The use according to claim 9, characterized in that, The platinum-based chemotherapy drug is cisplatin or carboplatin.

11. Use according to any one of claims 1 - 10, characterized in that The tumors mentioned are one or more of the following: brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colon cancer, rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, glioblastoma, and neuroendocrine tumors.

12. Use according to any one of claims 1 - 10, characterized in that, The tumor is a solid tumor.

13. Use according to claim 11 or 12, characterized in that, The tumor is non-small cell lung cancer.

14. Use according to claim 11 or 12, characterized in that, The tumor is colon cancer and / or rectal cancer.

15. Use according to claim 11 or 12, characterized in that, The tumor is pancreatic cancer.

16. The use according to claim 15, characterized in that, The pancreatic cancer mentioned is pancreatic ductal adenocarcinoma.

17. The use according to any one of claims 1 - 16, characterized in that The tumor contains RAS mutations.

18. The use according to any one of claims 1 to 17, characterized in that The tumor contains a KRAS mutation.

19. The use according to any one of claims 1 to 18, characterized in that The tumor contains a KRAS G12C mutation.

20. The use according to any one of claims 1 to 18, characterized in that The tumor contains a KRAS G12D mutation.

21. The use according to any one of claims 1 to 18, characterized in that, The tumor contains a KRAS G12V mutation.

22. The use according to any one of claims 1 - 16, characterized in that The tumor does not contain RAS mutations.

23. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) administered orally once daily.

24. The use according to any one of claims 1 to 22, characterized in that, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) administered orally once daily.

25. The use according to any one of claims 1 to 22, characterized in that, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) administered orally once daily.

26. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) administered orally once daily.

27. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) administered orally once daily.

28. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) orally once daily.

29. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) orally once daily.

30. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) administered orally once daily.

31. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) administered orally twice daily.

32. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) administered orally twice daily.

33. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) administered orally twice daily.

34. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) administered orally twice daily.

35. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) administered orally twice daily.

36. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) administered orally twice daily.

37. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) administered orally twice daily.

38. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) administered orally twice daily.

39. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) orally, three times daily.

40. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) orally, three times daily.

41. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) orally, three times daily.

42. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) orally, three times daily.

43. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) orally, three times daily.

44. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) orally, three times daily.

45. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) orally, three times daily.

46. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) orally, three times daily.

47. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 8 mg (in the free form of compound 1) administered orally every other day.

48. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 12 mg (in the free form of compound 1) administered orally every other day.

49. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 16 mg (in the free form of compound 1) administered orally every other day.

50. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 20 mg (in the free form of compound 1) administered orally every other day.

51. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 24 mg (in the free form of compound 1) administered orally every other day.

52. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 32 mg (in the free form of compound 1) orally, once every other day.

53. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 40 mg (in the free form of compound 1) administered orally every other day.

54. The use of any one of claims 1-22, wherein, The single dose of compound 1 or a pharmaceutically acceptable salt thereof is 48 mg (in the free form of compound 1) administered orally every other day.

55. The use according to any one of claims 4 to 50, wherein the use is characterized in that, The single dose of evokinemab is 20 mg / kg (based on body weight), administered intravenously once every three weeks.

56. The use of claim 55, wherein, The combination is applied for one or more cycles, each of which is three weeks.

57. Use of a RAS inhibitor in the preparation of a medicament for treating tumors in combination with a PD-1 / PD-L1 inhibitor and optionally an additional tumor therapeutic agent as described in any one of claims 8, 9 or 10, wherein the RAS inhibitor, the PD-1 / PD-L1 inhibitor and the tumor are as described in any one of claims 1–56.

58. A pharmaceutical combination product or kit comprising a RAS inhibitor and a PD-1 / PD-L1 inhibitor, and optionally an additional oncology therapeutic agent as described in claims 8, 9, or 10; wherein the RAS inhibitor and the PD-1 / PD-L1 inhibitor are as described in any one of claims 1–56.

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