Epidermal growth factor receptor tyrosine kinase inhibitors in combination with HGF-receptor inhibitors for treatment of cancer

Abstract

The present disclosure relates to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for use in the treatment of cancer, wherein the EGFR TKI is administered in combination with a c-MET inhibitor.

Description

Technical Field

[0001] The present disclosure relates to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for use in treating cancer (e.g., non-small cell lung cancer [NSCLC]), wherein the EGFR TKI is administered in combination with a c-MET (also known as HGF-receptor or mesenchymal epithelial transition factor) inhibitor. Background Art

[0002] The discovery of activating mutations in the epidermal growth factor receptor (EGFR) has revolutionized the treatment of the disease. In 2004, it was reported that activating mutations in EGFR exons 18-21 were associated with responses to EGFR-TKI therapy in NSCLC, and it is estimated that these mutations are prevalent in approximately 10%-16% of human patients with NSCLC in the United States and Europe and in approximately 30%-50% of human patients with NSCLC in Asia. The two most important EGFR activating mutations are missense mutations in exon 19 deletions and exon 21. Exon 19 deletions account for approximately 45% of known EGFR mutations. Missense mutations in exon 21 account for approximately 39%-45% of known EGFR mutations, of which the substitution mutation L858R accounts for approximately 39% of total mutations in exon 21.

[0003] There are 3 generations of EGFR TKIs: the first generation EGFR TKIs (e.g., gefitinib, erlotinib) are ATP competitive inhibitors; the second generation EGFR TKIs (e.g., afatinib, dacomitinib) are irreversible inhibitors that covalently bind to EGFR; and the third generation EGFR TKIs (e.g., osimertinib) are designed to more selectively target T790M resistance mutations and EGFR sensitizing mutations compared to wild-type EGFR. All of these TKIs are effective in patients with NSCLC whose tumors have in-frame deletions in exon 19 and / or L858R point mutations in exon 21. These two mutations account for approximately 90% of all EGFR mutations. In approximately 50% of patients, resistance to first and second generation EGFR TKIs is mediated by the acquisition of the "gatekeeper" mutation T790M. Currently, osimertinib is the only third-generation EGFR TKI approved in the United States, which has activity against exon 19 deletions and L858R mutations, regardless of the presence of the T790M mutation. However, even patients treated with osimertinib will eventually progress, primarily due to the development of acquired resistance caused by other resistance mechanisms. Therefore, there remains a need to develop new therapies for the treatment of NSCLC, particularly for patients whose disease has progressed after treatment with EGFR TKIs.

[0004] Amplification of the MET gene has been reported as a secondary oncogenic event in 5% to 22% of EGFRm+NSCLCs with acquired resistance to EGFR TKIs. MET is a transmembrane receptor tyrosine kinase that can be activated by protein overexpression, increased expression of its ligand HGF, MET mutations, gene amplification, and exon 14 skipping. ctDNA data from two osimertinib clinical studies (AURA3 [NCT02151981], which studies osimertinib or platinum-pemetrexed in patients with EGFR T790M+ lung cancer, and FLAURA [NCT02296125], which studies osimertinib with standard EGFR TKIs [gefitinib or erlotinib] in patients with untreated EGFRm+ advanced NSCLC) showed that acquired MET amplification occurred after disease progression with osimertinib in 15% to 19% of the tested patients. MET overexpression and amplification in tumor tissues were detected in the context of acquired EGFR TKI resistance. However, although nonclinical models suggest that the combination of MET TKIs with EGFR TKIs can overcome MET-driven resistance, there are no approved therapies specifically indicated for the treatment of patients with tumors that are positive for MET amplification and / or overexpression, and no established standard of care specifically for patients who have developed MET-driven resistance following prior EGFR TKI therapy, including osimertinib.

[0005] The lack of therapy for patients who have developed MET-driven resistance after previous treatment with EGFR TKI may be due to uncertainty about how to identify patients who are most likely to benefit from MET TKI and EGFR TKI combination therapy. The prevalence of MET amplification and overexpression depends on the sample type, detection method and determination cutoff used. Several clinical 1b / 2 phase studies (such as NCT02143466, NCT01610336 and NCT01982955) have studied the efficacy of MET TKI combined with EGFR TKI in MET amplification and / or overexpression. However, in these studies, different amplification or overexpression determination cutoffs were used for patient selection, and in NCT01610336, the cutoff was even changed during the study. In addition, there is considerable fluctuation in the objective response rate (ORR), so the applicability of MET amplification and overexpression as a predictor of clinical benefit is doubted. Therefore, there remains a considerable unmet medical need for means to identify EGFRm+ NSCLC patients who are most likely to benefit from MET TKI and EGFR TKI combination therapy. Summary of the invention

[0006] The present disclosure enables the use of defined MET amplification and / or overexpression determination cutoffs to identify EGFRm+NSCLC patients who are most likely to benefit from MET TKI and EGFR TKI combination therapy. Without being bound by theory, it has been found that clinical benefit is not only determined by the presence of MET amplification and / or overexpression, but by the degree to which such MET amplification and / or overexpression exist. Specifically, high or very high levels of MET amplification and / or overexpression predict clinical benefit. Unexpectedly, it has been found that after the use of third-generation EGFR-TKI progress, high or very high levels of MET amplification and / or overexpression are sufficiently common in EGFRm NSCLC, so that these biomarkers can be used to select EGFRm+NSCLC patients who are most likely to benefit from MET TKI and EGFR TKI combination therapy.

[0007] In one embodiment, an EGFR TKI for use in treating cancer in a human patient is provided, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, and wherein the cancer has high or very high levels of MET amplification and / or overexpression.

[0008] In one embodiment, a c-MET inhibitor is provided for use in treating cancer in a human patient, wherein the c-MET inhibitor is administered in combination with an EGFR TKI, and wherein the cancer has high or very high levels of MET amplification and / or overexpression.

[0009] In one embodiment, an EGFR TKI for use in treating cancer in a human patient is provided, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, characterized in that prior to administration of the EGFR TKI in combination with the c-MET inhibitor, the cancer has been found to have high or very high levels of MET amplification and / or overexpression.

[0010] In one embodiment, a c-MET inhibitor is provided for use in treating cancer in a human patient, wherein the c-MET inhibitor is administered in combination with an EGFR TKI, characterized in that prior to administration of the c-MET inhibitor in combination with the EGFR TKI, the cancer has been found to have a high or very high level of MET amplification and / or overexpression.

[0011] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression.

[0012] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of a c-MET inhibitor, wherein the c-MET inhibitor is administered in combination with a therapeutically effective amount of an EGFR TKI, and wherein the cancer has high or very high levels of MET amplification and / or overexpression.

[0013] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor, and characterized in that prior to administration of the EGFR TKI in combination with the c-MET inhibitor, the cancer has been found to have high or very high levels of MET amplification and / or overexpression.

[0014] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of a c-MET inhibitor, wherein the c-MET inhibitor is administered in combination with a therapeutically effective amount of an EGFR TKI, and characterized in that prior to administration of the c-MET inhibitor in combination with the EGFR TKI, the cancer has been found to have high or very high levels of MET amplification and / or overexpression.

[0015] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising: i) identifying a patient whose cancer has high or very high levels of MET amplification and / or overexpression; and ii) administering a therapeutically effective amount of an EGFR TKI to the identified patient, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor.

[0016] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising: i) identifying a patient whose cancer has high or very high levels of MET amplification and / or overexpression; and ii) administering a therapeutically effective amount of a c-MET inhibitor to the identified patient, wherein the c-MET inhibitor is administered in combination with a therapeutically effective amount of an EGFR TKI.

[0017] In one embodiment, there is provided use of an EGFR TKI in the preparation of a medicament for treating cancer in a human patient, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, and wherein the cancer has high or very high levels of MET amplification and / or overexpression.

[0018] In one embodiment, there is provided a use of a c-MET inhibitor in the preparation of a medicament for treating cancer in a human patient, wherein the c-MET inhibitor is administered in combination with an EGFR TKI, and wherein the cancer has high or very high levels of MET amplification and / or overexpression.

[0019] In one embodiment, there is provided the use of an EGFR TKI in the preparation of a medicament for treating cancer in a human patient, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, and characterized in that prior to administration of the EGFR TKI in combination with the c-MET inhibitor, the cancer has been found to have high or very high levels of MET amplification and / or overexpression.

[0020] In one embodiment, there is provided a use of a c-MET inhibitor in the preparation of a medicament for treating cancer in a human patient, wherein the c-MET inhibitor is administered in combination with an EGFR TKI, and characterized in that prior to administration of the c-MET inhibitor in combination with the EGFR TKI, the cancer has been found to have high or very high levels of MET amplification and / or overexpression.

[0021] In one embodiment, a method of extending progression-free survival (PFS) in a patient suffering from cancer is provided, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression.

[0022] In one embodiment, a method of increasing ORR in a patient having cancer is provided, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression.

[0023] In one embodiment, a method of extending median progression-free survival (PFS) in a patient suffering from cancer is provided, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression.

[0024] The term "treatment" refers to at least partially alleviating, inhibiting, preventing and / or improving a condition, disorder or disease (such as lung cancer). The term "cancer treatment" includes both in vitro and in vivo treatments, including in warm-blooded animals (such as humans). The effectiveness of cancer treatment can be assessed in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including reversal of cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement of symptoms; duration of relief for treatment; delay of disease progression; and extended survival. Treatment can also be assessed based on the nature and extent of side effects associated with treatment. In addition, effectiveness can be assessed based on biomarkers, such as expression or phosphorylation levels of proteins known to be associated with specific biological phenomena. Other assessments of effectiveness are known to those skilled in the art.

[0025] The phrase "in combination with" and similar terms (including "a combination of") encompass administration of two or more active pharmaceutical ingredients to a subject and includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present.

[0026] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to achieve the intended application (including but not limited to disease treatment). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition to be treated (e.g., the subject's weight, age and gender), the severity of the disease condition, the mode of administration, etc., which can be easily determined by one of ordinary skill in the art. The term also applies to doses that will induce a specific response in target cells (e.g., the amount of apoptosis). The specific dose will vary depending on the specific compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system that carries the compound.

[0027] In another embodiment, a pharmaceutical composition comprising an EGFR TKI, a c-MET inhibitor and a pharmaceutically acceptable excipient is provided.

[0028] The term "pharmaceutically acceptable" is used to indicate that an object (e.g., salt, dosage form, or excipient [such as a diluent or carrier]) is suitable for use with a patient. An exemplary list of pharmaceutically acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", edited by P.H. Stahl and C.G. Wermuth, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent versions.

[0029] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 : Kaplan-Meier plot showing progression-free survival (PFS) of patients based on MET amplification and / or overexpression status.

[0031] Figure 2 : Waterfall plot showing the best percent change in target lesions in patients with high or very high levels of MET amplification and / or overexpression. DETAILED DESCRIPTION

[0032] EGFR mutation-positive NSCLC, patient selection, dosing, and diagnostic approaches

[0033] In embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).

[0034] In embodiments, the NSCLC is EGFR mutation-positive NSCLC.

[0035] In an embodiment, the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR. In a further embodiment, the EGFR mutation-positive NSCLC comprises a non-resistant mutation. In a further embodiment, the activating mutation in EGFR comprises an activating mutation in exons 18-21. In a further embodiment, the activating mutation in EGFR comprises a missense mutation in exon 19 deletion or exon 21. In a further embodiment, the activating mutation in EGFR comprises an exon 19 deletion or an L858R substitution mutation. In a further embodiment, the mutation in EGFR comprises a T790M mutation.

[0036] In embodiments, the EGFR mutation-positive NSCLC is locally advanced EGFR mutation-positive NSCLC.

[0037] In embodiments, the EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC.

[0038] In embodiments, the EGFR mutation-positive NSCLC is not amenable to curative surgery or radiation therapy.

[0039] There are many methods for detecting EGFR activating mutations that will be appreciated by those skilled in the art. Tests provided by laboratories certified by the Clinical Laboratory Improvement Amendments (CLIA) and / or tests approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) or the China National Medical Products Administration (NMPA) are suitable for these methods. These methods include diagnostic methods based on both tumor tissue and plasma. Typically, a tumor tissue biopsy sample obtained from a human patient is first used to assess EGFR mutation status. If a tumor sample is not available, or if the tumor sample is negative, a plasma sample can be used to assess EGFR mutation status. A specific example of a suitable diagnostic test for detecting EGFR mutations and particularly detecting exon 19 deletions, L858R substitution mutations and T790M mutations is the Cobas TM EGFR Mutation Test v2 (Roche Molecular Diagnostics). Other examples of suitable diagnostic tests include FoundationOne CDx (Foundation Medicine), which can detect activating mutations and resistance mutations in tissue samples; Guardant360CDx (Guardant Health), which can detect activating mutations and resistance mutations in plasma samples; and FoundationOne Liquid CDx (Foundation Medicine), which can detect activating mutations in plasma samples.

[0040] Thus, in embodiments, EGFR mutation-positive NSCLC includes activating mutations in EGFR (such as activating mutations in exons 18-21, e.g., exon 19 deletions, missense mutations in exon 21, and L858R substitution mutations; and resistance mutations (such as T790M mutations), wherein the EGFR mutation status of the human patient has been determined using an appropriate diagnostic test. In further embodiments, the EGFR mutation status has been determined using a tumor tissue sample. In further embodiments, the EGFR mutation status has been determined using a plasma sample. In further embodiments, the diagnostic method uses an FDA-approved test and / or a test provided by a CLIA-certified laboratory. In further embodiments, the diagnostic method uses a CobasTM EGFR mutation test (v1 or v2) or FoundationOne CDx or Guardant360 CDx or FoundationOne Liquid CDx.

[0041] In embodiments, the human patient is an EGFR TKI-naive human patient. In embodiments, the human patient has previously been treated with an EGFR TKI. In embodiments, the human patient has previously been treated with a third generation EGFR TKI. In embodiments, the human patient has previously been treated with osimertinib or a pharmaceutically acceptable salt thereof. In embodiments, the human patient has developed EGFR T790M mutation-positive NSCLC.

[0042] Various techniques known to those skilled in the art can be used to detect high or very high levels of MET amplification and / or overexpression in tumors. For example, by applying fluorescent in situ hybridization (FISH) and / or immunohistochemistry (IHC) to tumor tissue samples. MET amplification can also be detected by applying next generation sequencing (NGS) to plasma and / or tumor samples.

[0043] In embodiments, the cancer has a high or very high level of MET amplification determined by NGS. In embodiments, the cancer has a high or very high level of MET amplification, defined by ≥5 MET copies (NGS5+) in the tumor ploidy by NGS.

[0044] In embodiments, the cancer has a high or very high level of MET amplification and / or overexpression determined by FISH and / or IHC. In embodiments, the cancer has a high or very high level of MET amplification and / or overexpression determined by FISH and / or IHC using a test approved by a regulatory agency and / or a test provided by a CLIA-certified laboratory. Relevant regulatory agencies include EMA, FDA, and NMPA. In embodiments, the cancer has a high or very high level of MET amplification and / or overexpression determined by FISH and / or IHC using a test approved by the FDA and / or a test provided by a CLIA-certified laboratory.

[0045] In embodiments, the cancer has a high or very high level of MET amplification and / or overexpression, which is defined by a MET gene copy number ≥6 by FISH (FISH6+) and / or ≥60% of tumor cells by IHC with strong (3+) membrane and / or cytoplasmic staining intensity (IHC60+); or by a MET gene copy number ≥7 by FISH (FISH7+) and / or ≥70% of tumor cells by IHC with strong (3+) membrane and / or cytoplasmic staining intensity (IHC70+); or by a MET gene copy number ≥7 by FISH (FISH7+) and / or ≥70% of tumor cells by IHC with strong (3+) membrane and / or cytoplasmic staining intensity (IHC70+); The cancer may be defined as having a copy number of ≥8 (FISH8+) and / or having a strong (3+) membrane and / or cytoplasmic staining intensity (IHC80+) by ≥80% of tumor cells by IHC; or as having a copy number of ≥9 (FISH9+) by FISH and / or having a strong (3+) membrane and / or cytoplasmic staining intensity (IHC90+) by ≥90% of tumor cells by IHC; or as having a copy number of ≥10 (FISH10+) by FISH and / or having a strong (3+) membrane and / or cytoplasmic staining intensity (IHC90+) by ≥90% of tumor cells by IHC. In embodiments, the cancer may have a high or very high level of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+, or FISH10+. In embodiments, the cancer may have a high or very high level of MET amplification and / or overexpression as defined by FISH10+. In embodiments, the cancer has a high or very high level of MET amplification and / or overexpression defined by IHC60+, IHC70+, IHC80+, or IHC90+. In embodiments, the cancer has a high or very high level of MET amplification and / or overexpression defined by IHC90+.

[0046] In embodiments, the cancer is EGFR mutation-positive NSCLC and has a high or very high level of MET amplification and / or overexpression defined by FISH10+ and / or IHC90+. In embodiments, the cancer is EGFR mutation-positive NSCLC and has a high or very high level of MET amplification and / or overexpression defined by FISH10+. In embodiments, the cancer is EGFR mutation-positive NSCLC and has a high or very high level of MET amplification and / or overexpression defined by IHC90+.

[0047] In embodiments, prior to administration of the combination of an EGFR TKI and a c-MET inhibitor, the cancer has been found to have high or very high levels of MET amplification and / or overexpression.

[0048] There are many FISH and / or IHC assays that can be used to detect MET amplification and / or overexpression that will be appreciated by those skilled in the art. In embodiments, the assay can be FDA-approved and / or provided by a CLIA-certified laboratory. An example of a suitable FISH assay is the Vysis MET FISH probe kit (Abbott Molecular Inc., Des Plaines, IL), and an example of a suitable IHC assay is the VENTANA MET (SP44) RxDx assay (Ventana Medical Systems, Inc., Tucson, Arizona). An example of a suitable NGS assay is F1CDx (Foundation Medicine, Cambridge, MA).

[0049] The present disclosure discloses a combination of an EGFR TKI and a c-MET inhibitor as a first-line (1L) treatment (i.e., in EGFR TKI-naive patients); as a second-line (2L) treatment (i.e., in patients who have previously received one line of EGFR TKI treatment); as a third-line or fourth-line (3L-4L) treatment (i.e., in patients who have previously received one line of EGFR TKI treatment followed by chemotherapy, or in patients who have previously received two or more lines of EGFR TKI treatment followed by or without chemotherapy).

[0050] In embodiments, the patient may have received 1, 2, or 3 lines of prior therapy, which must include an EGFR TKI as one of the prior lines of therapy, but may also include other EGFR TKIs, chemotherapy, or chemotherapy in combination with immuno-oncology (IO) agents in the metastatic setting. In embodiments, the patient has received a third generation EGFR TKI as one of the prior lines of therapy. In embodiments, the patient has received osimertinib as one of the prior lines of therapy. In embodiments, the patient has received a third generation EGFR TKI as the most recent line of prior therapy. In embodiments, the patient has received osimertinib as the most recent line of prior therapy.

[0051] In embodiments, both the EGFR TKI and the c-MET inhibitor are administered once daily (QD).In embodiments, the EGFR TKI is administered once daily (QD) and the c-MET inhibitor is administered twice daily (BID).

[0052] In embodiments, treatment provides an ORR of at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%.

[0053] In embodiments, treatment provides a median PFS of at least 5.5 months, at least 6 months, at least 6.5 months, at least 7 months, or at least 7.5 months.

[0054] EGFR TKI

[0055] The third generation EGFR TKI is an inhibitor of EGFR carrying an activating mutation, which also significantly inhibits EGFR carrying the T790M mutation, and does not significantly inhibit wild-type EGFR. Examples of third generation TKIs include compounds of formula (I), osimertinib, AZD3759 (zorifertinib), lazertinib, nazartinib (EGF816), CO1686 (rociletinib), HM61713 (olmutinib), ASP8273 (naquotinib), PF-06747775 ( The drugs include mavelertinib, avitinib (abivertinib), alflutinib (AST2818), CX-101 (olafertinib; RX-518), ametinib (HS-10296; aumolertinib / almonertinib), and BPI-7711 (rezivertinib).

[0056] In one embodiment, EGFR TKI is a third generation EGFR TKI. In another embodiment, the third generation EGFR TKI is a compound of formula (I) as defined below. In another embodiment, the third generation EGFR TKI is selected from the group consisting of osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, avitinib or a pharmaceutically acceptable salt thereof, vometinib or a pharmaceutically acceptable salt thereof, CX-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof, and BPI-7711 or a pharmaceutically acceptable salt thereof. In another embodiment, the third generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

[0057] Compounds of formula (I)

[0058] In one embodiment, the EGFR TKI is a compound of formula (I):

[0059]

[0060] in:

[0061] G is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, indol-3-yl, indazol-1-yl, 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl, 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl, pyrrolo[3,2-b]pyridin-3-yl and pyrazolo[1,5-a]pyridin-3-yl;

[0062] R 1 is selected from hydrogen, fluorine, chlorine, methyl and cyano;

[0063] R 2 is selected from the group consisting of methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy and methyl;

[0064] R 3 selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy, 2-(methylamino)ethoxy, 5-methyl-2,5-diazaspiro[3.4]octan-2-yl, (3aR,6aR)-5-methylhexa 4-[(2S)-2-aminopropanoyl]piperazin-1-yl;

[0065] R 4 is selected from hydrogen, 1-piperidinomethyl and N,N-dimethylaminomethyl;

[0066] R 5 independently selected from methyl, ethyl, propyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro and cyclopropyl;

[0067] X is CH or N; and

[0068] n is 0, 1, or 2;

[0069] or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, a compound of formula (I) as defined above is provided, wherein G is selected from indol-3-yl and indazol-1-yl; R 1 is selected from hydrogen, fluorine, chlorine, methyl and cyano; R 2 is selected from methoxy and 2,2,2-trifluoroethoxy; R 3 is selected from [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy and 2-(methylamino)ethoxy; R 4 is hydrogen; R 5 is selected from methyl, 2,2,2-trifluoroethyl and cyclopropyl; X is CH or N; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0071] Examples of the compound of formula (I) include those described in WO 2013 / 014448, WO 2015 / 175632, WO 2016 / 054987, WO 2016 / 015453, WO 2016 / 094821, WO 2016 / 070816 and WO 2016 / 173438.

[0072] Osimertinib and its pharmaceutical composition

[0073] Osimertinib has the following chemical structure:

[0074]

[0075] The free base of osimertinib is known by the chemical name: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide. Osimertinib is described in WO 2013 / 014448. Osimertinib is also known as AZD9291.

[0076] Osimertinib is available in the form of a mesylate salt: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate. Osimertinib mesylate is also known as TAGRISSO TM .

[0077] Osimertinib mesylate is currently approved as a once-daily oral tablet formulation with a dosage of 80 mg (expressed as free base, equivalent to 95.4 mg osimertinib mesylate) for the treatment of metastatic EGFR T790M mutation-positive NSCLC patients. If dose adjustment is required, a 40 mg once-daily oral tablet formulation (expressed as free base, equivalent to 47.7 mg osimertinib mesylate) is available. The tablet core contains a drug diluent (such as mannitol and microcrystalline cellulose), a disintegrant (such as low-substituted hydroxypropyl cellulose) and a lubricant (such as sodium stearyl fumarate). The tablet formulation is described in WO 2015 / 101791.

[0078] Therefore, in one embodiment, osimertinib or a pharmaceutically acceptable salt thereof is in the form of a methanesulfonate salt, i.e., N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate.

[0079] In one embodiment, osimertinib or a pharmaceutically acceptable salt thereof is administered once daily. In another embodiment, osimertinib mesylate is administered once daily.

[0080] In one embodiment, the total daily dose of osimertinib is about 80 mg. In another embodiment, the total daily dose of osimertinib mesylate is about 95.4 mg.

[0081] In one embodiment, the total daily dose of osimertinib is about 40 mg. In another embodiment, the total daily dose of osimertinib mesylate is about 47.7 mg.

[0082] In one embodiment, osimertinib or a pharmaceutically acceptable salt thereof is in the form of a tablet.

[0083] In one embodiment, osimertinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients (e.g., diluents or carriers). In another embodiment, the composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low-substituted hydroxypropyl cellulose), or one or more pharmaceutical lubricants (such as sodium stearyl fumarate).

[0084] In one embodiment, the composition is in the form of a tablet, wherein the tablet core comprises: (a) 2 to 70 parts of osimertinib or a pharmaceutically acceptable salt thereof; (b) 5 to 96 parts of two or more drug diluents; (c) 2 to 15 parts of one or more drug disintegrants; and (d) 0.5 to 3 parts of one or more drug lubricants; and wherein all parts are by weight and the sum of the parts (a) + (b) + (c) + (d) = 100.

[0085] In one embodiment, the composition is in the form of a tablet, wherein the tablet core comprises: (a) 7 to 25 parts of osimertinib or a pharmaceutically acceptable salt thereof; (b) 55 to 85 parts of two or more drug diluents, wherein the drug diluents include microcrystalline cellulose and mannitol; (c) 2 to 8 parts of a drug disintegrant, wherein the drug disintegrant includes low-substituted hydroxypropyl cellulose; (d) 1.5 to 2.5 parts of a drug lubricant, wherein the drug lubricant includes sodium stearyl fumarate; and wherein all parts are by weight and the sum of the parts (a) + (b) + (c) + (d) = 100.

[0086] In one embodiment, the composition is in the form of a tablet, wherein the tablet core comprises: (a) about 19 parts of osimertinib mesylate; (b) about 59 parts of mannitol; (c) about 15 parts of microcrystalline cellulose; (d) about 5 parts of low-substituted hydroxypropyl cellulose; and (e) about 2 parts of sodium stearyl fumarate; and wherein all parts are by weight and the sum of the parts (a) + (b) + (c) + (d) + (e) = 100.

[0087] AZD3759 (Zolitinib)

[0088] AZD3759 has the following chemical structure:

[0089]

[0090] The free base of AZD3759 is known by the chemical name: 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl (2R)-2,4-dimethyl-1-piperazinecarboxylate. AZD3759 is described in WO 2014 / 135876.

[0091] In one embodiment, AZD3759 or a pharmaceutically acceptable salt thereof is administered twice daily.In another embodiment, AZD3759 is administered twice daily.

[0092] In one embodiment, the total daily dose of AZD3759 is about 400 mg. In another embodiment, about 200 mg of AZD3759 is administered twice daily.

[0093] Lazertinib

[0094] Lazertinib has the following chemical structure:

[0095]

[0096] The chemical name of the free base of lazertinib is known: N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}-2-pyrimidinyl)amino]-4-methoxy-2-(4-morpholinyl)phenyl}acrylamide. Lazertinib is described in WO 2016 / 060443. Lazertinib is also known by the names YH25448 and GNS-1480.

[0097] In one embodiment, lazertinib or a pharmaceutically acceptable salt thereof is administered once daily. In another embodiment, lazertinib is administered once daily.

[0098] In one embodiment, the total daily dose of lazertinib is about 20 mg to 320 mg.

[0099] In one embodiment, the total daily dose of lazertinib is about 240 mg.

[0100] Avitinib

[0101] Avitinib has the following chemical structure:

[0102]

[0103] The chemical name of the free base of Avitinib is known as: N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)phenyl)prop-2-enamide. Avitinib is disclosed in US2014038940. Avitinib is also known as Avitinib.

[0104] In one embodiment, Avitinib or a pharmaceutically acceptable salt thereof is administered twice daily. In another embodiment, Avitinib maleate is administered twice daily.

[0105] In one embodiment, the total daily dose of Avitinib Maleate is about 600 mg.

[0106] Vometinib

[0107] Vometinib has the following chemical structure:

[0108]

[0109] The free base of Vometinib is known by the chemical name:

[0110] N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide. Vometinib is disclosed in WO 2016 / 15453. Vometinib is also known as AST2818.

[0111] In one embodiment, vometinib or a pharmaceutically acceptable salt thereof is administered once daily. In another embodiment, vometinib mesylate is administered once daily.

[0112] In one embodiment, the total daily dose of vometinib mesylate is about 80 mg.

[0113] In one embodiment, the total daily dose of vometinib mesylate is about 40 mg.

[0114] CX-101 (Olavutinib; RX-518)

[0115] CX-101 has the following chemical structure:

[0116]

[0117] The free base of CX-101 is known by the chemical name: N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide. CX-101 is disclosed in WO 2015 / 027222. CX-101 is also known as RX-518 and olavutinib.

[0118] HS-10296 (almonertinib; aumolertinib)

[0119] HS-10296 (almonertinib; aumolertinib) has the following chemical structure:

[0120]

[0121] The chemical name of the free base of HS-10296 is known as: N-[5-[[4-(1-cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-phenyl]prop-2-enamide. HS-10296 is disclosed in WO 2016 / 054987.

[0122] In one embodiment, the total daily dose of HS-10296 is about 110 mg.

[0123] BPI-7711 (Rizitinib)

[0124] BPI-7711 has the following chemical structure:

[0125]

[0126] The chemical name of the free base of BPI-7711 is known as: N-[2-[2-(dimethylamino)ethoxy]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide. BPI-7711 is disclosed in WO2016 / 94821.

[0127] In one embodiment, the total daily dose of BPI-7711 is about 180 mg.

[0128] c-MET inhibitors

[0129] In an embodiment, a c-MET inhibitor is any molecule that binds to and inhibits the activity of one or more isoforms of c-MET (also known as mesenchymal-epidermal transition factor).

[0130] In an embodiment, the c-MET inhibitor is selected from the group consisting of savolitinib ( AZD6094; HMPL-504; volitinib) or a pharmaceutically acceptable salt thereof, capmatinib or a pharmaceutically acceptable salt thereof, tepotinib or a pharmaceutically acceptable salt thereof, glumetinib (SCC224) or a pharmaceutically acceptable salt thereof and cabozantinib or a pharmaceutically acceptable salt thereof.

[0131] In an embodiment, the c-MET inhibitor is selected from the group consisting of: savotinib ( AZD6094; HMPL-504; savolitinib) or a pharmaceutically acceptable salt thereof, capmatinib or a pharmaceutically acceptable salt thereof and tepotinib or a pharmaceutically acceptable salt thereof.

[0132] In an embodiment, the c-MET inhibitor is sirotinib ( AZD6094; HMPL-504; savolitinib) or a pharmaceutically acceptable salt thereof.

[0133] In an embodiment, the c-MET inhibitor is sirotinib ( AZD6094; HMPL-504; savolitinib).

[0134] Savotinib ( AZD6094; HMPL-504; savolitinib)

[0135] Savotinib has the following chemical structure:

[0136]

[0137] The chemical name of the free base of savotinib is known as: 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrrol-3-yl)triazolo[4,5-b]pyrazine. savotinib is described in WO2011079804 (Compound 270).

[0138] In one embodiment, sirolimus or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In another embodiment, the composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low-substituted hydroxypropyl cellulose) or one or more pharmaceutical lubricants (such as magnesium stearate).

[0139] In one embodiment, the composition is in the form of a tablet.

[0140] In combination with EGFR TKIs (such as osimertinib, sirotinib, or pharmaceutically acceptable salts thereof), it is generally administered to a subject at a daily dose of about 100 mg to about 1200 mg.

[0141] In some embodiments, savotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 200 mg to about 800 mg. In one embodiment, savotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg to about 600 mg.

[0142] In some embodiments, savotinib or a pharmaceutically acceptable salt thereof is administered to a subject once a day (QD). In some embodiments, savotinib or a pharmaceutically acceptable salt thereof is administered to a subject twice a day (BID).

[0143] In one embodiment, savotinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 600 mg.

[0144] In another embodiment, savotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of about 300 mg. In another embodiment, savotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of about 600 mg. In another embodiment, savotinib or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of about 300 mg.

[0145] Capmatinib

[0146] Capmatinib has the following chemical structure:

[0147]

[0148] The chemical name of known capmatinib is: 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine-2-yl]benzamide. Capmatinib is disclosed in US7767675. In an embodiment, capmatinib or a pharmaceutically acceptable salt thereof is administered once or twice a day. In a further embodiment, capmatinib hydrochloride is administered twice a day.

[0149] In embodiments, the total daily dose of capmatinib is about 800 mg (i.e. 400 mg, twice a day). In embodiments, the total daily dose of capmatinib is about 600 mg (i.e. 300 mg, twice a day). In embodiments, the total daily dose of capmatinib is about 400 mg (i.e. 200 mg, twice a day).

[0150] Tepotinib

[0151] Tepotinib has the following chemical structure:

[0152]

[0153] The chemical name of the free base of tepotinib is known as: 3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]benzyl]methyl]-6-oxopyridazin-3-yl]benzonitrile. Tepotinib is disclosed in US 8329692. In an embodiment, tepotinib or a pharmaceutically acceptable salt thereof is administered once or twice daily. In a further embodiment, tepotinib hydrochloride hydrate is administered once daily. In an embodiment, the total daily dose of tepotinib is about 450 mg.

[0154] Glumetinib (SCC224)

[0155] Glumetinib has the following chemical structure:

[0156]

[0157] The chemical name of the free base of GUMETINIB is known as: 6-(1-methyl-1H-pyrazol-4-yl)-1-((6-(1-methyl-1H-pyrazol-4-yl)imidazo(1,2-a)pyridin-3-yl)sulfonyl)-1H-pyrazolo(4,3-b)pyridine. GUMETINIB is disclosed in WO2014201857. In an embodiment, GUMETINIB or a pharmaceutically acceptable salt thereof is administered once or twice a day. In a further embodiment, GUMETINIB is administered once a day. In an embodiment, the total daily dose of GUMETINIB is about 400 mg. In an embodiment, the total daily dose of GUMETINIB is about 300 mg.

[0158] Cabozantinib

[0159] Cabozantinib has the following chemical structure:

[0160]

[0161] The chemical name of the free base of cabozantinib is known as: N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxysuccinate. Cabozantinib is disclosed in US7579473. In an embodiment, cabozantinib or a pharmaceutically acceptable salt thereof is administered once or twice a day. In a further embodiment, (S)-malic acid cabozantinib is administered once a day. In an embodiment, the total daily dose of cabozantinib is about 60 mg.

[0162] Further implementation plans

[0163] In one embodiment, an EGFR TKI for use in treating cancer in a human patient is provided, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In embodiments, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is an EGFR mutation-positive NSCLC. In yet further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0164] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In embodiments, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is an EGFR mutation-positive NSCLC. In yet further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0165] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a first amount of an EGFR TKI and a second amount of a c-MET inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In embodiments, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is an EGFR mutation-positive NSCLC. In yet further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0166] In one embodiment, there is provided a use of an EGFR TKI in the preparation of a medicament for treating a cancer in a human patient, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is an EGFR mutation-positive NSCLC. In a further embodiment, a high or very high level of MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0167] In one embodiment, a combination of an EGFR TKI and a c-MET inhibitor for use in treating a cancer in a human patient is provided, wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is an EGFR mutation-positive NSCLC. In a further embodiment, a high or very high level of MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0168] In one embodiment, a method for treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI and a therapeutically effective amount of a c-MET inhibitor in combination, wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is an EGFR mutation-positive NSCLC. In a further embodiment, a high or very high level of MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0169] In one embodiment, a method for treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a first amount of EGFR TKI and a second amount of a c-MET inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, NSCLC is EGFR mutation-positive NSCLC. In a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0170] In one embodiment, there is provided a combination of an EGFR TKI and a c-MET inhibitor for use in the preparation of a medicament for treating cancer in a human patient, wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously been treated with EGFR TKI. In a further embodiment, the human patient has previously been treated with osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, NSCLC is an EGFR mutation-positive NSCLC. In a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0171] In one embodiment, a combination of osimertinib or a pharmaceutically acceptable salt thereof and a c-MET inhibitor for use in treating cancer in a human patient is provided, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient prior to administration of the c-MET inhibitor to the human patient, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is EGFR mutation-positive NSCLC. In a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0172] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of osimertinib or a pharmaceutically acceptable combination of osimertinib and a therapeutically effective amount of a c-MET inhibitor, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient prior to administering the c-MET inhibitor to the human patient, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In embodiments, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In further embodiments, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is EGFR mutation-positive NSCLC. In yet further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0173] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a first amount of osimertinib or a pharmaceutically acceptable salt thereof and a second amount of a c-MET inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient prior to administering the c-MET inhibitor to the human patient, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In embodiments, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In further embodiments, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is EGFR mutation-positive NSCLC. In yet further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0174] In one embodiment, there is provided a use of a combination of osimertinib or a pharmaceutically acceptable salt thereof and a c-MET inhibitor in the preparation of a medicament for treating cancer in a human patient, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient before the c-MET inhibitor is administered to the human patient, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is EGFR mutation-positive NSCLC. In a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0175] In one embodiment, an EGFR TKI for use in treating cancer in a human patient is provided, wherein the treatment comprises administering to the human patient separately, sequentially or simultaneously i) an EGFR TKI and ii) a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. When the treatment is separate or sequential, the interval between the dose of the EGFR TKI and the dose of the c-MET inhibitor can be selected to ensure a combined therapeutic effect.

[0176] A "therapeutic effect" encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0177] In embodiments, administration of the EGFR TKI and the c-MET inhibitor is sequential, and the EGFR TKI is administered prior to the c-MET inhibitor.

[0178] In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is EGFR mutation-positive NSCLC. In a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0179] In one embodiment, a method for treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient separately, sequentially or simultaneously i) a therapeutically effective amount of an EGFR TKI and ii) a therapeutically effective amount of a c-MET inhibitor, wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is an EGFR mutation-positive NSCLC. In a further embodiment, a high or very high level of MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0180] In one embodiment, a method for treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient separately, sequentially or simultaneously i) a first amount of EGFR TKI and ii) a second amount of a c-MET inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, NSCLC is EGFR mutation-positive NSCLC. In a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0181] In one embodiment, there is provided the use of EGFR TKI in the preparation of a medicament for treating cancer in a human patient, wherein the treatment comprises administering i) EGFR TKI and ii) c-MET inhibitor to the human patient separately, sequentially or simultaneously, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, NSCLC is EGFR mutation-positive NSCLC. In a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0182] In one embodiment, a c-MET inhibitor is provided for use in treating cancer in a human patient, wherein the c-MET inhibitor is administered in combination with an EGFR TKI, and wherein the cancer has high or very high levels of MET amplification and / or overexpression.

[0183] In one embodiment, a c-MET inhibitor for use in treating cancer in a human patient is provided, wherein the treatment comprises administering i) a c-MET inhibitor and ii) an EGFR TKI to the human patient separately, sequentially or simultaneously, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is an EGFR mutation-positive NSCLC. In a further embodiment, a high or very high level of MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0184] In one embodiment, there is provided a use of a c-MET inhibitor in the preparation of a medicament for treating cancer in a human patient, wherein the treatment comprises administering i) EGFR TKI and ii) a c-MET inhibitor to the human patient separately, sequentially or simultaneously, and wherein the cancer has a high or very high level of MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savotinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In a further embodiment, the NSCLC is an EGFR mutation-positive NSCLC. In a further embodiment, a high or very high level of MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0185] In one embodiment, a method of treating locally advanced or metastatic NSCLC in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of osimertinib or a pharmaceutically acceptable salt thereof, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered in combination with sirotinib, wherein the locally advanced or metastatic NSCLC has a high or very high level of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or ​​IHC90+, and wherein the locally advanced or metastatic NSCLC in the human patient has progressed during or after prior treatment with osimertinib or a pharmaceutically acceptable salt thereof.

[0186] In one embodiment, a method of treating locally advanced or metastatic NSCLC in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of sirotinib, wherein sirotinib is administered in combination with osimertinib or a pharmaceutically acceptable salt thereof, wherein the locally advanced or metastatic NSCLC has a high or very high level of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or ​​IHC90+, and wherein the locally advanced or metastatic NSCLC in the human patient has progressed during or after prior treatment with osimertinib or a pharmaceutically acceptable salt thereof.

[0187] In one embodiment, a kit is provided, the kit comprising:

[0188] - a first pharmaceutical composition comprising an EGFR TKI and a pharmaceutically acceptable excipient; and

[0189] - A second pharmaceutical composition comprising a c-MET inhibitor and a pharmaceutically acceptable excipient.

[0190] Example

[0191] The following detailed description with reference to the accompanying drawings is provided for illustrative purposes only and should not be construed as limiting the teachings herein.

[0192] Study D5084C00007 (SAVANNAH)

[0193] The combination of osimertinib (80 mg QD) and savotinib (300 mg QD, 300 mg BID, or 600 mg QD) is being investigated in the ongoing Phase 2 study D5084C00007 (SAVANNAH) to overcome MET amplification and / or MET overexpression as a resistance mechanism in patients with locally advanced or metastatic EGFRm+ NSCLC who have experienced disease progression following osimertinib therapy.

[0194] The identification of MET amplification and / or overexpression status in the SAVANNAH study was primarily based on prospective central testing of tumor biopsies collected after progression on prior treatment with osimertinib using 2 assays: METFISH (Vysis MET FISH probe kit) and MET IHC (VENTANA MET (SP44) RxDx assay). Positive MET results in either or both of the two assays qualify patients for screening to enroll in the trial. According to the inclusion criteria, patients were allowed to have received up to 3 lines of prior therapy, which must include osimertinib as one of the prior lines of therapy, but may also include other EGFR TKIs, chemotherapy, or chemotherapy in combination with IO agents in the setting of metastasis. The primary objective of this study is to determine efficacy.

[0195] In this study, approximately 259 patients are planned to be enrolled and treated with osimertinib 80 mg QD in combination with either sirotinib 300 mg QD (approximately n=196), sirotinib 300 mg BID (approximately n=33), or sirotinib 600 mg QD (approximately n=33). Although SAVANNAH is currently ongoing, recruitment of patients into the 300 mg QD dosing cohort has been completed.

[0196] As of the data cutoff date (DCO) in June 2021, a total of 253 patients have received at least one dose of study treatment in SAVANNAH. Of these 253 patients, 196 patients (87 2L patients [44.4%] and 109 ≥3L patients [55.6%]) have received treatment with a starting dose of 300 mg QD in combination with osimertinib (80 mg QD). Thirty-six patients (18.4%) have received prior platinum-based chemotherapy, and 12 patients (6%) have received prior PD-(L)1 therapy. In addition, at this DCO, 27 patients (17 2L patients and 10 ≥3L patients) and 30 patients (8 2L patients and 22 ≥3L patients) have received treatment with a starting dose of 300 mg BID and 600 mg QD, respectively, in combination with osimertinib (80 mg QD).

[0197] A total of 108 patients had received at least one dose of savotinib 300mg QD plus osimertinib 80mg QD and had high MET level status (IHC90+ and / or FISH10+). At the start of the study, thirty-five patients (32%) had recurrent disease and 38 patients (35%) had brain metastases. Fifty patients (46%) received 2L treatment, 37 patients (34%) received ≥3L treatment in the metastatic setting but had not received previous chemotherapy, and 21 patients (19.4%) received ≥3L treatment in the metastatic setting and had received previous chemotherapy. Fifty-five patients (50.9%) received one previous line of EGFR TKI, and 51 patients (47.2%) received two previous lines of EGFR TKI. At the start of the study, ninety-nine patients (92%) received osimertinib as their most recent line of previous therapy.

[0198] At the time of the second interim analysis (DCO October 2020), 137 patients (33 2L patients and 104 ≥3L patients) had received treatment with a starting dose of 300 mg QD in combination with osimertinib and had the opportunity to have at least 2 post-baseline Response Evaluation Criteria in Solid Tumors (RECIST) scans. The confirmed objective response rate (ORR) and duration of response (DoR) results from these patients are summarized in Table 1.

[0199]

[0200] Biomarker cutoffs are FISH5+ and / or IHC50+; CI is confidence interval

[0201] Table 1

[0202] An exploratory analysis was performed in these 137 patients who progressed during or after osimertinib to better understand the relationship between the level of MET amplification and / or overexpression and efficacy. Analysis of ORR and median progression-free survival (PFS) based on MET overexpression levels as detected by central MET IHC and FISH assays (Tables 2 and 3) showed a trend toward improved response rates as the level of MET overexpression and amplification increased. Therefore, ≥10 copies of the MET gene (called FISH10+) and ≥90% of tumor cells stained at 3+ intensity (called IHC90+) were selected as the temporary optimal cutoff values ​​for MET FISH and MET IHC.

[0203]

[0204] a 132 patients had valid central laboratory MET IHC results available for analysis

[0205] b IHC50+ indicates a cutoff of ≥50% of tumor cells with strong 3+ intensity staining, which was used to select patients for entry into the SAVANNAH study

[0206] Table 2

[0207]

[0208]

[0209] a 130 patients had valid central laboratory MET FISH results available for analysis

[0210] b FISH 5+ indicates a cutoff of MET gene copy number ≥5 or MET:CEP7 ratio ≥2 (%), which was used to select patients for entry into the SAVANNAH study [CEP7 is centromere 7]

[0211] Table 3

[0212] Subsequently, efficacy in the high biomarker group (FISH10+ and / or IHC90+) was further evaluated in a larger cohort of patients with longer follow-up who had received treatment with a starting dose of 300 mg savotinib QD in combination with osimertinib and had the opportunity to undergo at least 2 post-baseline RECIST scans (DCO was June 2021; N=193). In this cohort, 108 patients met the criteria for FISH10+ and / or IHC90+ status. As summarized in Table 4, efficacy was improved in patients with FISH10+ and / or IHC90+ positive status (ORR 49.1%, DoR 9.6 months, PFS 7.1 months) compared with all patients (ORR 32.1%, DoR 8.3 months, PFS 5.3 months), and particularly improved compared with the subgroup without FISH10+ and IHC90+ status (ORR 9.1%, DoR 6.9 months, PFS2.8 months).

[0213]

[0214] a Patients with FISH5+ and / or IHC50+ status who have been treated with osimertinib at a starting dose of 300 mg QD and have had access to at least 2 post-baseline RECIST scans. b and c The 8 patients excluded

[0215] b Subgroups of patients with FISH10+ and / or IHC90+ status based on exploratory analysis of central laboratory data. c For patients who are positive for the qualifying cutoff but do not have FISH10+ and IHC90+ status based on exploratory analysis of central laboratory data

[0216] Table 4

[0217] In addition, in terms of PFS, Figure 1 The Kaplan-Meier curves showed good separation between patients with FISH10+ and / or IHC90+ status and those without FISH10+ and / or IHC90+ status, further supporting the optimal cutoff value for identifying the population to be treated.

[0218] As shown in Table 5, in the FISH10+ and / or IHC90+ population, an ORR of 60.0% (95% CI 45.2, 73.6) was observed in 2L patients (N=50), an ORR of 40.5% (95% CI 24.8, 57.9) was observed in ≥3L patients who had not received prior chemotherapy (N=37), and an ORR of 38.1% (95% CI 18.1, 61.6) was observed in ≥3L patients who had received prior chemotherapy (N=21). The median DoR was 9.6 months in 2L patients, 10.6 months in ≥3L patients who had not received prior chemotherapy, and 7.2 months in ≥3L patients who had received chemotherapy.

[0219]

[0220] Table 5

[0221] Tumor response was shown in Figure 2 In the figure, this is a waterfall plot showing the best percentage change in target lesions in patients with FISH10+ and / or IHC90+. The efficacy evaluable set is defined as dosing patients with measurable disease at baseline who have received ≥2 on-treatment RECIST scans. FISH10+, fluorescence in situ hybridization (MET copy number ≥10); IHC90+, 3+ immunohistochemistry overexpression in ≥90% of tumor cells; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

Claims

1. An EGFR TKI for use in treating cancer in a human patient, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression.

2. EGFR TKI for use according to claim 1, wherein before administration of the EGFR TKI in combination with the c-MET inhibitor, the cancer has been found to have a high or very high level of MET amplification and / or overexpression.

3. The EGFR TKI for use according to claim 1 or claim 2, wherein the cancer has a high or very high level of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or ​​IHC90+.

4. The EGFR TKI for use according to any one of claims 1 to 3, wherein the administration of the EGFR TKI and the c-MET inhibitor is separate, sequential or simultaneous.

5. The EGFR TKI for use according to any one of claims 1 to 4, wherein the high or very high level of MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

6. The EGFR TKI for use according to any one of claims 1 to 5, wherein the EGFR TKI is a compound of formula (I): in: G is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, indol-3-yl, indazol-1-yl, 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl, 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl, pyrrolo[3,2-b]pyridin-3-yl and pyrazolo[1,5-a]pyridin-3-yl; R 1 is selected from hydrogen, fluorine, chlorine, methyl and cyano; R 2 is selected from the group consisting of methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy and methyl; R 3 selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy, 2-(methylamino)ethoxy, 5-methyl-2,5-diazaspiro[3.4]octan-2-yl, (3aR,6aR)-5-methylhexa 4-[(2S)-2-aminopropanoyl]piperazin-1-yl; R 4 is selected from hydrogen, 1-piperidinomethyl and N,N-dimethylaminomethyl; R 5 independently selected from methyl, ethyl, propyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro and cyclopropyl; X is CH or N; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

7. The EGFRTKI for use according to claim 6, wherein G is selected from indol-3-yl and indazol-1-yl; R 1 is selected from hydrogen, fluorine, chlorine, methyl and cyano; R 2 is selected from methoxy and 2,2,2-trifluoroethoxy; R 3 is selected from [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy and 2-(methylamino)ethoxy; R 4 is hydrogen; R 5 is selected from methyl, 2,2,2-trifluoroethyl and cyclopropyl; X is CH or N; and n is 0 or 1; or a pharmaceutically acceptable salt thereof.

8. The EGFR TKI for use according to any one of claims 1 to 5, wherein the EGFR TKI is selected from the group consisting of osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, vometinib or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof and lazertinib or a pharmaceutically acceptable salt thereof. 9 . The EGFR TKI for use according to claim 8 , wherein the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

10. The EGFR TKI for use according to any one of the preceding claims, wherein the c-MET inhibitor is selected from the group consisting of: savotinib ( AZD6094; HMPL-504; savolitinib) or a pharmaceutically acceptable salt thereof, capmatinib or a pharmaceutically acceptable salt thereof and tepotinib or a pharmaceutically acceptable salt thereof.

11. The EGFR TKI for use according to claim 10, wherein the c-MET inhibitor is savotinib ( AZD6094; HMPL-504; savolitinib) or a pharmaceutically acceptable salt thereof.

12. The EGFR TKI for use according to claim 11, wherein the sirolimus ( AZD6094; HMPL-504; savolitinib) or a pharmaceutically acceptable salt thereof is administered at a dose of about 600 mg once a day, about 300 mg twice a day, or about 300 mg once a day.

13. The EGFR TKI for use according to any one of the preceding claims, wherein the cancer is EGFR mutation-positive non-small cell lung cancer.

14. The EGFR TKI for use according to claim 13, wherein the EGFR mutation-positive non-small cell lung cancer comprises an activating mutation in EGFR selected from the group consisting of exon 19 deletion and L858R substitution mutation.

15. The EGFR TKI for use according to any one of claims 1 to 14, wherein the human patient's cancer has progressed during or after previous treatment with osimertinib.

16. Use of an EGFR TKI in the preparation of a medicament for treating cancer in a human patient, wherein the EGFR TKI is administered in combination with a c-MET inhibitor, and wherein the cancer has a high or very high level of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or ​​IHC90+.

17. A method of treating cancer in a human patient in need of such treatment, the method comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of a c-MET inhibitor, and wherein the cancer has high or very high levels of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or ​​IHC90+.

18. A method of treating cancer in a human patient in need of such treatment, the method comprising administering to the human patient a first amount of an EGFR TKI and a second amount of a c-MET inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the cancer has a high or very high level of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or ​​IHC90+.

19. A c-MET inhibitor for use in treating cancer in a human patient, wherein the c-MET inhibitor is administered in combination with an EGFR TKI, and wherein the cancer has a high or very high level of MET amplification and / or overexpression as defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or ​​IHC90+.

20. The c-MET inhibitor for use in treating cancer according to claim 18, wherein the cancer is non-small cell lung cancer, and wherein the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

21. The c-MET inhibitor for use in treating non-small cell lung cancer according to claim 19 or claim 20, wherein the cancer is non-small cell lung cancer, and wherein the c-MET inhibitor is savotinib ( AZD6094; HMPL-504; savolitinib) or a pharmaceutically acceptable salt thereof.

Images