A combination drug for the prevention and / or treatment of cancer and its application

Abstract

This invention provides a combination drug for the prevention and / or treatment of cancer and its application. The combination drug comprises: (1) a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof; and (2) a c-Met inhibitor or a pharmaceutically acceptable salt and / or solvate thereof; wherein the compound of formula I is as follows: wherein R 1 R 2 R 4 R 5 R 6 Z 1 Z 2 X is defined as described in the specification, and the c-Met inhibitor is as described in the specification. The combination drug of the present invention exhibits excellent therapeutic efficacy for diseases mediated by EGFR and / or MET (e.g., non-small cell lung cancer), with few side effects and good safety profile.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a combination drug for the prevention and / or treatment of cancer and its application, specifically to a combination drug comprising a tyrosine kinase inhibitor and its application. Background Technology

[0002] EGFR is a member of the ErbB receptor family of receptor tyrosine kinases. When EGFR binds to its ligand outside the cell, the receptor undergoes iso- or heterodimerization and autophosphorylation, activating downstream signaling pathways and ultimately promoting cell growth, proliferation, and division. Overexpression (upregulation) or hyperactivity (amplification or mutation) of EGFR has been shown to be associated with many cancers, including head and neck cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colorectal cancer, non-small cell lung cancer, and glioma.

[0003] Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. A report released by the International Agency for Research on Cancer (IARC) of the World Health Organization in February 2024 showed that in 2022, lung cancer was the leading cause of cancer-related morbidity and mortality globally, with approximately 2.5 million new cases, accounting for 12.4% of all cancer cases; and approximately 1.8 million deaths, accounting for 18.7% of all cancer-related deaths. In China, lung cancer is also the leading cause of cancer-related morbidity and mortality, with 1.0606 million new cases and 733,300 deaths in 2022. In the United States, lung cancer is the second most common cancer after breast cancer, with approximately 226,650 new cases annually, while it is the leading cause of cancer-related mortality, with approximately 124,730 deaths annually. EGFR gene mutations are found in approximately 50% of Asians and 19% of Westerners among lung cancer patients. EGFR is an oncogene, leading to targeted therapies using EGFR small molecule inhibitors (EGFR-TKIs). Currently, three generations of EGFR small molecule inhibitors are approved for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). These drugs have achieved great success in the treatment of NSCLC, especially third-generation EGFR-TKIs. However, in treatment-naïve patients with EGFR-sensitive mutations, resistance still develops in some patients after 10.4-18.9 months of monotherapy with EGFR-TKIs. Resistance mechanism studies have found that MET gene amplification accounts for approximately 7%-15%, and MET gene overexpression accounts for approximately 50%. In patients with EGFR-secondary resistance mutations (T790M) in lung cancer, MET gene amplification occurs in approximately 10%-22% after progression on third-generation EGFR-TKIs (such as osimertinib). In lung cancer patients with primary EGFR-TKI resistance, MET gene amplification occurs in 2%-8%. Furthermore, MET gene amplification is also one of the main mechanisms of resistance to small molecule inhibitors of common lung cancer driver genes such as ALK fusion, RET fusion, ROS1 fusion, and KRAS mutations, with incidence rates of 11%, 15%, 6%, and 20%, respectively.

[0004] For patients resistant to osimertinib, there are currently no approved treatment options. Platinum-based chemotherapy has limited efficacy in this group, with an objective response rate (ORR) of 27%-42.9% and a median progression-free survival (mPFS) of 4.4-5.6 months. Efficacy is even worse for patients with MET gene amplification. In clinical studies, for patients with MET gene amplification who have progressed on osimertinib treatment, c-Met inhibitor monotherapy is not ideal, with an ORR of only 8%-33% and an mPFS of 4.0-7.1 months. While some combination therapies have improved the ORR, mPFS has not improved accordingly; or intracranial lesions are not well treated or controlled; or the incidence of grade 3 or higher adverse events is high and intolerable; or copy number limitation is required for patients with MET gene amplification, resulting in fewer benefiting patients. For example, preliminary results from the SAVANNAH trial showed that, after progression on osimertinib treatment, the ORR of osimertinib combined with cerovatinib was only 49% in patients with high levels of MET overexpression and / or amplification (defined as IHC90+ and / or FISH 10+), with a median progression-free survival (mPFS) of 7.1 months. In patients with IHC50+ and / or FISH5+, the ORR was only 32%, with an mPFS of only 5.3 months. Furthermore, the efficacy was very low in patients without IHC90+ and / or FISH10+, with an ORR of only 9% and an mPFS of 2.8 months (MJ Ahn, FD Marinis, L Bonanno, et al. WCLC, 2022, abstract#EP08.02-140). The INSIGHT 2 trial results showed that for patients who had progressed after first-line osimertinib treatment and had MET gene amplification, osimertinib combined with terpoxetine improved the overall ORR to 50%, but did not improve PFS accordingly, with a PFS of only 5.6 months. Furthermore, subgroup analysis revealed that the intracranial assessment ORR was only 29.2%, and the intracranial mPFS was 7.8 months (95% CI 3.9-NE) (Lancet Oncol. 2024, 25(8): 989-1002). The European Society for Medical Oncology (EMSO) reported in 2022 that in non-small cell lung cancer patients who had progressed with EGFR TKIs and had MET gene amplification, the ORR of gumetinib combined with osimertinib was 60% [95% CI 40.6-77.3], the median duration of response (mDOR) was only 5.8 months [95% CI 3.9-12.7], and the PFS was 6.9 months [95% CI 3.9-8.9] (Y.Yu, N.Yang, Y.Zhang, et al. ESMO, 2022, abstract#305MO).In the use of combination therapies of small molecule and large molecule drugs, the MARIPOSA-2 study showed that in patients with MET gene amplification after progression on osimertinib treatment, the ORR and PFS were 64% (95% CI 55%-72%) vs. 63% (95% CI 57%-69%) vs. 36% (95% CI 30%-42%) and 6.3 months (95% CI 5.6-8.4) vs. 8.3 months (95% CI 6.8-8.4) vs. 4.2 months (95% CI 4.0-4.4) respectively. The ORR and PFS were improved in the amivantamab plus chemotherapy group, and in the amivantamab plus chemotherapy and Lazertinib groups compared to the chemotherapy group. However, 72% and 92% of subjects, respectively, experienced grade 3 or higher adverse events, indicating poor tolerability (Ann). Oncol. 2024, 35(1): 77-90). In patients with MET overexpression who progressed after osimertinib treatment, telisotuzumab vedotin combined with osimertinib had an ORR of 50.0% and a PFS of 7.4 months (95% CI 5.4, NR). However, for patients with baseline brain metastases, the ORR assessed by the independent review committee and investigator were 0% and 14.3%, respectively, indicating almost no efficacy in patients with brain metastases (Ann Oncol. 2025, 11: S0923-7534(25)00005-5). Therefore, there remains an unmet clinical need for osimertinib-resistant patients.

[0005] Furthermore, the central nervous system (CNS) is a common site of distant metastasis progression in EGFR-mutant (EGFRm) NSCLC, occurring more frequently than in patients without EGFR mutations, and is a poor prognostic factor affecting quality of life. The reported 3-year cumulative incidence of CNS metastases is 29%-60% in patients with EGFR-mutant NSCLC, compared to 22%-28% in patients without EGFR mutations. Therefore, drugs that can treat and control intracranial metastases are crucial for improving patient survival and quality of life. Summary of the Invention

[0006] In order to overcome the shortcomings of the prior art, the present invention provides a combination drug for the prevention and / or treatment of cancer and its application, and in particular, a combination drug comprising a tyrosine kinase inhibitor and its application.

[0007] In a first aspect, the present invention provides a combination medicament for the prevention and / or treatment of cancer, the combination medicament comprising:

[0008] (1) A compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof; and

[0009] (2) c-Met inhibitors or their pharmaceutically acceptable salts and / or solvates;

[0010] Among them, the compounds of formula I are as follows:

[0011]

[0012] In equation I,

[0013] R 1 For hydrogen atoms or

[0014] R 2 C 1-6 Alkyl or OR 8 , where R 8 For hydrogen atoms, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 3-7 cycloalkyl-C 1-6 Alkyl groups, unsubstituted 4-7 membered heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, and unsubstituted 4-7 membered heterocyclic groups containing 1-2 heteroatoms selected from N, O, or S -C 1-8 alkyl;

[0015] X represents chemical bonds, O, S, CO, NR 3 , where R 3 For hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-8 Alkyl-CO or 4-6 membered heterocyclic groups;

[0016] R 4 C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-7 membered heterocyclic groups, which may optionally be substituted by 1-3 independent substituents selected from the following: C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, halogenated C 3-6Cycloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkyl-amino-C 1-6 Alkyl, halogen, hydroxyl, cyano, cyano-C 1-8 Alkyl, amino, C 1-6 Alkyl-amino, di(C) 1-6 alkyl)-amino, C 3-6 Cycloalkyl-amino, C 1-6 alkyl carbonyl, C 1-6 alkyl-amino-acyl, di(C 1-6 alkyl)-amino-acyl, C 3-6 Cycloalkyl-amino-acyl, C 1-6 Acyl-amino, unsubstituted 4-7 membered heterocyclic groups;

[0017] R 5 Selected from the following groups:

[0018]

[0019] R 6 It is hydrogen, halogen, hydroxyl, nitrile, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkoxy, halogenated C 3-6 Cycloalkoxy;

[0020] Z 1 For CR 7 Z 2 For N, or Z 1 For N, Z 2 For CR 7 , where R 7 Hydrogen, halogen, nitrile, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl.

[0021] The c-Met inhibitors are selected from Vebreltinib (Bozitinib, APL-101), Savolitinib (AZD6094, HMPL-504), Capmatinib (INC280, NVP-INC280, INCB28060), Tepotinib (EMD 1214063, MSC2156119), Glumetinib (SCC244), MK-2461, HS-10241, and AMG. 337. JNJ-38877618 (OMO-1), Elzovantinib (TPX-0022, CSF1R-IN-2), Crizotinb (PF-02341066), ABN-401 (KDDF-2016 03-08), SPH-3348 (I-020), MK-8033 (APG-8361, HQP-8361, HQP8361), SAR125844, ASKC202, GST-HG161 (GST-HG161-I).

[0022] In some embodiments, in the compound of formula I, R 1 For hydrogen atoms; R 2 OR 8 , where R 8 Methyl, ethyl, or difluoromethyl; X represents a chemical bond or NR. 3 , where R 3 For hydrogen, C 1-6 Alkyl groups (e.g., methyl, ethyl);

[0023] R 4 Selected from the following groups:

[0024]

[0025] R 5 Selected from the following groups:

[0026]

[0027] R 6 It is hydrogen or halogen;

[0028] Z 1 For CH, Z 2 For N, or Z 1 For N, Z 2 For CH.

[0029] In some embodiments, the compound of formula I is selected from the compound of formula II:

[0030]

[0032] In some embodiments, the c-Met inhibitor is selected from veboleltinib (Bozitinib, APL-101).

[0033] In some embodiments, the mass ratio between (1) a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof and (2) a c-Met inhibitor or a pharmaceutically acceptable salt and / or solvate thereof is 1-1000:1-800, preferably 20-400:100-600, and more preferably 80:300.

[0034] Secondly, this application provides a pharmaceutical composition for the prevention and / or treatment of cancer, the pharmaceutical composition comprising the aforementioned combination drug and a pharmaceutically acceptable carrier.

[0035] In some embodiments, the pharmaceutically acceptable carrier is selected from one or more of diluents, cosolvents, solubilizers, excipients, fillers, binders, wetting agents, coating materials, surfactants, disintegrants, emulsifiers, osmotic pressure regulators, lubricants, colorants, pH adjusters, antioxidants, and antibacterial agents.

[0036] In some embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the composition comprises:

[0037] (1) A compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof; and

[0038] (2) c-Met inhibitors or their pharmaceutically acceptable salts and / or solvates; and

[0039] (3) At least one pharmaceutically acceptable carrier;

[0040] In compound I, R 1 For hydrogen atoms; R 2 OR 8 , where R 8 Methyl, ethyl, or difluoromethyl; X represents a chemical bond or NR. 3 , where R 3 For hydrogen, C 1-6 Alkyl groups (e.g., methyl, ethyl);

[0041] R 4 Selected from the following groups:

[0042]

[0043] R 5Selected from the following groups:

[0044]

[0045] R 6 It is hydrogen or halogen;

[0046] Z 1 For CH, Z 2 For N, or Z 1 For N, Z 2 For CH;

[0047] The c-Met inhibitors are selected from Vebreltinib (Bozitinib, APL-101), Savolitinib (AZD6094, HMPL-504), Capmatinib (INC280, NVP-INC280, INCB28060), Tepotinib (EMD 1214063, MSC2156119), Glumetinib (SCC244), MK-2461, HS-10241, and AMG. 337. JNJ-38877618 (OMO-1), Elzovantinib (TPX-0022, CSF1R-IN-2), Crizotinb (PF-02341066), ABN-401 (KDDF-2016 03-08), SPH-3348 (I-020), MK-8033 (APG-8361, HQP-8361, HQP8361), SAR125844, ASKC202, GST-HG161 (GST-HG161-I);

[0048] The pharmaceutically acceptable carrier is selected from one or more of the following: diluents, solubilizers, excipients, fillers, binders, wetting agents, coating materials, surfactants, disintegrants, emulsifiers, osmotic pressure regulators, lubricants, colorants, pH adjusters, antioxidants, and antibacterial agents.

[0049] In some embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the composition comprises:

[0050] (1) A compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof; and

[0051] (2) c-Met inhibitors or their pharmaceutically acceptable salts and / or solvates; and

[0052] (3) At least one pharmaceutically acceptable carrier;

[0053] The compound of formula I is selected from the compound of formula II:

[0054]

[0055] The c-Met inhibitor mentioned above is selected from veboleltinib (Bozitinib, APL-101);

[0056] The pharmaceutically acceptable carrier is selected from one or more of the following: diluents, solubilizers, excipients, fillers, binders, wetting agents, coating materials, surfactants, disintegrants, emulsifiers, osmotic pressure regulators, lubricants, colorants, pH adjusters, antioxidants, and antibacterial agents.

[0057] In some embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the composition comprises:

[0058] (1) 1-1000 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 1-800 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; (3) at least one pharmaceutically acceptable carrier.

[0059] In some embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the composition comprises:

[0060] (1)5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 1 10mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280m (1) 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg or 500 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg g, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 1OOmg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 20 0mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg (2) 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg or 600 mg of Vebreltinib (Bozitinib, APL-101) or its pharmaceutically acceptable salts and / or solvates; and (3) at least one pharmaceutically acceptable carrier.

[0061] In some embodiments, the effective dose of the compound of formula II is 5 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, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 2... Total daily doses of 10mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, and 500mg.

[0062] In some embodiments, the effective dose of beritinib is 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, or 260 mg. Total daily dose of g, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg.

[0063] In some specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the composition comprises: (1) 20-400 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 100-600 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0064] In some specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the composition comprises: (1) 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 200 mg, 240 mg, 280 mg, 320 mg, 360 mg, 400 mg or 480 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0065] In some specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the pharmaceutical composition comprises: (1) 160 mg of a compound of formula II or a pharmaceutically acceptable salt thereof; (2) 200 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0066] In some specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the pharmaceutical composition comprises: (1) 160 mg of a compound of formula II or a pharmaceutically acceptable salt thereof; (2) 300 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0067] In some specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the pharmaceutical composition comprises: (1) 160 mg of a compound of formula II or a pharmaceutically acceptable salt thereof; (2) 400 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0068] In some specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the pharmaceutical composition comprises: (1) 80 mg of a compound of formula II or a pharmaceutically acceptable salt thereof; (2) 200 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0069] In some of the most specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the pharmaceutical composition comprises: (1) 80 mg of a compound of formula II or a pharmaceutically acceptable salt thereof; (2) 300 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0070] In some specific embodiments, the present invention provides a pharmaceutical composition for the prevention and / or treatment of cancer, wherein the pharmaceutical composition comprises: (1) 80 mg of a compound of formula II or a pharmaceutically acceptable salt thereof; (2) 400 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

[0071] In some embodiments, the pharmaceutical composition is administered at the following frequencies: (1) once daily, twice daily, or three times daily for the compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) once daily, twice daily, or three times daily for vebritinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof.

[0072] In some specific embodiments, the pharmaceutical composition is administered at the following frequencies: (1) the compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof is administered once daily; and (2) vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof is administered twice daily.

[0073] In some embodiments, the pharmaceutical composition is administered in the following manner: (1) a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof is administered at a dose of 40 mg, 80 mg, 160 mg, 240 mg or 320 mg once daily, continuously; and (2) vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof is administered at a dose of 100 mg, 150 mg or 300 mg twice daily, continuously;

[0074] In some embodiments, the compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof and vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof may be used simultaneously, separately or sequentially;

[0075] In some specific embodiments, (1) the compound of formula II or its pharmaceutically acceptable salt and / or solvate is administered at a dose of 80 mg once daily for continuous administration; (2) the vebretinib (Bozitinib, APL-101) or its pharmaceutically acceptable salt and / or solvate is administered at a dose of 150 mg twice daily for continuous administration; the compound of formula II or its pharmaceutically acceptable salt and / or solvate and the vebretinib (Bozitinib, APL-101) or its pharmaceutically acceptable salt and / or solvate may be used simultaneously, separately or sequentially.

[0076] Thirdly, the present invention provides the use of the aforementioned combination drug or pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of EGFR and / or MET-mediated diseases.

[0077] In some embodiments, the disease is selected from cancer, including solid tumors or hematologic malignancies;

[0078] Preferably, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, brain cancer, glioma, cervical cancer, head and neck cancer, multiple myeloma, malignant lymphoma, leukemia, thyroid tumor, bladder tumor, gallbladder cancer, bile duct cancer, pharyngeal cancer, nasal cancer, oral cancer, tongue cancer, vaginal cancer, or choriocarcinoma;

[0079] More preferably, the cancer is selected from lung cancer, glioma, and more preferably non-small cell lung cancer.

[0080] In some embodiments, the cancer is selected from brain metastases, preferably brain metastases from lung cancer, and more preferably brain metastases from non-small cell lung cancer.

[0081] In some embodiments, the non-small cell lung cancer is selected from EGFR-mediated non-small cell lung cancer that has not received any prior treatment, and non-small cell lung cancer that has received prior EGFR drug treatment and carries MET gene amplification and / or MET overexpression;

[0082] Preferred candidates are non-small cell lung cancer patients who have previously received first-generation or second-generation EGFR drugs and are T790M mutation negative and carry MET gene amplification and / or MET overexpression, or non-small cell lung cancer patients who have previously received third-generation EGFR drugs and carry MET gene amplification and / or MET overexpression.

[0083] In some embodiments, the EGFR is selected from EGFR overexpression, EGFR gene amplification, and EGFR mutation;

[0084] Preferably, EGFR is selected from EGFR exon 18 mutation, EGFR exon 19 mutation, EGFR exon 19 deletion, EGFR exon 20 mutation, and EGFR exon 21 mutation;

[0085] More preferably, the EGFR is selected from EGFR E709K / Q / A / G / V, L718Q, L718V, G719C / S / A / R, G724S, I744T, E746K, L747S, E749Q, A750P, A755V, V765M, S768I, C775Y, T790M, L792H, L792V, G796S, G796R, G796C, C797S, T854I, L858P, L858R, L861Q, delE746_E749, delE746_E749InsP, delE746 - A750, delE746_A750InsHS, delE746_A750insQP, delE746_A750insRP, delE746 - T751, delE746_T751InsA, delE746_T751InsAPT, delE746_T751InsFPT, delE746_T751InsKV, delE746_T751InsL, delE746_T751InsVA, delE746_S752InsIP, delE746_S752InsV, delE746_P753InsMS, delE746_P753InsVS, delE746_K754InsGG, delL747 - E749, delL747_A750InsP, delL747 - T751, delL747_T751InsN, delL747_T751InsP, delL747 - S752, delL747_S752InsPI, delL747_S752InsPT, delL747 - P753, delL747_P753InsNS, delL747_P753InsS, delL747 - K754, dekL747_T751InsS, dekL747 - T751, delR748 - S752, delR748 - P753, delA750_I759InsPT, delT751 - E758, delT751_I759InsD, delT751_I759InsN, elT751_I759InsSS, delT751_I759InsT, delT751_D761InsNLY, delS752 - I759, delS752 - I759InsN, D761_E762InsEAFQ, A763_Y764InsFQEA, Y764_Y765InsHH, M766_A767InsA, M766_A767InsAl, M766_A767InsASV, P772_H773InsNS,A767_S768InsIA, A767_S768InsTLA, S768_V769InsAWT, S768_V769InsVAS, S768_V769InsSVA, V769_D770InsAS V, D770_N771InsSVD, D770_N771InsG, N771_P772InsH, N771_P772InsN, P772_H773InsYNP, P772_H773InsNP, P77 One or more of the following: 2_H773InsPR, P772_H773InsDNP, P772_H773InsNPH, P772_H773InsGNP, P772_H773InsYNP, P772_H773InsTHP, P772_H773InsQV, P772_H773InsV, H773_V774InsH, H773_V774InsPH, H773_V774InsNPH, and V774_C775InsHV.

[0086] In some embodiments, the MET is selected from MET overexpression, MET gene mutation, MET gene amplification, and MET gene fusion; wherein, MET overexpression is defined as IHC results of 1+, 2+, or 3+ in tumor tissue; MET gene amplification is defined as the presence of MET gene amplification confirmed by FISH or NGS detection; and MET gene mutation is defined as MET exon 14 skipping, MET D1228N / H / A / G / V / Y / E, Y1230H / C / S / A / D / N, H1094Y, L1195V, F1200I / L, H1094L, K1244R, L1195F, M1250I / T, P991S, T1173I, T992I, V1092I, Y1235D, G1163R, G1090A, or MET-D1228_M1229delin. sFL; MET gene fusion is PTPRZ1-MET, CLIP2-MET, CAPZA2-MET, ST7-MET, KIF5B-MET, TPR-MET, TFG-MET, BAIAP2L1-MET, C8orf34-MET, TRIM4-MET, PPFIBP1-MET, LRRFIP1-MET, EPS15-MET, DCTN1-MET;

[0087] Preferably, MET is selected from MET overexpression. IHC detection of tumor tissue yields 2+ or 3+; MET gene amplification is determined by FISH detection of GCN≥5 and / or MET / CEP7≥2, FISH detection of 2<GCN<5 and MET / CEP7<2; and NGS detection confirms the presence of MET gene amplification.

[0088] Fourthly, the present invention provides a method for preventing and / or treating EGFR and / or MET-mediated diseases using the aforementioned combination drug or pharmaceutical composition, the method comprising administering a therapeutically effective amount of the aforementioned combination drug or pharmaceutical composition to a patient in need;

[0089] The patient is preferably a mammal, and the mammal is preferably a human.

[0090] In some embodiments, the disease is selected from cancer, including solid tumors or hematologic malignancies;

[0091] In some embodiments, the cancers include: breast cancer, ovarian cancer, prostate cancer, melanoma, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, brain cancer, glioma, cervical cancer, head and neck cancer, multiple myeloma, malignant lymphoma, leukemia, thyroid tumor, bladder tumor, gallbladder cancer, bile duct cancer, pharyngeal cancer, nasal cancer, oral cancer, tongue cancer, vaginal cancer, or choriocarcinoma.

[0092] In some embodiments, the cancer includes: lung cancer, glioma, and more preferably non-small cell lung cancer.

[0093] In some embodiments, the cancer includes: brain metastases, preferably brain metastases from lung cancer, more preferably brain metastases from non-small cell lung cancer.

[0094] In some embodiments, the administration route includes: oral, injection, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternae dorsalis, vaginal, peritoneal, bladder, and nasal administration.

[0095] This invention relates to combination drugs or pharmaceutical compositions that can enter the body through any suitable route, such as oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal, or subcutaneous routes.

[0096] In some embodiments, the combination drugs or drug compositions provided in this invention can be used simultaneously, separately, or sequentially.

[0097] In some embodiments, the combination drugs or drug compositions provided in this invention can be used continuously.

[0098] In some embodiments, the combination drugs or pharmaceutical compositions provided in this invention can be formulated into dosage forms suitable for drug release, administered via injection routes (e.g., subcutaneous, intravenous, intra-articular, sheath, intracapsular, intra-frame, intracardiac, intradermal, intraperitoneal, tracheal, epidermal, intra-articular, subcapsular, subarachnoid, intraspinal, intrasternal, and / or infusion) and non-injection routes (e.g., oral, enteric, oral, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal, or topical epidermal administration).

[0099] Suitable dosage forms include (but are not limited to) dosage forms for injection such as emulsions, solutions, and suspensions; dosage forms for oral administration such as tablets, capsules, pills, sugar-coated pills, powders, and granules; dosage forms for topical or transdermal absorption such as sprays, ointments, pastes, creams, lotions, gels, solutions, medicated patches, and inhalers; and dosage forms for vaginal or rectal administration such as suppositories. These dosage forms can be prepared according to the compound and suitable excipients under appropriate conditions, and the methods and processes for preparation are well known, for example, as provided in Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins.

[0100] Technical effect

[0101] The pharmaceutical composition of the present invention exhibits a synergistic effect, demonstrating beneficial efficacy and good tolerability in treating patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET gene amplification or MET overexpression. At the RP2D dose, the overall objective response (ORR) reached 57.1%, and the progression-free survival (PFS) reached 9.9 months, achieving a more durable response. It also showed significant efficacy in patients with brain metastases, with an ORR of 47.4% and a PFS of 9.5 months. Furthermore, when MET amplification was detected by NGS, both low- and high-fold MET gene amplification benefited from treatment with the pharmaceutical composition of the present invention, achieving an ORR of 61.7% and a PFS of 9.6 months. Simultaneously, the pharmaceutical composition of the present invention can use lower doses of the active ingredient, for example, requiring a lower dose than the single active ingredient, thus reducing the incidence or severity of side effects. In summary, the pharmaceutical composition of the present invention provides a more durable benefit for lung cancer patients and also benefits patients with brain metastases, with good tolerability, improving patients' quality of life.

[0102] Definitions and Explanations

[0103] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. Technical and scientific terms not specifically defined have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0104] "Solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention through intermolecular forces. Solvents that form solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, acetic acid, etc.

[0105] "Combination drug" refers to a drug that combines two or more active ingredients. When using a combination drug, the two or more active ingredients are administered simultaneously and independently or separately at time intervals.

[0106] "Pharmaceutical acceptable" means that, within the limits of reasonable medical judgment, it is suitable for contact with mammalian (e.g., human) tissues without excessive toxicity, irritation, allergic reactions, immunogenicity or other problems or complications, and has a reasonable benefit-risk ratio and is effective for its intended use.

[0107] "Effective amount" or "therapeutic effective amount" refers to the amount of a compound or pharmaceutical composition that is suitable for treating or improving an identified disease or condition, or for achieving a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of treatment and can be determined by someone skilled in the art using known techniques, as provided in Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins.

[0108] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, component, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or potting material, which participates in loading or delivering the active compound of the present invention from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part. A pharmaceutically acceptable carrier can be a medium, diluent, excipient, or other material that does not have excessive toxicity or side effects and is suitable for contact with animal tissues.

[0109] Some pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth gum; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Lipids, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Sterile pyrogen-free water; (17) Physiological saline; (18) Ringer's solution; (19) Alcohols, such as ethanol and propanol; (20) Phosphate buffer; (21) Other substances that are non-toxic and compatible with pharmaceutical dosage forms, such as acetone.

[0110] Each pharmaceutically acceptable carrier should be compatible with other components, such as forming formulations with the compounds provided in this invention, and should not cause excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications to living biological tissues or organs, and should have a reasonable benefit-risk ratio.

[0111] Pharmaceutical ingredients can be formulated into any suitable dosage form, such as solid dosage forms (e.g., tablets, capsules, powders, granules, etc.) and liquid dosage forms (e.g., aqueous solutions, emulsions, elixirs, syrups, etc.). The methods and processes for preparing pharmaceutical compositions are well-known and can be carried out according to conventional processes, such as those described in Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins.

[0112] "Administration" refers to the physical introduction of the active agents in the combination of the present invention into the body using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of the compositions of the present invention include oral, intravenous (e.g., infusion, drip, or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local, or other parenteral administration routes. Accordingly, the active agents in the combinations disclosed herein can be formulated into capsules, tablets, injections (including infusions or injection solutions), syrups, sprays, lozenges, liposomes, or suppositories, etc.

[0113] "EGFR inhibitor," "EGFR small molecule inhibitor," or "EGFR-TKI" refers to a compound capable of targeting, inhibiting, reducing, lowering, or reducing the activity of at least one epidermal growth factor receptor (EGFR). The EGFR inhibitors described in this invention include, but are not limited to, aminopyrimidine compounds represented by general formula I as described in patent CN108707139A and their pharmaceutically acceptable salts or solvates, osimertinib and its pharmaceutically acceptable salts or solvates, ametinib and its pharmaceutically acceptable salts or solvates, vormetinib and its pharmaceutically acceptable salts or solvates, befotinib and its pharmaceutically acceptable salts or solvates, retizinib and its pharmaceutically acceptable salts or solvates, riertinib and its pharmaceutically acceptable salts or solvates, lazertinib, and... Pharmaceutically acceptable salts or pharmaceutically acceptable solvates of suvortinib and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, gefitinib and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, icotinib and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, erlotinib and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, afatinib and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, dacomitinib and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, lapatinib and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, cetuximab and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, and amivantamab and its pharmaceutically acceptable salts or pharmaceutically acceptable solvates.

[0114] "c-Met inhibitors" refer to compounds that can target, inhibit, reduce, decrease, or reduce the activity of at least one c-Met tyrosine kinase. The "c-Met inhibitors" described in this invention include, but are not limited to, Vebreltinib (APL-101), Savolitinib (AZD6094, HMPL-504), Capmatinib (INC280, NVP-INC280, INCB28060), Tepotinib (EMD1214063, MSC2156119), Glumetinib (SCC244), MK-2461, HS-10241, and AMG. 337. JNJ-38877618 (OMO-1), Elzovantinib (TPX-0022, CSF1R-IN-2), Crizotinib (PF-02341066), ABN-401 (KDDF-2016 03-08), SPH-3348 (I-020), MK-8033 (APG-8361, HQP-8361, HQP8361), SAR125844, ASKC202, GST-HG161 (GST-HG161-I).

[0115] "Oral dosage form" includes unit dosage forms intended for oral administration.

[0116] "Continuous administration" means daily administration. In the case of continuous administration, the drug may be administered once or multiple times a day, for example, once a day, twice a day, or three times a day, preferably once a day or twice a day.

[0117] "Treatment" refers to administering internal or external therapeutic agents to patients to control, alleviate, reduce or reduce disease symptoms, delay disease onset and / or reduce the development or worsening of disease.

[0118] "Subject" or "patient" refers to both mammals and non-mammals. Mammals include, but are not limited to: humans, non-human primates, cattle, horses, sheep, pigs, rabbits, dogs, and cats. Humans are preferred.

[0119] The terms “comprising” and “including” are used in an open and non-limiting sense in this invention.

[0120] "Pharmaceutically acceptable salts" refer to conventional acid-addition or base-addition salts in which the bioavailability of the active compound remains unchanged, and which are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid-addition salts include those derived from inorganic acids and organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid. Examples of organic acids include acetic acid, propionic acid, malonic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, hydroxyethylsulfonic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, benzoic acid, etc. Examples of base-addition salts include those derived from inorganic acids and organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, and magnesium salts. The organic bases include salts of primary, secondary, and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc. Chemically modifying pharmaceutical compounds (i.e., drugs) into salts is a well-known technique among pharmacists to obtain improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compounds.

[0121] "Synergy" refers to a therapeutic combination that is more effective than the sum of two or more individual active agents.

[0122] The pharmacological activities of the combinations disclosed in this invention have been demonstrated in preclinical animal tumor models or in clinical studies, as primarily described below.

[0123] The following embodiments illustrate the technical content of this disclosure, but they do not limit the scope of this disclosure in any way. The beneficial effects of the combinations of the present invention can also be determined by other test models known to those skilled in the art. Attached Figure Description

[0124] Figure 1 Tumor growth curves of NCI-H820 xenograft tumor-bearing mice after administration of the test substance;

[0125] Figure 2 This graph shows the relative body weight change (%) for mice in different groups; the relative body weight change was calculated based on the animals' body weight at the start of drug administration. Data points represent the percentage change in mean body weight within the group, and error bars represent standard errors (SEM). Detailed Implementation

[0126] abbreviations

[0127]

[0128]

[0129] The structure of the compound of formula II is as follows:

[0130]

[0131] Example 1

[0132] In vivo efficacy study of compound II in combination with beritinib in human non-small cell lung cancer NCI-H820 subcutaneous xenograft tumor model. 1. Experimental objective

[0133] The in vivo efficacy of the Formula II compound in combination with beritinib in a human non-small cell lung cancer NCI-H820 subcutaneous xenograft mouse model of Balb / c nude.

[0134] 2. Experimental methods and statistical analysis

[0135] 2.1 Test Methods

[0136] The tumor growth status is examined to reflect the treatment effect. The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compound was evaluated using TGI (%) or relative tumor proliferation rate T / C (%). TGI (%) reflects the tumor growth inhibition rate.

[0137] Calculation of TGI (%): 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 control group - mean tumor volume at the start of treatment in the control group)] × 100%.

[0138] Relative tumor proliferation rate T / C (%): The calculation formula is as follows: T / C% = T / C × 100% (T: average tumor volume in the treatment group; C: average tumor volume in the control group).

[0139] Synergistic analysis of combined drug therapy was performed using the King's Law formula to calculate the q-value (Jin ZJ, 1980; Jin ZJ, 2004): q = EAB / (EA + EB - EA × EB), where EAB is the inhibition rate of the combined drug, and EA and EB are the inhibition rates of each drug alone. A q-value greater than 1.15 indicates a synergistic effect between the two drugs; a q-value between 0.85 and 1.15 indicates an additive effect; and a q-value less than 0.85 indicates an antagonistic effect.

[0140] 2.2 Statistical Analysis

[0141] Statistical analysis included the mean and standard error (SEM) of tumor volume at each time point for each group. Two-way ANOVA was used to analyze differences in tumor volume between groups at each time point. Statistical analysis was performed based on tumor volume data at the end of the trial to assess differences between groups. The t-test was used for comparisons between two groups; one-way ANOVA was used for comparisons between three or more groups. If the F-value was statistically significant, multiple comparisons should be performed after ANOVA analysis. Two-way ANOVA was used to test the interaction between the two drugs in the combination therapy group. All data were analyzed using GraphPad Prism. A p-value < 0.05 was considered statistically significant.

[0142] 3. Experimental Materials

[0143] 3.1 Laboratory Animals

[0144] Balb / c nude mice, female, 6–8 weeks old, weighing 18.84–24.39 g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. All test mice were housed in the experimental environment for 3–7 days before the start of the experiments.

[0145] 3.2 Rearing Environment

[0146] The test animals were housed in SPF-grade animal facilities using IVC (independent ventilation system) cages (4 animals per cage). All cages, bedding, and water were sterilized before use. Cages, feed, and water were changed twice a week. Temperature: 20–26°C, humidity: 40–70%, light: 12 hours. The experimental animals had free access to food throughout the experimental period.

[0147] 3.3 Instruments and Reagents

[0148]

[0149]

[0150] 4. Experimental Procedure

[0151] 4.1 Cell Culture

[0152] Human non-small cell lung cancer NCI-H820 cells (ATCC, catalog number: ATCC-HTB-181) were cultured in vitro as a monolayer under the following conditions: RPMI 1640 with 5% fetal bovine serum and 1% penicillin-streptomycin, at 37°C and 5% CO2. Cells were passaged twice a week using trypsin-EDTA digestion. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested, counted, and seeded.

[0153] 4.2 Tumor inoculation

[0154] 0.2 mL (10 × 10)6 NCI-H820 cells (PBS:Matrigel = 2:1) were subcutaneously inoculated into the right posterior dorsal region of each mouse, and tumor growth was observed. The NCI-H820 model was established when the average tumor volume reached 166 mm². 3 At that time, the tumor-bearing mice were randomly divided into 6 groups of 8 mice each, based on the size of the tumor.

[0155] 4.3 Administration

[0156] The experiment was divided into four groups: a beritinib (0.8 mg / kg, 0.4 mg / kg) group, a compound II (10 mg / kg) group, a beritinib combined with compound II (0.8 mg / kg + 10 mg / kg, 0.4 mg / kg + 10 mg / kg) group, and a solvent control group. Beritinib and compound II were provided by Beijing Anshi Biosciences Co., Ltd., and were administered orally by gavage for 24 days. Animal grouping and administration regimens are shown in Table 1.

[0157] Table 1. Animal grouping and dosing regimen for in vivo efficacy studies of compound II combined with beritinib in a human non-small cell lung cancer NCI-H820 subcutaneous xenograft tumor model.

[0158]

[0159] Note: N 1 Number of mice per group; Solvent control group: 10% gum arabic

[0160] 4.4 Daily Observation

[0161] Monitor the animals' health status and mortality daily. Routine checks include observing the effects of tumor growth and drug treatment on the animals' daily behavior, such as activity levels, food and water intake, weight changes (measure weight twice a week), physical signs, or other abnormalities.

[0162] 4.5 Measure tumor volume and animal weight

[0163] Before the trial began, tumor diameter and animal weight were measured using calipers. During the trial, tumor diameter and animal weight were measured twice a week or every other day using calipers. The in vivo tumor-suppressing efficacy of the Formula II compound in combination with beritinib was evaluated based on TGI (%) or relative tumor proliferation rate T / C (%).

[0164] 5. Experimental Results

[0165] The antitumor efficacy of compound II in combination with beritinib in a human non-small cell lung cancer NCI-H820 xenograft model is shown in Table 2. Figure 1 As shown.

[0166] Table 2. Evaluation of the antitumor efficacy of compound II in combination with beritinib in a human non-small cell lung cancer NCI-H820 xenograft model (calculated based on tumor volume on day 23 after administration).

[0167]

[0168] Note: a: Tumor growth inhibition T / C = T / C × 100% (T: mean tumor volume in the treatment group; C: mean tumor volume in the solvent control group); b: TGI (TGI(%)) = [1-(T... 23 -T0) / (V 23 -V0)]×100,T 23 T0: Mean tumor volume on day 23 of treatment; V: Mean tumor volume before day 1 of treatment. 23 V0: Mean tumor volume on day 23 after solvent administration; c: Mean tumor volume before the start of solvent administration on day 1; p-value (one-way ANOVA) calculated based on tumor volume.

[0169] From Table 2 and Figure 1 As can be seen from the data, on day 23 of administration, compared with the solvent control group, the T / C values ​​of the beritinib (0.8 mg / kg) monotherapy group, the beritinib (0.4 mg / kg) monotherapy group, the compound II (10 mg / kg) monotherapy group, the beritinib (0.8 mg / kg) and compound II (10 mg / kg) combination therapy group, and the beritinib (0.4 mg / kg) and compound II (10 mg / kg) combination therapy group were 20.83%, 28.64%, 45.89%, 5.39%, and 15.67%, respectively; the TGI values ​​were 96.48%, 86.97%, 65.94%, 115.28%, and 102.76%, respectively. The combination therapy groups showed significant tumor-suppressing effects (p values ​​< 0.0001 for all groups), and the TGI values ​​of the combination therapy groups were greater than those of the monotherapy groups.

[0170] Table 3 shows the significant differences in efficacy between groups in the NCI-H820 xenograft model of human non-small cell lung cancer when beritinib was administered in combination with compound II. The table shows that the efficacy of beritinib in combination with compound II was significantly enhanced (p < 0.0001). According to the King's Law, a q-value greater than 1.15 indicates a synergistic effect between the two drugs. The q-value for beritinib (0.8 mg / kg) combined with compound II (10 mg / kg) was 1.1668, which is greater than 1.15. Therefore, the combination of beritinib (0.8 mg / kg) and compound II (10 mg / kg) has a synergistic effect.

[0171] Table 3. Analysis of significant differences among groups in the trial endpoints of compound II combined with beritinib in a human non-small cell lung cancer NCI-H820 xenograft model (calculated based on tumor volume on day 23).

[0172] Group <![CDATA[p-value (two-way ANOVA) a > <![CDATA[p-value (two-way ANOVA) b > <![CDATA[q value c > 1 -- -- -- 2 ＜0.0001 --- - 3 ＜0.0001 --- - 4 ＜0.0001 --- - 5 ＜0.0001 ＜0.0001 1.1668 6 ＜0.0001 ＜0.0001 1.0753

[0173] Note: --: Not calculated; a: p-value calculated based on tumor volume on day 23 (vs solvent); b: p-value calculated based on tumor volume on day 23 (combination therapy group vs. compound II); c: q-value calculated according to the King's formula.

[0174] In a safety study of beritinib combined with compound II in a human non-small cell lung cancer NCI-H820 subcutaneous xenograft model, all treatment groups of tumor-bearing mice showed good tolerability to the test drugs, with no significant weight loss. (See Table 4 and...) Figure 2 As shown.

[0175] Table 4. Body weight changes in different groups in the human non-small cell lung cancer NCI-H820 subcutaneous xenograft model after combination therapy with beritinib and compound of formula II.

[0176]

[0177] a: Average weight of animals before starting medication on day 1

[0178] In summary, the combination of beritinib and compound II demonstrated significant tumor-suppressive effects in the human non-small cell lung cancer NCI-H820 subcutaneous xenograft model, with the TGI value of the combination group being higher than that of each single-drug group. Furthermore, the combination of beritinib (0.8 mg / kg) and compound II (10 mg / kg) exhibited synergistic tumor-suppressive effects, showing a significant difference compared to compound II alone. Moreover, the tumor-bearing mice showed good tolerance to the test drugs, with no significant weight loss.

[0179] Example 2

[0180] Clinical trials of beritinib in combination with compound II

[0181] This is an open-label, multicenter phase Ib / II clinical trial evaluating the safety, efficacy, and pharmacokinetic characteristics of beritinib in combination with a type II compound for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET overexpression or MET gene amplification. The trial is divided into two phases: phase Ib (dose escalation and dose expansion) and phase II (efficacy confirmation).

[0182] 1. Clinical trial protocol

[0183] 1.1 Indications

[0184] Locally advanced or metastatic non-small cell lung cancer with MET overexpression or MET gene amplification after EGFR-TKI treatment failure

[0185] 1.2 Research Objectives

[0186] 1.2.1 Phase Ib Study

[0187] 1.2.1.1 Dosage escalation phase

[0188] 1.2.1.1.1 Main Purpose

[0189] To evaluate the safety and tolerability of beritinib in combination with a type II compound for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET overexpression or MET gene amplification;

[0190] Determine the dose-limiting toxicities (DLT) (if any) and the maximum tolerated dose (MTD) (if any) for combination therapy.

[0191] 1.2.1.1.2 Secondary Objectives

[0192] To evaluate the preliminary efficacy of beritinib in combination with type II compounds in the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET overexpression or MET gene amplification.

[0193] 1.2.1.2 Dosage expansion phase

[0194] 1.2.1.2.1 Main Purpose

[0195] To evaluate the preliminary efficacy of beritinib in combination with type II compounds in the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET overexpression or MET gene amplification;

[0196] Determine the recommended dose (RP2D) for the combined drug phase II clinical trial.

[0197] 1.2.1.2.2 Secondary Objectives

[0198] To evaluate the safety of beritinib in combination with a type II compound for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET overexpression or MET gene amplification.

[0199] To evaluate the efficacy of beritinib in combination with type II compounds in patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET overexpression (different IHC ratios) or MET gene amplification (different copy numbers).

[0200] 1.2.2 Phase II Study

[0201] 1.2.2.1 Main Purpose

[0202] To evaluate the efficacy of beritinib in combination with type II compounds under RP2D in patients with locally advanced or metastatic non-small cell lung cancer who have failed first- or second-generation EGFR-TKI therapy, are T790M mutation negative, and have MET gene amplification.

[0203] To evaluate the efficacy of beritinib in combination with compound II under RP2D in patients with locally advanced or metastatic non-small cell lung cancer with MET gene amplification after failure of third-generation EGFR-TKI therapy;

[0204] To evaluate the efficacy of beritinib in combination with a type II compound under RP2D in patients with locally advanced or metastatic non-small cell lung cancer who have failed first- / second- or third-generation EGFR-TKI therapy and have MET overexpression (IHC result of 3+ in tumor tissue detected by IHC).

[0205] 1.2.2.2 Secondary Objectives

[0206] To evaluate the safety of beritinib in combination with a type II compound for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have failed EGFR-TKI therapy and have MET overexpression or MET gene amplification;

[0207] To evaluate the efficacy of beritinib in combination with type II compounds for the treatment of locally advanced or metastatic non-small cell lung cancer with c-Met amplification in patients who have failed EGFR-TKI therapy, considering different MET gene amplification copy number ranges using different detection methods.

[0208] 1.3 Study Endpoints

[0209] 1.3.1 Phase Ib Study

[0210] 1.3.1.1 Dosage escalation phase

[0211] 1.3.1.1.1 Primary study endpoint

[0212] Safety and tolerability: Throughout the study, the safety and tolerability of beritinib in combination with compound II will be assessed based on monitoring of adverse events (AEs), physical examination, vital signs, 12-lead electrocardiogram, echocardiography, ophthalmological examination, and laboratory tests.

[0213] The DLT and MTD of the beritinib combination II compound will be determined based on safety, tolerability, pharmacokinetics, preliminary efficacy, and other available data.

[0214] 1.3.1.1.2 Secondary study endpoints

[0215] Preliminary efficacy evaluation: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

[0216] 1.3.1.2 Dosage expansion phase

[0217] 1.3.1.2.1 Primary study endpoint

[0218] Efficacy evaluation: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS);

[0219] The RP2D of the beritinib combination compound II will be determined based on preliminary efficacy data, combined with safety, tolerability, pharmacokinetic and other available data.

[0220] 1.3.1.2.2 Secondary study endpoints

[0221] Safety: Throughout the study, the safety of beritinib in combination with compound II will be assessed based on monitoring of adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiograms, echocardiograms, ophthalmological examinations, and laboratory tests. Adverse event severity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.

[0222] 1.3.2 Phase II Study

[0223] 1.3.2.1 Primary study endpoint

[0224] Primary efficacy assessment: Objective response rate (ORR) (RECIST 1.1 criteria);

[0225] Secondary efficacy assessments include: disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS).

[0226] 1.3.2.2 Secondary study endpoints

[0227] Safety: Throughout the study, the safety of beritinib in combination with compound II will be assessed based on monitoring of adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiograms, echocardiograms, ophthalmological examinations, and laboratory tests. Adverse event severity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.

[0228] 1.4 Dosing regimen

[0229] 1.4.1 Dosage escalation phase

[0230] Possible dosage combinations include:

[0231] 1) Beritinib 100mg BID + Compound II 160mg QD, with each 21-day period constituting one treatment cycle.

[0232] 2) Beritinib 150mg BID + Compound II 160mg QD, with each 21-day period constituting one treatment cycle.

[0233] 3) Beritinib 200mg BID + Compound II 160mg QD, with each 21-day period constituting one treatment cycle.

[0234] 4) Beritinib 100mg BID + Compound II 80mg QD, with each 21-day period constituting one treatment cycle.

[0235] 5) Beritinib 150mg BID + Compound II 80mg QD, with each 21-day period constituting one treatment cycle.

[0236] 6) Beritinib 200mg BID + Compound II 80mg QD, with each 21-day period constituting one treatment cycle.

[0237] 1.4.2 Dosage expansion phase (continuous administration)

[0238] During dose escalation, based on the PK data, safety, and preliminary efficacy of the completed dose groups, the investigator and the sponsor jointly decide to select ≥2 dose groups for dose expansion studies.

[0239] 1.4.3 Phase II Study

[0240] Based on the results of Phase Ib, RP2D was selected to proceed to Phase II.

[0241] 1.5 Definition of MTD

[0242] MTD is defined as the highest dose at which the proportion of DLT events occurring during the DLT observation period is less than 1 / 3.

[0243] The dose level preceding a dose level in which 2 out of 3 subjects or at least 2 out of 6 subjects have DLT.

[0244] 1.6 Selection Criteria

[0245] To be included in this study, candidates must meet the following inclusion criteria:

[0246] 1) Able to understand and voluntarily sign a written informed consent form;

[0247] 2) Males or females aged 18 years or older;

[0248] 3) Patients with locally advanced (stage IIIB / IIIC), metastatic, or recurrent (stage IV) NSCLC who are clinically diagnosed as untreatable and ineligible for radical concurrent chemoradiotherapy;

[0249] 4) Subjects with known EGFR mutations associated with EGFR-TKI sensitivity (including 19del and exon 21L858R mutations); subjects who have received only first-generation and / or second-generation EGFR-TKI treatment in the phase II trial must have a negative T790M test result.

[0250] 5) MET overexpression and / or MET gene amplification confirmed after disease progression following EGFR-TKI treatment:

[0251] a) Phase Ib

[0252] ①MET overexpression, IHC 3+ or IHC 2+;

[0253] ②MET gene amplification;

[0254] b) Phase II

[0255] ①MET overexpression:

[0256] Cohort 4: The IHC result of tumor tissue tested by the central laboratory was 3+;

[0257] ②MET gene amplification:

[0258] Cohort 1 and Cohort 2: Tumor tissue samples, with GCN ≥ 5 or MET / CEP 7 ≥ 2 as determined by FISH testing at the central laboratory;

[0259] Cohort 3: Tumor tissue samples, with GCN <5 and MET / CEP7 <2 as determined by FISH testing at the central laboratory, and NGS testing results confirming the presence of MET gene amplification (NGS test results from local testing institutions / central laboratories are acceptable);

[0260] Cohort 4: Tumor tissue samples, confirmed negative for MET gene amplification by FISH and NGS testing at the central laboratory;

[0261] 6) Applicable only to Phase Ib dose extension and Phase II: Patients who have received ≤3 lines of systemic antitumor therapy;

[0262] 7) At least one measurable lesion is assessed according to RECIST 1.1 criteria (lesions that have previously received radiotherapy cannot be considered target lesions unless there is clear progression of the lesion after radiotherapy);

[0263] 8) ECOG physical condition score ≤ 1 point;

[0264] 9) Laboratory test indicators meet the following requirements:

[0265] a) Absolute neutrophil count ≥1.5×10 9 / L (if no growth factors were used within 7 days prior to the start of treatment);

[0266] b) Hemoglobin ≥90g / L (without blood transfusion or growth factor use within 7 days prior to treatment);

[0267] c) Platelet count ≥75×10 9 / L (Phase Ib dose escalation phase, platelet count ≥100×10⁶) 9 / L)(without blood transfusion or growth factor use within 7 days prior to the start of treatment);

[0268] d) Serum total bilirubin ≤1.5×Upper Limit of Normal (ULN) (If the patient has Gilbert's syndrome or liver metastases, total bilirubin ≤3×ULN and direct bilirubin ≤1.5×ULN are allowed).

[0269] e) Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN (for patients with liver metastases, both AST and ALT ≤5×ULN):

[0270] f) Creatinine clearance (Ccr) ≥ 60 mL / min. Creatinine clearance is calculated using the Cockcroft-Gault formula: (140 - age [yr]) × weight (kg) × 1.23 × (0.85, if female) / serum creatinine (μmol / L).

[0271] g) International Normalized Ratio (INR) ≤ 1.5 × ULN;

[0272] h) Asymptomatic serum amylase ≤ grade 2 (NCI-CTCAE v5.0). For patients with grade 2 serum amylase abnormalities at the start of the study, it must be confirmed that there are no signs and / or symptoms suggestive of pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal pancreatic imaging results, etc.);

[0273] i) Serum lipase ≤ 1.5 × ULN;

[0274] 10) Both men of childbearing age and women of reproductive age (WOCBP) must agree to use effective contraception from the time of signing the informed consent form until 3 months after the last dose of the study drug. Women of reproductive age must have a negative serum pregnancy test result within ≤7 days prior to the first dose of the study drug. Exceptions are made for women who have undergone sterilization or are postmenopausal.

[0275] 11) Based on the researcher's judgment, the expected survival time is ≥3 months.

[0276] 1.7 Exclusion Criteria

[0277] Subjects who meet any of the following criteria will not be eligible to participate in this study:

[0278] 1) Previously received c-Met targeted therapy and HGF targeted therapy;

[0279] 2) Positive ALK fusion and positive ROS1 fusion were observed;

[0280] 3) Patients with spinal cord compression, meningeal metastases, or symptomatic brain metastases, or those requiring increased steroid dosage to control central nervous system (CNS) disease, are eligible to participate in this trial if symptomatic CNS metastases are under control (patients must have stable neurological function, with no new neurological deficits detected on clinical examination and no new problems found on CNS imaging. If patients require steroid treatment for CNS metastases, their steroid dosage must have been stable for at least two weeks prior to entering the study).

[0281] 4) Having other malignant tumors (excluding any type of carcinoma in situ that has been completely removed, basal cell and squamous cell skin cancer, or other tumors / cancers that have been radically treated and have been free of disease for at least 3 years);

[0282] 5) Previous history of anti-tumor treatment meets one of the following conditions:

[0283] a) The patient had received antitumor and investigational drug treatment within 2 weeks prior to the first dose of the study or within 5 times the drug half-life (whichever is longer);

[0284] If the prior treatment was a monoclonal antibody, it must be discontinued at least 2 weeks before the first dose; if the prior treatment was an oral targeted drug, it must be discontinued at least 5 times the drug's half-life before the first dose.

[0285] b) Received traditional Chinese medicine or proprietary Chinese medicine with anti-tumor indications within 1 week prior to the first administration of the study drug;

[0286] c) Patients who have received radiation therapy to the lung fields and whole brain within 4 weeks prior to the first administration of the study drug, or to other sites (excluding the lung fields and whole brain) within 2 weeks prior to administration, except for palliative radiation therapy to bone metastases to relieve pain or prevent bone events.

[0287] d) Patients who have undergone major surgery (e.g., intrathoracic, intraperitoneal, or intrapelvic surgery) within 4 weeks prior to the first dose of the study (or brain metastasis resection within 2 weeks prior), or who have not recovered from the side effects of such surgery. Thoracoscopic biopsy and mediastinoscopy are not considered major surgeries, and patients can be enrolled ≥1 week after surgery (thoracentesis, paracentesis, and percutaneous effusion are not considered surgeries);

[0288] 6) Failure to recover from any toxicity and / or complications of previous antitumor treatments such as chemotherapy, surgery, and radiotherapy, i.e., failure to reduce to ≤1 grade (National Cancer Institute Adverse Events Common Toxicity Criteria [NCI-CTCAE] v5.0), excluding hair loss and irreversible permanent radiation damage; neurotoxicity from platinum-based therapy can be acceptablely reduced to ≤2 grade;

[0289] 7) P-glycoprotein inducers (such as rifampin) or inhibitors (such as ritonavir) need to be used within one week before the first administration of the study drug and during the study period;

[0290] 8) Strong inhibitors or strong inducers of cytochrome P450 3A4 enzyme (CYP3A4) are required within one week before the first administration of the study drug and during the study period;

[0291] 9) Any serious or uncontrollable systemic disease, including but not limited to:

[0292] a) Uncontrolled hypertension (defined as systolic blood pressure >160 mmHg and / or diastolic blood pressure >100 mmHg after treatment) allows for the initiation or adjustment of antihypertensive medication before screening;

[0293] b) Anti-HIV (+), or both anti-HCV and HCV-RNA (+), or HBsAg positive and HBV-DNA ≥500 IU / mL (if HBV-DNA decreases to less than 500 IU / mL after antiviral treatment during the screening period and lasts for ≥2 weeks, the candidate can be enrolled and must continue to receive antiviral treatment during the study period; for subjects who previously needed or were receiving antiviral treatment at the time of screening, they must continue to receive antiviral treatment throughout the study period to be included in the study).

[0294] c) Onset of keratitis or ulcerative keratitis;

[0295] d) Active tuberculosis;

[0296] e) The patient had an active infection requiring systemic anti-infective therapy within 2 weeks prior to the first study drug administration;

[0297] f) Other severe illnesses, mental illnesses, or laboratory abnormalities, in which the investigator determines that the investigational drug is unsuitable for the patient or affects protocol adherence;

[0298] 10) Cardiac function and disease meeting one of the following conditions:

[0299] a) Under resting conditions, according to the Fridericia formula, the average corrected QT interval (QTcF) of three electrocardiograms during the screening period is >470ms.

[0300] b) Any significant cardiac arrhythmia such as ventricular arrhythmias, supraventricular or junctional arrhythmias that are not controlled by medication, and other cardiac arrhythmias that are not controlled by medication (such as complete left bundle branch block, grade III atrioventricular block, grade II cardiac conduction block, PR interval > 250 msec, etc.).

[0301] c) Any risk factors that increase QTc interval prolongation, such as severe hypokalemia, hereditary long QT syndrome, or taking medications that prolong the QT interval;

[0302] d) Congestive heart failure classified as ≥3 by the New York Heart Association (NYHA); echocardiography showing a left ventricular ejection fraction (LVEF) <50%;

[0303] 11) A history of interstitial lung disease, drug-induced interstitial lung disease, or radiation-induced pneumonia requiring hormone therapy, or currently receiving drug therapy or other clinical interventions, or having existing active interstitial lung disease.

[0304] 12) Has a history of coagulation disorders or bleeding tendency, including arterial or venous thromboembolic events (including myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, pulmonary embolism, severe deep vein thrombosis or any other serious thromboembolism) within 6 months prior to the first administration of the study drug, any life-threatening bleeding event (including those requiring blood transfusion, surgery or local treatment, or continuous drug treatment), or lesions involving large blood vessels, which the investigator judges to be bleeding tendency;

[0305] 13) Dysphagia, or active digestive system disease, or major gastrointestinal surgery that may significantly affect the administration or absorption of the investigational drug (e.g., ulcerative lesions, inability to swallow medication, uncontrollable nausea, vomiting, diarrhea, and malabsorption syndrome);

[0306] 14) Within 4 weeks prior to the first administration of the study drug, there was pleural effusion, pericardial effusion or ascites requiring drainage or accompanied by shortness of breath;

[0307] 15) The presence of any clinically significant systemic disease that the investigators deem necessary to treat, including but not limited to thyroid disease (patients with stable thyroid function who have undergone hormone replacement therapy can be enrolled), organ transplant patients, history of mental illness, substance abuse / addiction, alcoholism, or drug abuse.

[0308] 16) A history of acute or chronic pancreatitis, pancreatic surgery, or risk factors that may increase the risk of developing pancreatitis;

[0309] 17) Low-dose warfarin (<2 mg) is excluded for patients receiving thrombolytic or anticoagulant therapy to prevent central catheter-related thrombosis (Phase Ib dose escalation phase); patients receiving thrombolytic therapy cannot be included in Phase Ib dose expansion phase and Phase II studies, but patients receiving anticoagulant therapy are allowed to be included, provided they have received at least 1 week of stable-dose anticoagulant therapy before the first dose;

[0310] 18) Has known hypersensitivity to similar drugs and excipients of the investigational drug;

[0311] 19) Pregnant or breastfeeding women;

[0312] 20) Currently enrolled in other investigational devices or investigational drug treatments, or received other investigational drugs or investigational devices treatments within 2 weeks prior to the first administration of the investigational drug;

[0313] 21) Cognitive impairment may limit their understanding and implementation of informed consent forms;

[0314] 22) There may be risks associated with increasing administration of the study drug, or may affect the interpretation of the study results, or poor subject compliance, or any other situation that the investigator deems unsuitable for enrollment.

[0315] 1.8 Test Drug

[0316] Beritinib Enteric-coated Capsules: Dosage Form and Strength: Capsules, 25mg / capsule; 100mg / capsule

[0317] Formula II compound capsules: Dosage form and specifications: capsules, 40mg / capsule, 80mg / capsule; wherein, the preparation method of the 40mg / capsule and 80mg / capsule capsules is as follows: weigh 40mg and 80mg of Formula II compound respectively, add excipients: corn starch, mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and magnesium stearate, stir evenly using methods commonly used by those skilled in the art, and fill into gelatin empty capsules to obtain the product.

[0318] Storage: Store in a sealed container.

[0319] All the experimental drugs mentioned above were provided by Beijing Anshi Biotechnology Co., Ltd.

[0320] 1.9 Statistical Analysis

[0321] 1.9.1 Statistical Analysis Set

[0322] Full analysis set (FAS): Based on the intention-to-treat (ITT) principle, it includes subjects who have received at least one treatment with the study drug.

[0323] Safety analysis set (SS): All subjects who received at least one treatment with the study drug.

[0324] The DLT analysis set is a subset of the SS set, consisting of patients who meet the minimum drug exposure criteria and complete the DLT observation period, or whose DLT events occur during the DLT observation period.

[0325] Pharmacokinetic Set (PKS): Subjects who have used the study drug at least once and have at least one blood sample from which PK data can be evaluated. The PKS will be used to summarize PK concentration data and analyze PK parameters.

[0326] Efficacy Analysis Set (EAS): Patients who have used the study drug at least once and have baseline and at least one post-baseline tumor assessment.

[0327] 1.9.2 Statistical Methods

[0328] The final analysis of the study will be based on data collected from patients throughout the study period.

[0329] All safety and efficacy endpoints obtained were statistically described separately for the dose group (Phase Ib) and cohort (Phase II). Overall, continuous variables were described using the number of cases, mean, standard deviation, median, quartiles, minimum, and maximum values; categorical variables were described using the frequency and percentage of each category; time-event data were estimated using the Kaplan-Meier method for median survival and its two-sided 95% confidence interval (CI), and survival curves were plotted as necessary.

[0330] 1.9.3 Security

[0331] Safety assessment will include adverse events (AEs), physical examination, vital signs, 12-lead electrocardiogram, echocardiography, ophthalmological examination, and laboratory tests.

[0332] The incidence of DLT in each dose escalation cohort will be assessed based on the DLT analysis set.

[0333] Based on the SS (Systemic Organ Syndrome), adverse events (AEs) in each dose group (Phase Ib) / cohort (Phase II) and overall population will be summarized by systemic organ classification and preferred terminology. The incidence, severity, and relationship to the study drug for all AEs will be summarized.

[0334] Descriptive statistics will be performed on laboratory tests and vital signs for each dose group / cohort. Abnormal findings in adverse events (AEs), physical examination, vital signs, 12-lead electrocardiogram, echocardiography, ophthalmological examination, and laboratory tests will be listed.

[0335] All adverse events (AEs) will be coded using the MedDRA (Medical Dictionary for Drug Registration Affairs), and the severity of AEs will be classified according to the NCI CTCAE v5.0.

[0336] 1.9.4 Validity

[0337] All efficacy assessments, including ORR, DCR, DOR, PFS, TTR (Phase II only), and OS (Phase Ib dose extension and Phase II only), will be performed based on FAS and EAS according to RECIST v1.1. ORR and DCR will be summarized for each dose group (Phase Ib) / cohort (Phase II) and the overall RP2D dose (Phase Ib and Phase II), with 95% CI calculated using the Clopper-Pearson method. Median times and two-sided 95% CIs for DOR, PFS, TTR, and OS will be estimated using the Kaplan-Meier method.

[0338] 2. Experimental Results

[0339] From June 5, 2023 to December 31, 2024, enrolled subjects received four doses: Group A: Beritinib 100mg BID + Compound II 160mg QD; Group B: Beritinib 150mg BID + Compound II 160mg QD; Group C: Beritinib 150mg BID + Compound II 80mg QD; Group D: Beritinib 200mg BID + Compound II 80mg QD. Based on the safety analysis of the Phase Ib dose escalation phase, Groups A, B, and C were selected for a dose expansion study. Combining the preliminary efficacy and safety of the Phase Ib dose expansion, Group C (dose: Beritinib 150mg BID + Compound II 80mg QD) was designated as the RP2D and a Phase II clinical trial was conducted. As of December 31, 2024, the number of evaluable subjects and efficacy (ORR, mPFS, mDOR) in the four dose groups are shown in Table 5.

[0340] Table 5. Efficacy outcomes of the four dosage groups (ORR, mPFS, mDOR)

[0341]

[0342] NA: Not achieved

[0343] Table 5 shows that the objective response rate (ORR) in group C (beritinib 150 mg BID + compound II 80 mg QD) was higher than that in group A (beritinib 100 mg BID + compound II 160 mg QD) and group B (beritinib 150 mg BID + compound II 160 mg QD), with ORRs of 57.1%, 40%, and 38.5%, respectively. The median progression-free survival (mPFS) was longer in group C than in groups A and B, at 9.9 months, 8.5 months, and 9.6 months, respectively, indicating that the beritinib 150 mg BID + compound II 80 mg QD dose group benefited more patients and prolonged disease progression or worsening. Furthermore, all four dose groups were well-tolerated, with no subjects discontinuing treatment or dying due to treatment-related adverse events (TRAEs). At the RP2D dose, the incidence of grade 3 or higher treatment-related adverse events was 19.6%, indicating good tolerability.

[0344] The subgroup analysis results of RP2D (beritinib 150 mg BID + compound II QD 80 mg) are shown in Table 6. For subjects with baseline brain metastases, the ORR reached 47.4% and the PFS reached 9.5 months, which is superior to the drugs currently in clinical trials, with an ORR of 29.2% (INSIGHT2 trial). Moreover, when MET amplification was detected by NGS, both low-fold and high-fold MET gene amplification benefited from the treatment of the drug composition of the present invention, with an ORR of 61.7% and a PFS of 9.6 months. In addition, for subjects with MET overexpression (IHC detection of MET overexpression 3+), the ORR reached 62.2% and the PFS reached 9.6 months, which is also superior to the drugs currently in clinical trials, with an ORR of 50% and a PFS of 7.4 months (Ann Oncol. 2025, 11: S0923-7534(25)00005-5).

[0345] Table 6. Results of efficacy analysis in subgroup populations

[0346]

Claims

1. A combination drug for the prevention and / or treatment of cancer, said combination drug comprising: (1) A compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof; and (2) c-Met inhibitors or their pharmaceutically acceptable salts and / or solvates; in, The compounds of formula I are as follows: In equation I, R 1 For hydrogen atoms or R 2 C 1-6 Alkyl or OR 8 , where R 8 For hydrogen atoms, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 3-7 cycloalkyl-C 1-6 Alkyl groups, unsubstituted 4-7 membered heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, and unsubstituted 4-7 membered heterocyclic groups containing 1-2 heteroatoms selected from N, O, or S -C 1-8 alkyl; X represents chemical bonds, O, S, CO, NR 3 , where R 3 For hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-8 Alkyl-CO or 4-6 membered heterocyclic groups; R 4 C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-7 membered heterocyclic groups, which may optionally be substituted by 1-3 independent substituents selected from the following: C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, halogenated C 3-6 Cycloalkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, amino-C 1-6 Alkyl, C 1-6 Alkyl-amino-C 1-6 Alkyl, halogen, hydroxyl, cyano, cyano-C 1-8 Alkyl, amino, C 1-6 Alkyl-amino, di(C) 1-6 alkyl)-amino, C 3-6 Cycloalkyl-amino, C 1-6 alkyl carbonyl, C 1-6 alkyl-amino-acyl, di(C 1-6 alkyl)-amino-acyl, C 3-6 Cycloalkyl-amino-acyl, C 1-6 Acyl-amino, unsubstituted 4-7 membered heterocyclic groups; R 5 Selected from the following groups: R 6 It is hydrogen, halogen, hydroxyl, nitrile, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkoxy, halogenated C 3-6 Cycloalkoxy; Z 1 For CR 7 Z 2 For N, or Z 1 For N, Z 2 For CR 7 , where R 7 Hydrogen, halogen, nitrile, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl; The c-Met inhibitors are selected from Vebreltinib (Bozitinib, APL-101), Savolitinib (AZD6094, HMPL-504), Capmatinib (INC280, NVP-INC280, INCB28060), Tepotinib (EMD 1214063, MSC2156119), Glumetinib (SCC244), MK-2461, HS-10241, and AMG.

337. JNJ-38877618 (OMO-1), Elzovantinib (TPX-0022, CSF1R-IN-2), Crizotinb (PF-02341066), ABN-401 (KDDF-2016 03-08), SPH-3348 (I-020), MK-8033 (APG-8361, HQP-8361, HQP8361), SAR125844, ASKC202, GST-HG161 (GST-HG161-I).

2. The combination drug according to claim 1, wherein, In the compound of formula I, R 1 For hydrogen atoms; R 2 OR 8 , where R 8 Methyl, ethyl, or difluoromethyl; X represents a chemical bond or NR. 3 , where R 3 For hydrogen, C 1-6 Alkyl groups (e.g., methyl, ethyl); R 4 Selected from the following groups: R 5 Selected from the following groups: R 6 It is hydrogen or halogen; Z 1 For CH, Z 2 For N, or Z 1 For N, Z 2 For CH; Preferably, the compound of formula I is selected from the compound of formula II:

3. The combination drug according to claim 1 or 2, wherein, The c-Met inhibitor is selected from Vebreltinib (Bozitinib, APL-101).

4. The combination drug according to any one of claims 1 to 3, wherein, The mass ratio between (1) a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof and (2) a c-Met inhibitor or a pharmaceutically acceptable salt and / or solvate thereof is 1-1000:1-800, preferably 20-400:100-600, and more preferably 80:

300.

5. A pharmaceutical composition for the prevention and / or treatment of cancer, the pharmaceutical composition comprising the combination drug of any one of claims 1 to 4 and a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier is selected from one or more of diluents, cosolvents, solubilizers, excipients, fillers, binders, wetting agents, coating materials, surfactants, disintegrants, emulsifiers, osmotic pressure regulators, lubricants, colorants, pH adjusters, antioxidants, and antibacterial agents.

6. The pharmaceutical composition according to claim 5, wherein, The composition comprises: (1) A compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof; and (2) c-Met inhibitors or their pharmaceutically acceptable salts and / or solvates; and (3) At least one pharmaceutically acceptable carrier; Among them, the compounds of formula I are as follows: In equation I, R 1 For hydrogen atoms; R 2 OR 8 , where R 8 Methyl, ethyl, or difluoromethyl; X represents a chemical bond or NR. 3 , where R 3 For hydrogen, C 1-6 Alkyl groups (e.g., methyl, ethyl); R 4 Selected from the following groups: R 5 Selected from the following groups: R 6 It is hydrogen or halogen; Z 1 For CH, Z 2 For N, or Z 1 For N, Z 2 For CH; The c-Met inhibitors are selected from Vebreltinib (Bozitinib, APL-101), Savolitinib (AZD6094, HMPL-504), Capmatinib (INC280, NVP-INC280, INCB28060), Tepotinib (EMD 1214063, MSC2156119), Glumetinib (SCC244), MK-2461, HS-10241, and AMG.

337. JNJ-38877618 (OMO-1), Elzovantinib (TPX-0022, CSF1R-IN-2), Crizotinb (PF-02341066), ABN-401 (KDDF-2016 03-08), SPH-3348 (I-020), MK-8033 (APG-8361, HQP-8361, HQP8361), SAR125844, ASKC202, GST-HG161 (GST-HG161-I); The pharmaceutically acceptable carrier is selected from one or more of the following: diluents, solubilizers, excipients, fillers, binders, wetting agents, coating materials, surfactants, disintegrants, emulsifiers, osmotic pressure regulators, lubricants, colorants, pH adjusters, antioxidants, and antibacterial agents. Preferably, the composition comprises: (1) A compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof; and (2) c-Met inhibitors or their pharmaceutically acceptable salts and / or solvates; and (3) At least one pharmaceutically acceptable carrier; The compound of formula I is selected from the compound of formula II: The c-Met inhibitor is selected from veboleltinib (Bozitinib, APL-101); The pharmaceutically acceptable carrier is selected from one or more of the following: diluents, solubilizers, excipients, fillers, binders, wetting agents, coating materials, surfactants, disintegrants, emulsifiers, osmotic pressure regulators, lubricants, colorants, pH adjusters, antioxidants, and antibacterial agents.

7. The pharmaceutical composition according to claim 5 or 6, wherein, The composition comprises: (1) 1-1000 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 1-800 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier; Preferably, the composition comprises: (1) 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, (1) 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg or 500 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg or 100 mg. mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190m g, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 37 0 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg or 600 mg of Vebreltinib (Bozitinib, APL-101) or its pharmaceutically acceptable salts and / or solvates; and (3) at least one pharmaceutically acceptable carrier; Preferably, the composition comprises: (1) 20-400 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 100-600 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier; Preferably, the composition comprises: (1) 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 200 mg, 240 mg, 280 mg, 320 mg, 360 mg, 400 mg or 480 mg of a compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof; (2) 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of vebretinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition comprises: (1) 80 mg of a compound of formula II or a pharmaceutically acceptable salt thereof; and (2) 300 mg of veboletinib (Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof; and (3) at least one pharmaceutically acceptable carrier.

8. The combination drug according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 5 to 7, wherein, (1) A compound of formula I (e.g., a compound of formula II) or a pharmaceutically acceptable salt and / or solvate thereof is administered at a dose of 40 mg, 80 mg, 160 mg, 240 mg or 320 mg once daily for continuous administration; and (2) a c-Met inhibitor (e.g., Vebreltinib, Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof is administered at a dose of 100 mg, 150 mg or 300 mg twice daily for continuous administration; Preferably, (1) the compound of formula I (e.g., the compound of formula II) or its pharmaceutically acceptable salt and / or solvate is administered at a dose of 80 mg once daily for continuous administration; and (2) the c-Met inhibitor (e.g., Vebreltinib, Bozitinib, APL-101) or its pharmaceutically acceptable salt and / or solvate is administered at a dose of 150 mg twice daily for continuous administration; Preferably, a compound of formula I (e.g., a compound of formula II) or a pharmaceutically acceptable salt and / or solvate thereof and a c-Met inhibitor (e.g., Vebreltinib, Bozitinib, APL-101) or a pharmaceutically acceptable salt and / or solvate thereof are used simultaneously, separately, or sequentially.

9. Use of the combination drug of any one of claims 1 to 4, 8 or the pharmaceutical composition of any one of claims 5 to 8 in the preparation of a medicament for the prevention and / or treatment of EGFR and / or MET-mediated diseases; Preferably, the disease is selected from cancer, including solid tumors or hematologic malignancies; Preferably, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, brain cancer, glioma, cervical cancer, head and neck cancer, multiple myeloma, malignant lymphoma, leukemia, thyroid tumor, bladder tumor, gallbladder cancer, bile duct cancer, pharyngeal cancer, nasal cancer, oral cancer, tongue cancer, vaginal cancer, or choriocarcinoma; More preferably, the cancer is selected from lung cancer, glioma, and more preferably non-small cell lung cancer. Preferably, the cancer is selected from brain metastases, more preferably brain metastases from lung cancer, and even more preferably brain metastases from non-small cell lung cancer.

10. The use according to claim 9, wherein, The non-small cell lung cancer mentioned above is selected from EGFR-mediated non-small cell lung cancer that has not received any previous treatment, and non-small cell lung cancer that has received EGFR drug treatment and carries MET gene amplification and / or MET overexpression; Preferred candidates are non-small cell lung cancer patients who have previously received first-generation or second-generation EGFR drugs and are T790M mutation negative and carry MET gene amplification and / or MET overexpression, and non-small cell lung cancer patients who have previously received third-generation EGFR drugs and carry MET gene amplification and / or MET overexpression. Preferably, the EGFR is selected from EGFR overexpression, EGFR gene amplification, and EGFR mutation; Preferably, EGFR is selected from EGFR exon 18 mutation, EGFR exon 19 mutation, EGFR exon 19 deletion, EGFR exon 20 mutation, and EGFR exon 21 mutation; More preferably, the EGFR is selected from EGFR E709K / Q / A / G / V, L718Q, L718V, G719C / S / A / R, G724S, I744T, E746K, L747S, E749Q, A750P, A755V, V765M, S768I, C775Y, T790M, L792H, L792V, G796S, G796R, G796C, C797S, T854I, L858P, L858R, L861Q, delE746_E749, delE746_E749InsP, delE746-A750, delE746_A750InsHS, delE746_A750insQP, delE746_A750insRP, delE746-T751, delE746_T751InsA, delE746_T751InsAPT, delE746_T751InsFPT, delE746_T751InsKV, delE746_T751InsL, delE746_T751InsVA, delE746_S752InsIP, delE746_S752InsV, delE746_P753InsMS, delE746_P753InsVS, delE746_K754InsGG, delL747-E749, delL747_A750InsP, delL747-T751, delL747_T751InsN, delL747_T751InsP, delL747-S752, delL747_S752InsPI, delL747_S752InsPT, delL747-P753, delL747_P753InsNS, delL747_P753InsS, delL747-K754, dekL747_T751InsS, dekL747-T751, delR748-S752, delR748-P753, delA750_I759InsPT, delT751-E758, delT751_I759InsD, delT751_I759InsN, elT751_I759InsSS, delT751_I759InsT, delT751_D761InsNLY, delS752-I759, delS752-I759InsN, D761_E762InsEAFQ, A763_Y764InsFQEA, Y764_Y765InsHH, M766_A767InsA, M766_A767InsAI, M766_A767InsASV, P772_H773InsNS,A767_S768InsIA, A767_S768InsTLA, S768_V769InsAWT, S768_V769InsVAS, S768_V769InsSVA, V769_D770InsASV , D770_N771InsSVD, D770_N771InsG, N771_P772InsH, N771_P772InsN, P772_H773InsYNP, P772_H773InsNP, P772 One or more of the following: _H773InsPR, P772_H773InsDNP, P772_H773InsNPH, P772_H773InsGNP, P772_H773InsYNP, P772_H773InsTHP, P772_H773InsQV, P772_H773InsV, H773_V774InsH, H773_V774InsPH, H773_V774InsNPH, and V774_C775InsHV; Preferably, the MET is selected from MET overexpression, MET gene mutation, MET gene amplification, and MET gene fusion; wherein, MET overexpression is defined as IHC results of 1+, 2+, or 3+ in tumor tissue; MET gene amplification is confirmed by FISH or NGS detection; and MET gene mutation is defined as MET exon 14 skipping, MET D1228N / H / A / G / V / Y / E, Y1230H / C / S / A / D / N, H1094Y, L1195V, F1200I / L, H1094L, K1244R, L1195F, M1250I / T, P991S, T1173I, T9921, V1092I, Y1235D, Gl163R, G1090A, or MET-D1228_M1229delin. sFL; MET gene fusion is PTPRZ1-MET, CLIP2-MET, CAPZA2-MET, ST7-MET, KIF5B-MET, TPR-MET, TFG-MET, BAIAP2L1-MET, C8orf34-MET, TRIM4-MET, PPFIBP1-MET, LRRFIP1-MET, EPS15-MET, DCTN1-MET; Preferably, MET is selected such that the IHC result of the tumor tissue detected by IHC for MET overexpression is 2+ or 3+; the MET gene amplification is detected by FISH with GCN ≥ 5 and / or MET / CEP7 ≥ 2, or by FISH with 2 < GCN < 5 and MET / CEP7 < 2; and the NGS detection confirms the presence of MET gene amplification.

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