Combination of ras inhibitor and EGFR inhibitor and use thereof

Abstract

The present application relates to a combination of a RAS inhibitor and an EGFR inhibitor and a use thereof. Specifically, the present application relates to a combination of a RAS inhibitor and an EGFR inhibitor and a use thereof for treating tumors. In the combination, the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

Description

Combinations and uses of RAS inhibitors and EGFR inhibitors

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese Patent Application No. 202411625653.9, filed on November 13, 2024; Chinese Patent Application No. 202510391644.6, filed on March 28, 2025; Chinese Patent Application No. 202511620883.0, filed on November 6, 2025; and U.S. Patent Application No. 63 / 721,084, filed on November 15, 2024. The full text of the above four 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 an EGFR 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] Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein belonging to the ErbB family of tyrosine kinase receptors. EGFR activation leads to autophosphorylation of the receptor tyrosine kinase, which initiates a cascade of downstream signaling pathways involved in regulating cell proliferation, differentiation, and survival. EGFR is aberrantly activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation, and is associated with the development of various human cancers.

[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 RAS inhibitors and EGFR inhibitors and their uses.

[0008] This disclosure provides a pharmaceutical combination product comprising a RAS inhibitor and an EGFR inhibitor; wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof;

[0009] In some implementations, the drug combination product includes:

[0010] (i) a first pharmaceutical composition comprising the RAS inhibitor; and

[0011] (ii) A second pharmaceutical composition comprising the EGFR inhibitor.

[0012] This disclosure also provides the use of the above-described pharmaceutical combination product in the preparation of a medicament for treating tumors.

[0013] This disclosure also provides the use of a combination of a RAS inhibitor and an EGFR inhibitor in the preparation of a medicament for treating tumors, wherein the RAS inhibitor is as defined herein.

[0014] This disclosure also provides the use of a RAS inhibitor in the preparation of a medicament for the treatment of tumors in combination with an EGFR inhibitor, wherein the RAS inhibitor is as defined herein.

[0015] This disclosure also provides the use of an EGFR 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.

[0016] 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 an EGFR inhibitor, wherein the RAS inhibitor is as defined herein.

[0017] 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 an EGFR inhibitor.

[0018] This disclosure also provides a pharmaceutical combination product or kit, comprising:

[0019] (i) a pharmaceutical composition comprising a RAS inhibitor, wherein the RAS inhibitor is as defined herein; and

[0020] (ii) Instructions for the combined use of the RAS inhibitor with EGFR inhibitors and optional other tumor treatment agents.

[0021] This disclosure also provides a pharmaceutical combination product or kit, comprising:

[0022] (i) a pharmaceutical composition comprising a RAS inhibitor, wherein the RAS inhibitor is as defined herein; and

[0023] (ii) Instructions for the combined use of the RAS inhibitor and the EGFR inhibitor.

[0024] This disclosure provides a method for treating a tumor (e.g., cancer) in a subject with this need, the method comprising administering a therapeutically effective amount to the subject with this need:

[0025] (i) Compound 1 or a pharmaceutically acceptable salt thereof; and

[0026] (ii) EGFR inhibitors.

[0027] This disclosure provides a method for use in treating a subject with a tumor (e.g., cancer) comprising administering to the subject a therapeutically effective amount of a combination of compound 1 or a pharmaceutically acceptable salt thereof with an EGFR inhibitor.

[0028] In some embodiments, the EGFR inhibitor is a small molecule inhibitor. In some embodiments, the EGFR inhibitor is anti-EGFR.

[0029] In some implementations, the EGFR inhibitor is Rilertinib, Rezivertinib, Sunvozertinib, Befotertinib, Pyrotinib, Mobocertinib, Alflutinib, Lazertinib, Almonertinib, Dacomitinib, Neratinib, Brigatinib, Osimertinib, Afatinib, Icotinib, Lapatinib, Gefitinib, Limer The EGFR inhibitor is retinotinib, zorifertinib, mefatinib, larotinib, sevabertinib, avitinib, ruserontinib, varlitinib, asandeutertinib, zipalertinib, andamertinib, olafertinib, epertinib, sapitinib, allitinib, Kenaitinib, Nazartinib, sutetinib, selatinib, poziotinib, lifirafenib, vandetanib, erlotinib, canertinib, daphnetin, pelitinib, tivozanib, rociletinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is retinotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is retinotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is suvortinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is befotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is pyrotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is mobocetinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is vometinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is lanzatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is amitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is dacomitinib or a pharmaceutically acceptable salt thereof.In some embodiments, the EGFR inhibitor is neratinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is brigatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is osimertinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is afatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is icotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is lapatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is gefitinib or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the EGFR inhibitor is an EGFR antibody or its antigen-binding fragment. In some embodiments, the EGFR antibody is cetuximab, amivantamab, necitumumab, panitumumab, nimotuzumab, Izalontamab, modotuximab, pimurutamab, demupitamab, petosemtamab, ametumumab, lossatuxizumab, laprituximab, serclutamab, matuzumab, clezutoclax, mirzotamab, panitumamab, or bafisontamab.

[0031] In some embodiments, the EGFR inhibitor is cetuximab or its antigen-binding fragment. In some embodiments, the EGFR inhibitor is eleventuzumab or its antigen-binding fragment. In some embodiments, the EGFR inhibitor is nexituzumab or its antigen-binding fragment. In some embodiments, the EGFR inhibitor is panitumamab or its antigen-binding fragment. In some embodiments, the EGFR inhibitor is nimotuzumab or its antigen-binding fragment. In some embodiments, the EGFR inhibitor is panitumamab or its antigen-binding fragment.

[0032] In some implementations, the EGFR inhibitor is cetuximab.

[0033] In some embodiments, the EGFR inhibitor is AC480, AEE788, AG-1478, AG-18, AG-490, AST-1306, AV-412, AZ5104, AZD3759, BIBX 1382, CGP-52411, CL-387785, CNX-2006, CUDC-101, OSI-420, PD153035HCl, PD168393, TAK-285, Tyrphostin 9, Tyrphostin AG 183, WHI-P154, WHI-P180, WZ3146, or WZ4002.

[0034] In some embodiments, the combination or pharmaceutical combination product may further include one or more additional oncology therapeutic agents. In some embodiments, the one or more additional oncology therapeutic agents may be one or more chemotherapeutic agents and optionally chemotherapeutic adjuvants. In some embodiments, the one or more additional oncology therapeutic agents are platinum-based chemotherapy agents (e.g., oxaliplatin), leucovorin, and 5-fluorouracil. In some embodiments, the one or more additional oncology therapeutic agents are oxaliplatin, leucovorin, and 5-fluorouracil. In some embodiments, the one or more additional oncology therapeutic agents are irinotecan, leucovorin, and 5-fluorouracil.

[0035] In some embodiments, the combination or pharmaceutical combination product is a combination or pharmaceutical combination product of the RAS inhibitor, the EGFR inhibitor, oxaliplatin, leucovorin calcium, and 5-fluorouracil.

[0036] In some embodiments, the combination or pharmaceutical combination product is a combination or pharmaceutical combination product of the RAS inhibitor, the EGFR inhibitor, irinotecan, leucovorin calcium, and 5-fluorouracil.

[0037] In some embodiments, the combination or drug combination product does not include other oncology therapeutics besides the RAS inhibitor and the EGFR inhibitor.

[0038] In some implementations, the tumor is cancer.

[0039] In some implementations, the tumor may be a hematologic malignancy or a solid tumor.

[0040] In some implementations, the tumor may be 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, bladder cancer, etc. 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). 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.

[0041] In some implementations, the tumor is a solid tumor.

[0042] In some embodiments, the tumor is breast cancer, gastrointestinal cancer, head and neck cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, salivary gland tumor, thyroid cancer, or uterine cancer. In some embodiments, the gastrointestinal cancer is anal cancer, appendix cancer, bile duct cancer, cholangiocarcinoma, colorectal cancer, gallbladder cancer, small bowel cancer, or stomach cancer.

[0043] In some embodiments, the tumor is lung cancer. In some embodiments, the tumor is non-small cell lung cancer, such as lung adenocarcinoma, lung squamous cell carcinoma, lung large cell carcinoma, lung adenosquamous carcinoma, or lung carcinoid. In some embodiments, the tumor is lung adenocarcinoma.

[0044] In some implementations, the tumor is colon cancer and / or rectal cancer (which may also be collectively referred to as colorectal cancer).

[0045] In some implementations, the tumor is pancreatic cancer.

[0046] In some implementations, the tumor is cholangiocarcinoma.

[0047] In some implementations, the tumor is a RAS-dependent tumor.

[0048] In some implementations, the tumor contains RAS mutations.

[0049] 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. In some embodiments, the tumor is KRAS-driven, HRAS-driven, or NRAS-driven.

[0050] 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. In some embodiments, 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.

[0051] In some implementations, the tumor does not contain RAS mutations.

[0052] 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.

[0053] In some implementations, the pancreatic cancer, when it occurs anywhere, can be pancreatic ductal adenocarcinoma.

[0054] 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.

[0055] In some embodiments, the tumor is non-small cell lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma, lung large cell carcinoma, lung adenosquamous carcinoma, lung carcinoid), and the non-small cell lung cancer 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 non-small cell lung cancer containing a KRAS G12C mutation. In some embodiments, the tumor is non-small cell lung cancer containing a KRAS G12D mutation. In some embodiments, the tumor is non-small cell lung cancer (NSCLC) containing a KRAS G12V mutation. In some embodiments, the tumor is 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.

[0056] In some embodiments, this disclosure provides the use of a combination of a RAS inhibitor and cetuximab, a platinum-based chemotherapy agent (e.g., oxaliplatin), leucovorin, and 5-fluorouracil in the preparation of a medicament for treating RAS-mutant colorectal and / or rectal cancer, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, this disclosure provides the use of a RAS inhibitor in the preparation of a medicament for the treatment of RAS-mutant colorectal and / or rectal cancer in combination with cetuximab, platinum-based chemotherapy agents (e.g., oxaliplatin), leucovorin, and 5-fluorouracil, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, this disclosure provides a method for treating RAS-mutated colon and / or rectal cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a RAS inhibitor, cetuximab, a platinum-based chemotherapy agent (e.g., oxaliplatin), leucovorin, and 5-fluorouracil, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0059] 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 cetuximab, a platinum-based chemotherapy drug (e.g., oxaliplatin), leucovorin, and 5-fluorouracil.

[0060] In some embodiments, this disclosure provides the use of a combination of a RAS inhibitor and cetuximab, irinotecan, leucovorin calcium, and 5-fluorouracil in the preparation of a medicament for treating RAS-mutant colorectal cancer and / or rectal cancer, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, this disclosure provides the use of a RAS inhibitor in the preparation of a medicament for the treatment of RAS-mutant colorectal and / or rectal cancer in combination with cetuximab, irinotecan, leucovorin, and 5-fluorouracil, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, this disclosure provides a method for treating RAS-mutated colon and / or rectal cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a RAS inhibitor, cetuximab, irinotecan, leucovorin, and 5-fluorouracil, wherein the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0063] 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 cetuximab, irinotecan, leucovorin, and 5-fluorouracil.

[0064] In some embodiments, this disclosure provides a method for treating non-small cell lung cancer (NSCLC) in a subject with this need, the method comprising administering a therapeutically effective amount to the subject with this need:

[0065] (i) Compound 1 or a pharmaceutically acceptable salt thereof;

[0066] (ii) EGFR inhibitors; and

[0067] (iii) Additional treatments;

[0068] Among them, EGFR inhibitors can be as described in this disclosure.

[0069] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having an EGFR exon 19 deletion or an exon 21L858R mutation, and the additional therapeutic agent is afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib.

[0070] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional treatment agent is osimertinib plus pemetrexed.

[0071] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional treatment agent is osimertinib + pemetrexed + cisplatin or carboplatin.

[0072] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional therapeutic agent is erlotinib + ramucirumab.

[0073] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional therapeutic agent is erlotinib plus bevacizumab.

[0074] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having EGFR exon 19 deletion or exon 21L858R mutation, and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed.

[0075] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having EGFR S768I, L861Q and / or G719X mutations, and the additional therapeutic agent is afatinib, erlotinib, dacomitinib, gefitinib or osimertinib.

[0076] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having EGFR S768I, L861Q and / or G719X mutations, and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed.

[0077] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer has been identified as having an EGFR exon 20 insertion mutation, and the additional therapeutic agent is amivantamab-vmjw.

[0078] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having an EGFR exon 20 insertion mutation, and the additional therapeutic agent is amivantamab-vmjw + carboplatin + pemetrexed.

[0079] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having a KRAS G12C mutation, and the additional therapeutic agent is (adagrasib, divarasib, garsorasib, glecirasib, olomorasib, RMC-6291, or sotorasib) + / - anti-EGFR mab.

[0080] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having a BRAF V600E mutation, and the additional therapeutic agent is (dabrafenib + trametinib, encorafenib + binimetinib, dabrafenib, or vemurafenib) + / - anti-EGFR mab.

[0081] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is 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 mab.

[0082] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the cancer is identified as having a HER2 mutation, and the additional therapeutic agent is (fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine) + / - anti-EGFR mab.

[0083] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is determined to have non-squamous histology, and the additional treatment agent is (pembrolizumab or cemiplimab-rwlc) + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0084] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional treatment agent is pembrolizumab + pemetrexed + / - anti-EGFR mab.

[0085] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional treatment agent is atezolizumab + bevacizumab + carboplatin + paclitaxel + / - anti-EGFR mab.

[0086] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is atezolizumab + bevacizumab + / - anti-EGFR mab.

[0087] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is atezolizumab + carboplatin + albumin-bound paclitaxel + / - anti-EGFR mab.

[0088] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional treatment agent is nivolumab + ipilimumab + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0089] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is cemiplimab-rwlc + pemetrexed + (carboplatin / cisplatin) + / - anti-EGFR mab.

[0090] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is cemiplimab-rwlc + pemetrexed + / - anti-EGFR mab.

[0091] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is tremelimumab-actl + durvalumab + pemetrexed + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0092] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is durvalumab + pemetrexed + / - anti-EGFR mab.

[0093] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional treatment agent is carboplatin + pemetrexed + / - anti-EGFR mab.

[0094] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional treatment agent is cisplatin (+pemetrexed) + / - anti-EGFR mab.

[0095] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional treatment agent is bevacizumab + carboplatin + (paclitaxel or pemetrexed) + / - anti-EGFR mab.

[0096] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional treatment agent is bevacizumab + cisplatin + pemetrexed + / - anti-EGFR mab.

[0097] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is bevacizumab + / - anti-EGFR mab.

[0098] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is bevacizumab + pemetrexed + / - anti-EGFR mab.

[0099] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having non-squamous histological features, and the additional therapeutic agent is pemetrexed + / - anti-EGFR mab.

[0100] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having squamous histology, and the additional treatment agent is pembrolizumab + carboplatin + (paclitaxel or albumin-bound paclitaxel) + / - anti-EGFR mab.

[0101] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having squamous histological features, and the additional treatment agent is nivolumab + ipilimumab + paclitaxel + carboplatin + / - anti-EGFR mab.

[0102] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the subject in need is identified as having squamous histological features, and the additional therapeutic agent is tremelimumab-actl + durvalumab + gemcitabine + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0103] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is (pembrolizumab or atezolizumab or cemiplimab-rwlc or nivolumab or durvalumab or nivolumab + ipilimumab or tremelimumab-actl + durvalumab) + / - anti-EGFR mab.

[0104] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is fam-trastuzumab deruxtecan-nxki+ / -anti-EGFR mab.

[0105] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is ramucirumab + docetaxel + / - anti-EGFR mab.

[0106] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is gemcitabine + docetaxel + / - anti-EGFR mab.

[0107] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is gemcitabine + vinorelbine + / - anti-EGFR mab.

[0108] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is (albumin-bound paclitaxel or docetaxel or gemcitabine or paclitaxel) + / - anti-EGFR mab.

[0109] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is cemiplimab-rwlc + paclitaxel + (carboplatin or cisplatin) + / - anti-EGFR mab.

[0110] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is tremelimumab-actl + durvalumab + carboplatin + albumin-bound paclitaxel + / - anti-EGFR mab.

[0111] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is carboplatin + (albumin-bound paclitaxel or docetaxel or etoposide or gemcitabine or paclitaxel) + / - anti-EGFR mab.

[0112] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the additional therapeutic agent is cisplatin + (docetaxel or etoposide or gemcitabine or paclitaxel) + / - anti-EGFR mab.

[0113] In some embodiments of the aforementioned method for treating non-small cell lung cancer, the anti-EGFR mab is cetixumab or panitumuab.

[0114] In some embodiments, this disclosure provides a method for treating colorectal cancer (CRC) in a subject with this need, the method comprising administering a therapeutically effective amount to the subject with this need:

[0115] (i) Compound 1 or a pharmaceutically acceptable salt thereof;

[0116] (ii) EGFR inhibitors; and

[0117] (iii) Additional treatments;

[0118] Among them, EGFR inhibitors can be as described in this disclosure.

[0119] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having a dMMR / MSI-H mutation, and the additional therapeutic agent is anti-EGFR mab+ (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0120] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having a POLE / POLD1 mutation, and the additional therapeutic agent is anti-EGFR mab+ (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0121] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having a BRAF WT mutation, and the additional therapeutic agent is anti-EGFR mab+ (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0122] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having any RAS mutation, and the additional therapeutic agent is anti-EGFR mab+ (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0123] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having any KRAS mutation, and the additional therapeutic agent is anti-EGFR mab+ (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0124] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having any HER2 mutation, and the additional therapeutic agent is anti-EGFR mab+ (pembrolizumab or nivolumab or nivolumab + ipilimumab or dostarlimab-gxly).

[0125] In some embodiments of the aforementioned methods for treating colorectal cancer, the additional therapeutic agent is anti-EGFR mab plus chemotherapy.

[0126] In some embodiments of the aforementioned method for treating colorectal cancer, the additional therapeutic agent is anti-VEGFR mab + anti-EGFR mab + chemotherapy.

[0127] In some embodiments of the aforementioned methods for treating colorectal cancer, the additional therapeutic agent is anti-EGFR mab+ (fruquintinib or regorafenib).

[0128] In some embodiments of the aforementioned method for treating colorectal cancer, the additional therapeutic agent is an anti-EGFR mab.

[0129] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having a BRAF V600E mutation, and the additional therapeutic agent is encorafenib+ / -anti-EGFR mab.

[0130] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having a BRAF V600E mutation, and the additional therapeutic agent is naporafenib+ / - anti-EGFR mab.

[0131] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having HER2 amplification or IHC 3+, and the additional therapeutic agent is trastuzumab + (pertuzumab or lapatinib or tucatinib) + / - anti-EGFR mab.

[0132] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having HER2 amplification or IHC 3+, and the additional therapeutic agent is fam-trastuzumab deruxtecan-nxki+ / -anti-EGFR mab.

[0133] In some embodiments of the aforementioned method for treating colorectal cancer, the cancer is identified as having a KRAS G12C mutation, and the additional therapeutic agent is an anti-EGFR mab+ (adagrasib, sotorasib, olomorasib, divarasib, glecirasib, garsorasib, or RMC-6291).

[0134] In some embodiments of the aforementioned method for treating colorectal cancer, the anti-EGFR mab is cetuximab or panitumuab.

[0135] In some embodiments of the aforementioned method for treating colorectal cancer, the anti-VEGFR mab is bevacizumab, raucirumab, or zivaflibercept.

[0136] In some embodiments of the aforementioned methods for treating colorectal cancer, 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 combination of 5-FU also includes leucovorin.

[0137] In some embodiments, this disclosure provides a method for treating pancreatic ductal adenocarcinoma (PDAC) in a subject with this need, the method comprising administering a therapeutically effective amount to the subject with this need:

[0138] (i) Compound 1 or a pharmaceutically acceptable salt thereof;

[0139] (ii) EGFR inhibitors; and

[0140] (iii) Additional treatments;

[0141] Among them, EGFR inhibitors can be as described in this disclosure.

[0142] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is 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 mab.

[0143] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a BRAF WT mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0144] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having any RAS mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0145] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having any HER2 mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0146] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having any BRCA1 / 2 mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0147] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having any PALB2 mutation, and the additional therapeutic agent is (pembrolizumab or nivolumab or nivolumab) + (ipilimumab or dostarlimab-gxly) + / - anti-EGFR mab.

[0148] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the additional therapeutic agent is chemotherapy plus / - anti-EGFR mab.

[0149] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the additional therapeutic agent is an anti-EGFR mab.

[0150] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a BRAF V600E mutation, and the additional therapeutic agent is dabrafenib+(trametinib or binimetinib)+ / - anti-EGFR mab.

[0151] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a BRAF V600E mutation, and the additional therapeutic agent is naporafenib+(trametinib or binimetinib)+ / - anti-EGFR mab.

[0152] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a HER2-positive mutation or IHC 3+, and the additional therapeutic agent is fam-trastuzumab deruxtecan-nxki+ / -anti-EGFR mab.

[0153] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a KRAS G12C mutation, and the additional therapeutic agent is (adagrasib or sotorasib or olomorasib or divarasib or glecirasib or garsorasib or RMC-6291) + / - anti-EGFR mab.

[0154] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a BRCA1 / 2 mutation, and the additional therapeutic agent is gemcitabine + cisplatin + / - anti-EGFR mab.

[0155] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a BRCA1 / 2 mutation, and the additional therapeutic agent is rucaparib+ / -anti-EGFR mab.

[0156] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a BRCA1 / 2 mutation, and the additional therapeutic agent is olaparib (BRCA1 / 2 only) + / - anti-EGFR mab.

[0157] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a PALB2 mutation, and the additional therapeutic agent is gemcitabine + cisplatin + / - anti-EGFR mab.

[0158] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a PALB2 mutation, and the additional therapeutic agent is rucaparib+ / -anti-EGFR mab.

[0159] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the cancer is identified as having a PALB2 mutation, and the additional therapeutic agent is olaparib (BRCA1 / 2 only) + / - anti-EGFR mab.

[0160] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the anti-EGFR mab is cetuximab or panitumuab.

[0161] In some embodiments of the aforementioned method for treating pancreatic ductal adenocarcinoma, the anti-VEGFR mab is bevacizumab, raucirumab, or zivaflibercept.

[0162] In some embodiments of the aforementioned methods for treating pancreatic ductal adenocarcinoma, the chemotherapy may be (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.

[0163] In some embodiments, the non-small cell lung cancer, occurring anywhere, can be adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma, or carcinoid carcinoma. In some embodiments, the non-small cell lung cancer, occurring anywhere, can be adenocarcinoma.

[0164] In some implementations, the colon cancer and / or rectal cancer, when present in either location, may be adenocarcinoma.

[0165] 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.

[0166] In some embodiments, the tumor contains an EGFR mutation. In some embodiments, the tumor does not contain an EGFR mutation.

[0167] In some implementations, all types of tumors described in this disclosure may be advanced, locally advanced, recurrent, or metastatic.

[0168] In some embodiments, the subject has not received systemic antitumor therapy for advanced tumors prior to administration of the combination of this disclosure.

[0169] 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 therapy disclosed herein. In some embodiments, the tumor is resistant to at least one EGFR inhibitor, which may be one of the EGFR inhibitor classes described above. In some embodiments, the tumor is resistant to the drug combination product or an EGFR inhibitor contained in the combination. In some embodiments, the tumor is resistant to osimertinib.

[0170] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having BRCA1 / 2 mutations.

[0171] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be confirmed to have PALB2 mutations.

[0172] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having BRAF mutations.

[0173] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be confirmed to have a BRAF V600E mutation.

[0174] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be confirmed to have HER2 mutations.

[0175] In some implementations, the tumors described in this disclosure, and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.), may be identified as having MSI mutations.

[0176] In some implementations, the non-small cell lung cancer described in this disclosure may be confirmed to have a BRAF V600E mutation.

[0177] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be confirmed to have HER2 mutations.

[0178] In some embodiments, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having MET exon 14 skipping mutations.

[0179] In some embodiments, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be confirmed to have EGFR exon 19 deletion or exon 21L858R mutation.

[0180] In some embodiments, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having EGFR S768I, L861Q and / or G719X mutations.

[0181] In some embodiments, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having EGFR exon 20 insertion mutations.

[0182] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having MET amplification.

[0183] In some embodiments, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having MET exon 14 skipping mutations.

[0184] In some embodiments, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having NTRK 1 / 2 / 3 gene fusions.

[0185] In some embodiments, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having ALK (Anaplastic lymphoma kinase) gene rearrangements.

[0186] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having RET (Rearranged during transfection) rearrangements.

[0187] In some implementations, the tumors described in this disclosure and all types of tumors (e.g., non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.) may be identified as having ROS1 rearrangements.

[0188] In some embodiments, the tumors and all types of tumors described in this disclosure may be PD-L1 positive.

[0189] In some embodiments, the tumors and all types of tumors described in this disclosure may have a PD-L1 level of >= 50%.

[0190] In some embodiments, the tumors and all types of tumors described in this disclosure may have a PD-L1 level of ≥1%-49%.

[0191] In some embodiments, the tumors and all types of tumors described in this disclosure may be non-squamous cell carcinoma.

[0192] In some embodiments, the tumors and all types of tumors described in this disclosure may be squamous cell carcinoma.

[0193] In some embodiments, the tumors and all types of tumors described in this disclosure may have dMMR mutations.

[0194] In some embodiments, the tumors and all types of tumors described in this disclosure may have dMMR / MSI-H mutations.

[0195] In some embodiments, the tumors and all types of tumors described in this disclosure may have POLE / POLD1 mutations.

[0196] In some embodiments, the tumors and all types of tumors described in this disclosure may contain EGFR mutations. In some embodiments, all types of tumors described in this disclosure do not contain EGFR mutations.

[0197] In some embodiments, the tumors and all types of tumors described in this disclosure may contain ALK mutations. In some embodiments, the tumors and all types of tumors described in this disclosure may not contain ALK mutations.

[0198] In some implementations, the pancreatic ductal adenocarcinoma described in this disclosure may be confirmed to have RAS mutations.

[0199] In some embodiments, the pancreatic ductal adenocarcinoma described in this disclosure may be confirmed to have BRCA1 / 2 mutations.

[0200] In some embodiments, the pancreatic ductal adenocarcinoma described in this disclosure may be confirmed to have a PALB2 mutation.

[0201] In some embodiments, the pancreatic ductal adenocarcinoma described in this disclosure may be confirmed to have a BRAF mutation.

[0202] In some implementations, the pancreatic ductal adenocarcinoma described in this disclosure may be confirmed to have a HER2 mutation.

[0203] In some embodiments, the pancreatic ductal adenocarcinoma described in this disclosure may be confirmed to have an MSI mutation.

[0204] In some embodiments, the pancreatic ductal adenocarcinoma described in this disclosure may be confirmed to have dMMR mutations.

[0205] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having a RAS mutation.

[0206] In some implementations, the non-small cell lung cancer described in this disclosure may be confirmed to have a BRAF V600E mutation.

[0207] In some implementations, the non-small cell lung cancer described in this disclosure may be confirmed to have a HER2 mutation.

[0208] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having high levels of MET amplification.

[0209] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having a MET exon 14 skipping mutation.

[0210] In some embodiments, the non-small cell lung cancer described in this disclosure may be confirmed to have EGFR exon 19 deletion or exon 21L858R mutation.

[0211] In some embodiments, the non-small cell lung cancer described in this disclosure may be identified as having EGFR S768I, L861Q and / or G719X mutations.

[0212] In some embodiments, the non-small cell lung cancer described in this disclosure may be identified as having an EGFR exon 20 insertion mutation.

[0213] In some implementations, the non-small cell lung cancer described in this disclosure may be confirmed to have a BRAF V600E mutation.

[0214] In some implementations, the non-small cell lung cancer described in this disclosure may be confirmed to have a HER2 mutation.

[0215] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having MET amplification.

[0216] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having a MET exon 14 skipping mutation.

[0217] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having NTRK 1 / 2 / 3 gene fusions.

[0218] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having ALK gene rearrangements.

[0219] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having RET rearrangements.

[0220] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as having ROS1 rearrangements.

[0221] In some embodiments, the non-small cell lung cancer described in this disclosure may have a PD-L1 level of >= 50%.

[0222] In some embodiments, the non-small cell lung cancer described in this disclosure may have a PD-L1 level of ≥1%-49%.

[0223] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as non-squamous cell carcinoma.

[0224] In some implementations, the non-small cell lung cancer described in this disclosure may be identified as squamous cell carcinoma.

[0225] In some implementations, the colorectal cancer described in this disclosure may be confirmed to have RAS mutations.

[0226] In some implementations, the colorectal cancer described in this disclosure may be confirmed to have a BRAF mutation.

[0227] In some implementations, the colorectal cancer described in this disclosure may be confirmed to have HER2 amplification.

[0228] In some embodiments, the colorectal cancer described in this disclosure may be confirmed to have dMMR / MSI-H mutations.

[0229] In some embodiments, the colorectal cancer described in this disclosure may be confirmed to have a POLE / POLD1 mutation.

[0230] In some implementations, the RAS inhibitor, PD-1 / PD-L1 inhibitor, and other therapeutic agents (when present) may be administered simultaneously or sequentially.

[0231] In some implementations, the RAS inhibitor, EGFR inhibitor, and other therapeutic agents (when present) may be administered simultaneously or sequentially.

[0232] In this disclosure, the RAS inhibitors, EGFR 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 method of administration, the RAS inhibitors, EGFR 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.

[0233] In some implementations, the RAS inhibitor is administered orally.

[0234] The RAS inhibitor can be administered at a fixed dose or based on the individual's weight or body surface area.

[0235] 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.

[0236] 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.

[0237] In some embodiments, the RAS inhibitor 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of 1 to 100 mg (based on the free form of compound 1). In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of 1 to 80 mg (based on the free form of compound 1). In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of 1 to 60 mg (based on the free form of compound 1). In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of 1 to 40 mg (based on the free form of compound 1). In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered at a daily dose of 1 to 20 mg (based on the free form of compound 1). In some embodiments, the above daily doses may be administered once daily. In some embodiments, the above daily doses may be administered twice daily. In some embodiments, the above daily doses may be administered once daily. In some embodiments, the above daily doses may be administered three times daily.

[0272] In some embodiments, the EGFR inhibitor is administered via intravenous injection, intramuscular injection, subcutaneous injection, or intravenous infusion. In some embodiments, the EGFR inhibitor is administered orally.

[0273] The EGFR inhibitor can be administered at a fixed dose or based on the individual's weight or body surface area.

[0274] In some embodiments, the single-dose administration of the EGFR 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. The dosage ranges are 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg. In some embodiments, the single-dose administration of the EGFR inhibitor is from 100 mg to 500 mg.

[0275] In some embodiments, the single-dose administration of the EGFR 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, etc. The doses 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 EGFR inhibitor is from 0.1 mg / kg to 10 mg / kg.

[0276] In some embodiments, the single-dose administration of the EGFR inhibitor 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 0.8 mg / m 2 0.9 mg / m 2 1mg / m 2 2mg / m2 、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 / m 2 、625mg / m 2 、650mg / m 2 、675mg / m2 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 EGFR inhibitor is administered. In some embodiments, the single-dose dose of the EGFR inhibitor is 10 mg / m². 2 Up to 500mg / m 2 (Based on body surface area).

[0277] In some embodiments, the EGFR inhibitor 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. The EGFR inhibitor is administered once daily. In some embodiments, the EGFR inhibitor is administered twice daily. In some embodiments, the EGFR inhibitor is administered three times daily. In some embodiments, the EGFR inhibitor may be administered twice weekly. In some embodiments, the EGFR inhibitor (e.g., cetuximab) may be administered once weekly. In some embodiments, the EGFR inhibitor may be administered once every two weeks. In some embodiments, the EGFR inhibitor may be administered once every three weeks.

[0278] In some embodiments, the single-dose ratio of the RAS inhibitor to the EGFR inhibitor can be from 1:1000 to 1000:1, for example, 1:1000, 1:950, 1:900, 1:850, 1:800, 1:750, 1:700, 1:650, 1:625, 1:600, 1:550, 1:500, 1:450, 1:400, 1:350, 1:300, 1:250, 1:200, 1:150, 1:125. 1:100, 1:75, 1:50, 1:25, 1:5, 1:1, 5:1, 25:1, 50:1, 75:1, 100:1, 125:1, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 550:1, 600:1, 625:1, 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1, or 1000:1.

[0279] In some embodiments, the EGFR inhibitor is administered at the standard dose and frequency when the EGFR inhibitor is used alone, such as the recommended dose and frequency in the EGFR inhibitor's package insert (e.g., cetuximab is recommended to be administered once weekly with an initial dose of 400 mg / m²). 2 Body surface area, followed by 250 mg / m² per week 2 Body surface area; or 500 mg / m² 2 Body surface area, every two weeks; the recommended dose of icotinib is 125 mg three times daily. In some embodiments, the EGFR inhibitor may be administered at 5% to 95% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) of the standard dose when the EGFR inhibitor is used alone.

[0280] In some embodiments, the single dose of cetuximab is 500 mg / m². 2 (Based on body surface area), administered intravenously once every two weeks.

[0281] In some embodiments, the cetuximab is administered intravenously at a dose of 400 mg / m² once on day 1. 2 The initial dose (based on body surface area); thereafter, administered weekly at a dose of 250 mg / m². 2 (Based on body surface area).

[0282] 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 oxaliplatin, leucovorin, 5-fluorouracil, etc., may be administered at the recommended dose and frequency in the drug label of the therapeutic agent.

[0283] In some embodiments, the single dose of oxaliplatin is 85 mg / m². 2 (Based on body surface area), administered intravenously once every two weeks.

[0284] In some embodiments, the single-dose administration of the calcium folinate is 400 mg / m². 2 (Calculated as leucovorin, based on body surface area), administered intravenously once every two weeks.

[0285] In some embodiments, the 5-fluorouracil is administered via intravenous bolus injection at a dose of 400 mg / m². 2 (Based on body surface area), followed by a continuous intravenous infusion of a total volume of 2400 mg / m² over 46-48 hours. 2 5-Fluorouracil (based on body surface area), once every two weeks.

[0286] In some embodiments, the irinotecan may be in the form of irinotecan hydrochloride. In some embodiments, the single-dose administration of the irinotecan hydrochloride is 180 mg / m². 2 (Calculated as C33H38N4O6·HCl, based on body surface area), administered intravenously once every two weeks.

[0287] The combination of RAS inhibitors, EGFR 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, EGFR 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, EGFR inhibitors, and optional other therapeutic agents disclosed herein can be administered for one or more cycles, wherein each cycle can be four weeks. In some implementations, the RAS inhibitor, EGFR 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.

[0288] In some implementations, the combination of the RAS inhibitor, EGFR inhibitor, and optional other therapeutic agents achieves a synergistic effect.

[0289] 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.

[0290] 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.

[0291] 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 an EGFR inhibitor (e.g., for the treatment of cancer). In other embodiments, the drug combination product of this disclosure may include: a pharmaceutical composition containing an EGFR inhibitor; and a package insert indicating that the EGFR 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 an EGFR 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: individual pharmaceutical compositions comprising a RAS inhibitor and an EGFR inhibitor (i.e., a unit dosage form comprising both a RAS inhibitor and an EGFR inhibitor).

[0292] 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.

[0293] The term “comprising” (and related terms such as “having” or “including”) is not intended to exclude embodiments in which, for example, any embodiment of a material composition, composition, method or process described herein is “consistent with” or “substantially constitutes with” the described features.

[0294] The term "therapeutic agent" refers to a medicine used to treat, counteract, improve, or modify an undesirable condition or disease (such as a tumor) in a subject.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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).

[0300] The term "synergistic effect" refers to the effect achieved by using the drug combination of this disclosure that is greater than the sum of the effects of using them individually.

[0301] 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 EGFR inhibitor, 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.

[0302] 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, irinotecan is intended to include irinotecan free compound, irinotecan hydrochloride (commonly used in clinical practice), etc.

[0303] 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.

[0304] The names of EGFR antibodies mentioned in this disclosure include their biosimilars.

[0305] 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.

[0306] The positive and progressive effects of this disclosure are: providing a combination of a RAS inhibitor and an EGFR inhibitor, along with optional other therapeutic agents, which exhibits a synergistic effect in the treatment of tumors and is also effective against EGFR inhibitor-resistant tumor cells. Attached Figure Description

[0307] Figure 1 shows the mean tumor volume after administration of compound 1, cetuximab, and compound 1 in combination with cetuximab in the KRAS G12D mutant LS180 xenograft model (*In the Vehicle group, two mice were removed on day 7 due to tumor burden.**In the Vehicle group, one mouse was removed on day 10 due to burden).

[0308] Figure 2 shows the mean tumor volume after administration of compound 1, cetuximab, and compound 1 in combination with cetuximab in the KRAS G12V-mutant NCI-H441 xenograft model. Detailed Implementation

[0309] 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.

[0310] 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.

[0311] Example 1

[0312] The purpose of this experiment was to evaluate the inhibitory effects of compound 1 in combination with different EGFR inhibitors on different cell lines and their xenograft mouse models.

[0313] 1) The inhibitory effect of compound 1 in combination with EGFR small molecule inhibitors (ametinib, osimertinib, vometinib, befotinib or lanzatinib) on EGFR inhibitor-resistant non-small cell lung cancer cell lines (HCC827, PC9) and their xenograft mouse models.

[0314] 2) The inhibitory effect of compound 1 in combination with EGFR antibodies (cetuximab, panitumumab, or nexituzumab) on RAS-mutant non-small cell lung cancer cell lines (NCI-H2030, NCI-H2122, SW1573, NCI-H23, NCIH358, LU65, A549, NCI-H441, LU99, H358) and their xenograft tumor mouse models.

[0315] 3) The inhibitory effect of compound 1 in combination with EGFR antibodies (cetuximab, panitumumab, or nexituzumab) on RAS mutant colorectal cancer cell lines (SW1463, SW837, C106, RW7213, SW837, SNU1411, JVE015, LIM2099, GP2D, SW480, HCT116, LOVO) and their xenograft mouse models.

[0316] Cellular Experiments - General Methods

[0317] Using Promega's CellTiter-Glo method ( (Luminescent Cell Viability Assay). The experimental steps are as follows:

[0318] 1) Tumor cells are passaged regularly, and cells in the logarithmic growth phase are used for plating;

[0319] 2) Use trypan blue to stain cells and count viable cells, adjust the cell concentration to a suitable level, and seed the cells into a plate;

[0320] 3) Cells were treated with drugs (Compound 1 as a single agent, EGFR inhibitor as a single agent, and Compound 1 in combination with EGFR inhibitor) after serial dilution;

[0321] 4) Add Promega CellTiter-Glo working solution to the cell culture plate and wrap the plate with aluminum foil to protect it from light. After the culture plate has been incubated for a period of time and the luminescence signal has stabilized, detect the luminescence signal using a microplate reader.

[0322] CompuSyn software was used to calculate the combination index (CI) of drugs and assess their synergistic effects. CompuSyn is a commonly used software for drug combination effect analysis. It is based on the classic Chou-Talalay method (Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010, 15; 70(2):440-6), which calculates the combination index by analyzing the dose-response curves of drugs. The combination index reflects the synergistic effect when drugs are used in combination (Table 1).

[0323] Table 1

[0324] Example 1A: Compound 1 combined with osimertinib

[0325] The inhibitory effects of compound 1 in combination with osimertinib on the three cell lines in Table 2 were tested according to the general cell experiment method described above.

[0326] Table 2

[0327] Specific steps: Tumor cells were cultured in a 37℃, 5% CO2 incubator, passaged periodically, and cells in the logarithmic growth phase were used for plate seeding. Cells were stained with trypan blue and viable cells were counted. The cell concentration was adjusted to an appropriate level and seeded into plates. Cell suspension was added to each well of a 96-well plate (HCC827 cells, 2500 cells / well; PC9 cells, 200 cells / well; LU-01-1649 cells, 1000 cells / well). Cell culture medium without cells was added to the blank control wells, and cells were cultured overnight. Compound 1 and osimertinib were serially diluted with DMSO to treat cells (Compound 1 starting at 1 μM, 5-fold gradient, 6 concentrations in total; osimertinib starting at 1 μM, 5-fold gradient, 6 concentrations in total), with two replicates for each drug concentration. The final DMSO concentration per well was 0.25%. Cell plates were cultured at 37°C in a 5% CO2 incubator. HCC827 and PC9 cells were cultured for 7 days, and LU-01-1649 cells for 6 days. Cell viability assays were performed according to the Promega CellTiter-Glo luminescence assay kit instructions: 75 μL of CellTiter-Glo working solution was added to each well, and the cell plate was shaken in the dark for 2 minutes to induce cell lysis. The cell plate was then incubated at room temperature for 10 minutes to stabilize the luminescence signal, and the luminescence signal was then detected using a plate reader.

[0328] Data Analysis: The inhibition rate (IR) of the detected compound was calculated using the following formula: IR (%) = [1 – (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control)] * 100%. The inhibition rates of different concentrations of the compound were calculated in Excel. Then, inhibition curves were plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC50, were calculated using GraphPad Prism software. 50 The CI value was calculated using CalcuSyn software based on the formula CI = (D)1 / (DX)1 + (D)2 / (DX)2.

[0329] Experimental results:

[0330] 1) The CI values ​​of compound 1 in combination with osimertinib in osimertinib-resistant HCC827 cells are shown in Table 3.

[0331] Table 3

[0332] 3) The CI values ​​of compound 1 in combination with osimertinib in osimertinib-resistant PC9 cells are shown in Table 4.

[0333] Table 4

[0334] 4) The CI values ​​of compound 1 in combination with osimertinib in osimertinib-resistant LU-01-1649 cells are shown in Table 5.

[0335] Table 5

[0336] Experimental results showed that osimertinib monotherapy had a relative IC50 value for three cell types. 50 All values ​​were greater than 1 μM, indicating that the cells were resistant to osimertinib. Compound 1, in combination with osimertinib, showed synergistic antitumor effects in osimertinib-resistant HCC827 cells, osimertinib-resistant PC9 cells, and osimertinib-resistant LU-01-1649 cells.

[0337] Xenograft Tumor Mouse Model Experiment - General Experimental Methods

[0338] After establishing xenograft tumor models by inoculating mice with various cell lines, the mice were randomly divided into groups according to tumor size and then administered the drugs. The experiment included a solvent control group, a compound 1 monotherapy group, an EGFR inhibitor monotherapy group, and a compound 1 combined with an EGFR inhibitor group. Tumor volume was measured periodically after drug administration.

[0339] 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.

[0340] The formula for calculating relative tumor volume is: RTV = TV n / TV0×100%; where TV0 is the tumor volume on the day of group administration, and TV n To measure the tumor volume on that day.

[0341] Tumor inhibition rate (TGI) (%) = [1 – (mean tumor volume at the end of treatment – ​​mean tumor volume at the start of treatment) / (mean tumor volume at the end of treatment in the solvent control group – mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0342] Relative tumor proliferation rate (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.

[0343] The interaction between two drugs was evaluated using the 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.

[0344] Example 1B

[0345] The in vivo efficacy of compound 1 in combination with cetuximab in a human colon cancer CO-04-0070 cell subcutaneous xenograft tumor model was tested according to the general experimental method of the above xenograft tumor mouse model.

[0346] Laboratory animals: BALB / c Nude female mice, 6-8 weeks old, 18-22g, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.

[0347] Test method:

[0348] 1. Tumor culture

[0349] The human colon cancer CO-04-0070 model (KRAS G12C mutant colon cancer) was provided by Shanghai WuXi AppTec Co., Ltd. The human colon cancer CO-04-0070 model was initially established from tumor samples surgically removed in clinical settings, which were designated as generation P0 after implantation into immunodeficient mice. Implantation of generation P0 tumor tissue into the next generation was designated as generation P1. This process continued, with tumors being implanted into immunodeficient mice. Tumors at generation FP3 were obtained by re-reviving from generation P2. The next generation generated from generation FP3 was designated as generation FP4, and so on, with generation FP6 tumor tissue used in this experiment.

[0350] 2. Tumor inoculation and animal grouping

[0351] 20-30mm 3 CO-04-0070 tumor tissue blocks were subcutaneously inoculated into the right posterior back of each mouse, and tumor growth was observed. The average tumor volume reached approximately 139 mm². 3Randomization was performed on each group. The grouping day was defined as D0. Dosing began on the grouping day, and the dosing regimen is shown in Table 6 below.

[0352] Table 6: Grouping and Dosing Regimens

[0353] Experimental results

[0354] On day 28 after drug administration (D28), the tumor-suppressing effects of each group are shown in Table 7 below. The p-values ​​in the table are calculated based on tumor volume (compared with the Vehicle group), analyzed using one-way ANOVA, and then analyzed using the Games-Howell method.

[0355] Table 7: Antitumor effects of drugs in each group on day 28 after administration

[0356] The experimental results showed that compound 1, when used in combination with cetuximab, produced a synergistic antitumor effect. No significant weight loss was observed in any of the animal groups throughout the treatment process.

[0357] Example 2: Evaluation of the antitumor efficacy of compound 1 in combination with cetuximab or alone in a KRAS G12D-mutant LS180 xenograft model.

[0358] The aim of this study was to test the effects of compound 1 alone and in combination in an LS180 xenograft mouse model of colorectal adenocarcinoma carrying the KRAS G12D mutation.

[0359] Table 8: Experimental Design of the LS180 Xenograft Model

[0360] In vivo testing was conducted on the LS180 colorectal adenocarcinoma CDX model carrying the KRAS G12D mutation to evaluate the combination activity of compound 1 with cetuximab. The cell line was purchased from ATCC (Manassas, VA, USA) and maintained under low passage (≤P5) conditions, while undergoing regular pathogen detection at IDEXX (Westbrook, Maine) to ensure a pathogen-free state. Prior to inoculation, cells were maintained in vitro in Eagle's Minimum Essential Medium (ATCC formulation) supplemented with 10% FBS and 1% penicillin / streptomycin at 37°C and 5% CO2 atmosphere. Cells were typically passaged using trypsin-EDTA at 80-90% confluence, with the medium changed every 2-3 days.

[0361] Female nude mice (Nu / nu) were 7-8 weeks old at the time of inoculation. In accordance with IACUC protocols, the mice were housed in an animal facility environment and allowed 3 days to acclimatize to the new environment before starting any experiments.

[0362] Will contain 1x10 6 200 μL of cell suspension (in 50% Matrigel) per cell was inoculated into mice. The cell mixture was injected into the right abdomen of the mice using a syringe. When the average tumor volume reached 265.20 mm, the tumor was successfully treated. 3 At (D0), mice were randomly assigned to groups and administered compound 1 (1 mg / kg, PO, QD), cetuximab (20 mg / kg, IV, BIW), or a combination thereof. Tumor volume and body weight changes were monitored twice weekly, and animal health was monitored daily.

[0363] Compound 1, in combination with cetuximab, showed synergistic effects in the KRAS G12D CRC CDX LS180 model, as shown in Figure 1.

[0364] Example 3: Evaluation of the antitumor efficacy of compound 1 in combination with cetuximab or alone in a KRAS G12V-mutant NCI-H441 xenograft model.

[0365] NCI-H441 is a human non-small cell lung cancer cell line carrying the KRAS G12V mutation. This cell line was derived from ATCC and underwent pathogen testing to confirm its pathogen-free status. NCI-H441 cells were cultured in RPMI (Roswell Park Memorial Institute medium) containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin at 37°C with 5% CO2 atmosphere. The medium was changed every 2 to 5 days, and tumor cells were routinely passaged 1 to 2 times per week when confluence reached 80-90%. Cells in the exponential growth phase were harvested, counted, and used for inoculation.

[0366] Female Balb / c nude mice were purchased from Shanghai Sino-British SIPPR / BK Laboratory Animal. Mice were 6 to 8 weeks old at the time of inoculation. Mice were housed in an SPF (special pathogen-free) environment. In accordance with IACUC protocols, mice were allowed at least 72 hours to acclimatize to the new environment before the start of the experiment.

[0367] NCI-H441 tumor cells were divided into doses of 5 x 10⁶ per mouse. 6 Subcutaneous seeding of 200 μL containing 25 x 10 cells. 6A suspension of tumor cells was mixed with Matrigel at a 50:50 ratio and subcutaneously injected into the right abdomen of mice. Animal health was monitored daily. Tumor volume was measured twice weekly using calipers when the tumor was palpable and measurable. Tumor volume was considered complete when it reached an average of 150-200 mm. 3 Mice were randomly divided into four groups (Vehicle; Compound 1 group (0.3 mg / kg, PO, QD); Cetuximab group (20 mg / kg, IV, BIW); Compound 1 combined with Cetuximab group), with 7 mice in each group. The date of randomization was recorded as day 0 of treatment (D0).

[0368] On day 28 of treatment, the TGI (tumor responsiveness) was 81% in the compound 1 monotherapy group, 54% in the cetuximab monotherapy group, and 98% in the compound 1 plus cetuximab group, as shown in Figure 2. Compound 1 combined with cetuximab exhibited a synergistic antitumor effect. The combination therapy was well tolerated, and no significant weight loss or abnormalities were observed.

[0369] Example 3: Inhibitory activity of compound 1 in combination with afatinib against KRAS-mutant or WT-amplified cells

[0370] The experimental cells were cultured in the culture medium shown in Table 9 below at 37°C and 5% CO2.

[0371] Table 9: Test Cells

[0372] Cell viability was assessed using either the CellTiter-Glo 3D Cell Viability Assay Kit or the CellTiter-Glo 3D Cell Viability Assay Kit after five days of treatment with compound 1 in combination with afatinib. Cells were seeded at the densities shown in Table 9 in 96-well ULA plates (Corning #4520) for CellTiter-Glo 3D Cell Viability Assay (Promega #G9683) or in flat-bottom 96-well plates (Corning #3917) for CellTiter-Glo 3D Cell Viability Assay (Promega #G7573). After overnight cell attachment, cells were processed the following day using a Tecan D300e digital dispenser (Tecan Group Ltd., Switzerland). The combination matrix used for assays consisted of three-fold serial dilutions of one compound to form seven concentration points plus 0 nM, and three-fold serial dilutions of another compound to form ten concentration points plus 0 nM. The drug combination effect was calculated based on the HSA method.

[0373] The HSA (highest single agent) model is used for synergistic score calculation (Berenbaum MC, Pharmacol Rev. 1989; 41:93-141; the full text of this article is incorporated herein by reference). HSA is one reference model that assumes the expected combined effect is the maximum single-drug response at the corresponding concentration. Therefore, the HSA synergistic score S... HSA Defined as: S HSA =E A,B,…,N -max(E A E B ,…,E N ); where E A,B,…,N It is the combined effect of N drugs, E A E B ,…,E N It is a measurement response of a single drug.

[0374] The experimental results are shown in Table 10-20 (a result greater than 0 indicates a synergistic effect, and a result less than 0 indicates an antagonistic effect).

[0375] Table 10: Results of NCI-H358 cell (KRAS G12C, NSCLC) assay (CellTiter-Glo luminescence assay 3D cell viability detection)

[0376] Table 11: Results of AsPC-1 cell (KRAS G12C, NSCLC) assay (CellTiter-Glo luminescence assay 3D cell viability detection)

[0377] Table 12: Results of SU86.86 cell (KRAS G12D, PDAC) assay (CellTiter-Glo luminescence assay 3D cell viability detection)

[0378] Table 13: Results of LS-180 cell (KRAS G12D, CRC) assay (CellTiter-Glo luminescence assay 3D cell viability detection)

[0379] Table 14: Results of NCI-H727 cell (KRAS G12V, NSCLC) assay (CellTiter-Glo luminescence assay 3D cell viability detection)

[0380] Table 15: Results of NCI-H747 cell (KRAS G13D, CRC) assay (CellTiter-Glo chemiluminescence immunoassay for cell viability).

[0381] Table 16: Results of DLD-1 cell (KRAS G13D, CRC) assay (CellTiter-Glo chemiluminescence immunoassay for cell viability).

[0382] Table 17: Results of NCI-H1944 cell (KRAS G13D, NSCLC) assay (CellTiter-Glo chemiluminescence immunoassay for cell viability).

[0383] Table 18: Results of LS513 cell (KRAS G12D, CRC) assay (CellTiter-Glo chemiluminescence immunoassay for cell viability).

[0384] Table 19: Results of SK-CO-I cell (KRAS G12V, CRC) assay (CellTiter-Glo luminescence assay 3D cell viability detection)

[0385] Table 20: SNU-245 cells (KRAS) WTamp Results of a cholangiocarcinoma assay (CellTiter-Glo chemiluminescence immunoassay for cell viability).

[0386] Example 4: Clinical Trial

[0387] 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.

[0388] (1) Stage Ib: Compound 1 in combination with cetuximab for the treatment of patients with solid tumors.

[0389] Patients with advanced, unresectable locally advanced, recurrent, or metastatic solid tumors (including RAS-mutated and RAS-non-mutated patients) who have previously received at least one first-line systemic antitumor therapy and failed include, but are not limited to, non-small cell lung cancer, colorectal cancer, and pancreatic cancer (including pancreatic ductal adenocarcinoma).

[0390] Test drug: Compound 1, cetuximab.

[0391] Dosage regimen: Each treatment cycle is 28 days. The dosing regimen for compound 1 in combination with cetuximab is as follows:

[0392] 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.

[0393] Cetuximab was administered via intravenous infusion at a dose of 500 mg / m². 2 Administer on days 1 and 15 of each cycle. Alternatively, cetuximab can be administered intravenously at a dose of 400 mg / m² on day 1 of the first cycle. 2 The initial dose was 250 mg / m², followed by weekly administration at a dose of 250 mg / m². 2 .

[0394] (2) Phase II (Extended Study)

[0395] The process is divided into two queues.

[0396] Cohort 1: Compound 1 in combination with cetuximab + mFOLFOX6 chemotherapy regimen (oxaliplatin + leucovorin + 5-fluorouracil); Compound 1 in combination with cetuximab + FOLFIRI chemotherapy regimen (irinotecan + leucovorin + 5-fluorouracil) was used to treat patients with RAS-mutant colorectal cancer.

[0397] Investigational drugs: Compound 1, cetuximab, oxaliplatin, leucovorin calcium, 5-fluorouracil, and irinotecan hydrochloride.

[0398] Patients with advanced, unresectable, locally advanced, recurrent, or metastatic colorectal cancer carrying RAS mutations were enrolled, and had previously received at most one-line systemic anti-tumor therapy for advanced disease.

[0399] Dosage regimen:

[0400] Compound 1 combined with cetuximab + mFOLFOX6 chemotherapy regimen: Each treatment cycle is 28 days. The dosing regimen for Compound 1 and cetuximab was selected from the Phase Ib regimen. Oxaliplatin was administered intravenously at a dose of 85 mg / m². 2 Calcium leucovorin is administered intravenously at a dose of 400 mg / m², on days 1 and 15 of each cycle. 2 (Based on leucovorin), administered on days 1 and 15 of each cycle. 5-Fluorouracil, initially 400 mg / m². 2 Intravenous bolus injection, followed by 1200 mg / (m²) 2 ·d)×2 days of continuous intravenous infusion (46-48 hours, total infusion volume 2400mg / m²) 2 ), administered on days 1-2 and 15-16 of each cycle.

[0401] Compound 1 combined with cetuximab + FOLFIRI chemotherapy: Each treatment cycle is 28 days. The dosing regimen for Compound 1 and cetuximab was selected from the Phase Ib regimen. Irinotecan hydrochloride was administered intravenously at a dose of 180 mg / m². 2 Calcium leucovorin is administered intravenously at a dose of 400 mg / m², on days 1 and 15 of each cycle. 2 (Based on leucovorin), administered on days 1 and 15 of each cycle. 5-Fluorouracil, initially 400 mg / m². 2 Intravenous bolus injection, followed by 1200 mg / (m²) 2 ·d)×2 days of continuous intravenous infusion (46-48 hours, total infusion volume 2400mg / m²) 2 ), administered on days 1-2 and 15-16 of each cycle.

[0402] Cohort 2: Compound 1 in combination with cetuximab for the treatment of patients with solid tumors.

[0403] Patients with advanced, unresectable locally advanced, recurrent, or metastatic solid tumors (including those with RAS mutations and those without RAS mutations), including but not limited to non-small cell lung cancer, colorectal cancer, and pancreatic cancer (including pancreatic ductal adenocarcinoma), who have previously received at least one line of systemic antitumor therapy and failed, or who have not received any first-line systemic antitumor therapy, will be enrolled. Furthermore, advanced first-line patients carrying RAS mutations may also be considered for enrollment after evaluation.

[0404] Test drug: Compound 1, cetuximab.

[0405] Dosing regimen: Each treatment cycle is 28 days. The dosing regimen for compound 1 and cetuximab is selected from the dosing regimen of phase Ib.

[0406] 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, etc., or lower doses such as 12 mg or 8 mg), or different dosing frequencies may be adopted (e.g., compound 1 is administered twice daily, three times daily, or every other day, etc.), or the specific dosing regimen of other combination drugs may be adjusted (e.g., the starting dose and dosing frequency of mFOLFOX6 chemotherapy drugs, cetuximab, etc.). Considering the different sensitivities of different tumor types and the different tolerabilities of patients, different dosages may be selected for different cohorts / tumor types.

[0407] 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.

[0408] During the study, efficacy was assessed according to RECIST 1.1 criteria, including the following indicators.

[0409] Objective response rate (ORR): defined as the proportion of subjects who achieve complete remission (CR) or partial remission (PR) after treatment.

[0410] Disease control rate (DCR): defined as the proportion of subjects who achieve complete remission (CR), partial remission (PR), or stable disease (SD) after treatment.

[0411] 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.

[0412] 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.

[0413] Time to Response (TTR): Defined as the time from the start of study treatment to the first recorded objective response.

[0414] 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.

[0415] Overall survival (OS): defined as the time from the start of research treatment to death from any cause.

[0416] 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.

[0417] 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

Use of a combination of a RAS inhibitor and an EGFR 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; Use according to claim 1, characterized in that The EGFR inhibitor is an EGFR antibody or its antigen-binding fragment. Use according to claim 2, characterized in that The EGFR antibody is cetuximab, amivantamab, necitumumab, panitumumab, nimotuzumab, Izalontamab, modotuximab, pimurutamab, demupitamab, petosemtamab, ametumumab, lossatuxizumab, laprituximab, serclutamab, matuzumab, clezutoclax, mirzotamab, panitumamab, or bafisontamab. Use according to claim 1, characterized in that The EGFR inhibitor is cetuximab or its antigen-binding fragment. Use according to claim 1, characterized in that The EGFR inhibitors mentioned are Rilertinib, Rezivertinib, Sunvozertinib, Befotertinib, Pyrotinib, Mobocertinib, Alflutinib, Lazertinib, Almonertinib, Dacomitinib, Neratinib, Brigatinib, Osimertinib, Afatinib, Icotinib, Lapatinib, Gefitinib, and Limertinib. , Zorifertinib, Mefatinib, Larotinib, Sevabertinib, Avitinib, Ruserontinib, Varlitinib, Asandeutertinib, Zipalertinib, Andamertinib, Olafertinib, Epertinib, Sapitinib, All itinib, Kenaitinib, Nazartinib, Sutetinib, Selatinib, Poziotinib, lifirafenib, vandetanib, Erlotinib, canertinib, daphnetin, pelitinib, tivozanib, rociletinib or pharmaceutically acceptable salts thereof. Use according to any one of claims 1 - 5, characterized in that The combination does not include other tumor therapeutic agents besides the RAS inhibitor and the EGFR inhibitor; or, the combination includes one or more additional tumor therapeutic agents. Use according to claim 6, characterized in that The one or more additional tumor treatment agents are oxaliplatin, leucovorin, and 5-fluorouracil; or, the one or more additional tumor treatment agents are irinotecan, leucovorin, and 5-fluorouracil. Use according to any one of claims 1 - 7, 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. Use according to any one of claims 1 - 7, characterized in that The tumor is a solid tumor. Use according to claim 8 or 9, characterized in that, The tumor is non-small cell lung cancer. Use according to claim 8 or 9, characterized in that, The tumor is colon cancer and / or rectal cancer. Use according to claim 8 or 9, characterized in that, The tumor is pancreatic cancer. Use according to claim 12, characterized in that The pancreatic cancer mentioned is pancreatic ductal adenocarcinoma. Use according to any one of claims 1 - 13, characterized in that The tumor contains RAS mutations. Use according to any one of claims 1 - 14, characterized in that The tumor contains a KRAS mutation. Use according to any one of claims 1 - 15, characterized in that The tumor contains a KRAS G12C mutation. Use according to any one of claims 1 - 15, characterized in that The tumor contains a KRAS G12D mutation. Use according to any one of claims 1 - 15, characterized in that The tumor contains a KRAS G12V mutation. Use according to any one of claims 1 - 13, characterized in that The tumor does not contain RAS mutations. Use according to any one of claims 1 - 19, characterized in that The tumor contains an EGFR mutation. Use according to any one of claims 1 - 19, characterized in that The tumor does not contain EGFR mutations. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, 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. Use according to any one of claims 1 - 21, 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, 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 twice daily. Use according to any one of claims 1 - 21, 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 twice daily. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, 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) orally, three times daily. Use according to any one of claims 1 - 21, 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) orally, three times daily. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, 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 every other day. Use according to any one of claims 1 - 21, 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 every other day. Use according to any one of claims 1 - 21, characterized in that 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. Use according to any one of claims 1 - 21, characterized in that The single administration dose of the compound 1, or a pharmaceutically acceptable salt thereof, is 24 mg (as compound 1 free form), administered orally, once every other day. Use according to any one of claims 1 - 21, characterized in that The single administration dose of the compound 1, or a pharmaceutically acceptable salt thereof, is 32 mg (as compound 1 free form), administered orally, once every other day. Use according to any one of claims 1 - 21, characterized in that The single administration dose of the compound 1, or a pharmaceutically acceptable salt thereof, is 40 mg (as compound 1 free form), administered orally, once every other day. Use according to any one of claims 1 - 21, characterized in that The single administration dose of the compound 1, or a pharmaceutically acceptable salt thereof, is 48 mg (as compound 1 free form), administered orally, once every other day. Use according to any one of claims 4 and 6-53, characterized in that, The single dose of cetuximab is 500 mg / m². 2 (Based on body surface area), administered intravenously every two weeks; or, the aforementioned cetuximab administered intravenously at a dose of 400 mg / m² on day 1. 2 The initial dose (based on body surface area); thereafter, administered weekly at a dose of 250 mg / m². 2 (Based on body surface area). Use according to claim 54, characterized in that The combination is administered for one or more cycles, wherein each cycle is four weeks. Use of a RAS inhibitor in the manufacture of a medicament for the conjoint treatment of a tumor with an EGFR inhibitor and, optionally, an additional oncology therapeutic of claim 6 or 7, wherein the RAS inhibitor, the EGFR inhibitor, and the tumor are as described in any one of claims 1-55. A pharmaceutical combination or kit comprising a RAS inhibitor and an EGFR inhibitor and, optionally, an additional oncology therapeutic of claim 6 or 7; wherein the RAS inhibitor and the EGFR inhibitor are as described in any one of claims 1-55.

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