An epidermal growth factor receptor tyrosine kinase inhibitor combined with an HGF receptor inhibitor for the treatment of cancer

Abstract

This specification 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 an inhibitor of c-MET.

Description

Technical Field

[0001] This specification relates to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for use in the treatment of cancer (e.g., non-small cell lung cancer [NSCLC]), wherein the EGFR TKI is administered in combination with an inhibitor of c-MET (also known as the HGF receptor, or hepatocyte growth factor receptor).

Background Art

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

[0003] There are three generations of EGFR TKIs: First-generation EGFR TKIs (e.g., gefitinib, erlotinib) are ATP-competitive inhibitors; second-generation EGFR TKIs (e.g., afatinib, dacomitinib) are irreversible inhibitors that covalently bind to EGFR; and third-generation EGFR TKIs (e.g., osimertinib) are designed to target the T790M resistance mutation and EGFR sensitizing mutations more selectively than wild-type EGFR. All of these TKIs are effective in NSCLC patients whose tumors have an in-frame deletion in exon 19 and / or an L858R point mutation in exon 21. These two mutations account for approximately 90% of all EGFR mutations. In approximately 50% of patients, resistance to first-generation 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 that is active against exon 19 deletions and L858R mutations regardless of the presence of the T790M mutation. However, even patients treated with osimertinib ultimately progress, mainly due to the development of acquired resistance arising from other resistance mechanisms. Therefore, there remains a need to develop new therapies for the treatment of NSCLC, particularly for patients in whom the disease has progressed after treatment with EGFR TKIs.

[0004] Amplification of the MET gene has been reported as a secondary oncogenic event in 5% - 22% of EGFRm+ NSCLC 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 trials (AURA3 [NCT02151981], which investigated osimertinib or platinum-pemetrexed in patients with EGFR T790M+ lung cancer, and FLAURA [NCT02296125], which investigated osimertinib against standard EGFR TKIs [gefitinib or erlotinib] in untreated EGFRm+ advanced NSCLC patients) revealed acquired MET amplification after disease progression with osimertinib in 15% - 19% of the patients tested. MET overexpression and amplification in tumor tissue are detected in the setting of acquired EGFR TKI resistance. However, despite preclinical models suggesting that the use of MET TKIs in combination with EGFR TKIs may overcome MET-driven resistance, there are no approved therapies specifically indicated for the treatment of patients with tumors positive for MET amplification and / or overexpression, and no standard treatment specifically established for patients who develop MET-driven resistance after previous EGFR TKI therapy (including osimertinib).

[0005] The lack of therapies for patients who develop MET-driven resistance after previous treatment with EGFR TKIs can be due to uncertainties regarding how to identify the patients most likely to benefit from MET TKI and EGFR TKI combination therapies. The prevalence of MET amplification and overexpression depends on the sample type, detection method, and assay cut-off used. Several clinical phase 1b / 2 trials (e.g., NCT02143466, NCT01610336, and NCT01982955) investigated the efficacy of MET TKIs in combination with EGFR TKIs in MET amplification and / or overexpression. However, across these trials, different amplification or overexpression assay cut-offs were used for patient selection, and in NCT01610336, the cut-off was even changed during the trial. Furthermore, there was considerable variability in the objective response rate (ORR), thus casting doubt on the suitability of MET amplification and overexpression as predictors of clinical benefit. Therefore, a significant unmet medical need remains for means to identify EGFRm+ NSCLC patients most likely to benefit from combination therapies of MET TKI and EGFR TKI.

Summary of the Invention

[0006] This specification enables the identification of EGFRm+ NSCLC patients who are most likely to benefit from MET TKI and EGFR TKI combination therapies using defined MET amplification and / or overexpression assay cut-offs. Without being bound by theory, it has been discovered that clinical benefit is determined not simply by the presence of MET amplification and / or overexpression, but by the degree to which such MET amplification and / or overexpression is present. Specifically, high-level or very high-level MET amplification and / or overexpression predicts clinical benefit. Unexpectedly, high-level or very high-level MET amplification and / or overexpression is highly dominant in EGFRm NSCLC after progression on third-generation EGFR-TKIs, and it has been found that using these biomarkers enables the selection of EGFRm+ NSCLC patients who are most likely to benefit from combination therapies of MET TKI and EGFR TKI.

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

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

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

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

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

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

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

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

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

[0018] In one embodiment, there is provided the use of an inhibitor of c-MET in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the inhibitor of c-MET 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 manufacture of a medicament for the treatment of cancer in a human patient, wherein the EGFR TKI is administered in combination with an inhibitor of c-MET, and wherein the aforementioned cancer has been found to have high or very high levels of MET amplification and / or overexpression prior to administration of the EGFR TKI in combination with the inhibitor of c-MET.

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

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

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

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

[0024] The terms "treat", "treating", and "treatment" refer to at least partially alleviating, inhibiting, preventing, and / or ameliorating a condition, disorder, or disease such as lung cancer. The term "treatment of cancer" includes both in vitro and in vivo treatment, including treatment in warm-blooded animals such as humans. The effectiveness of cancer treatment can be evaluated in a variety of ways including, but not limited to, the following: inhibition of cancer cell proliferation (including reversal of cancer growth); promotion of cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement of symptoms; duration of response to treatment; delay in disease progression; and prolongation of survival. Treatment can also be evaluated with respect to the nature and extent of side effects associated with the treatment. Furthermore, effectiveness can be evaluated with respect to biomarkers such as the level of expression or phosphorylation of a protein known to be associated with a particular biological phenomenon. Other evaluations of effectiveness are known to those of ordinary skill in the art.

[0025] The phrases "in combination with" and similar terms (including "combination of") include administration of two or more active pharmaceutical ingredients to a subject, including co-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 the amount of a compound or combination of compounds described herein that is sufficient to provide the intended application, including, but not limited to, treatment of a disease. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight, age, and gender), the severity of the disease state, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to the dosage that induces a specific response in target cells (e.g., the amount of apoptosis). Specific dosages will vary depending on the particular compound selected, the dosage regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is carried.

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

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

[0029] Pharmaceutically acceptable acid addition salts can be formed using inorganic acids and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of 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 using inorganic bases and organic bases. Examples of inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of 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

Figure 2

Mode for Carrying Out the Invention

[0031] EGFR Mutation-Positive NSCLC, Patient Selection, Dosing, and Diagnostic Methods In an embodiment, the cancer is a lung cancer such as non-small cell lung cancer (NSCLC).

[0032] In an embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0033] In an embodiment, EGFR mutation-positive NSCLC includes activating mutations in EGFR. In a further embodiment, EGFR mutation-positive NSCLC includes non-resistant mutations. In a further embodiment, the activating mutations in EGFR include activating mutations in exons 18-21. In a further embodiment, the activating mutations in EGFR include exon 19 deletions or missense mutations in exon 21. In a further embodiment, the activating mutations in EGFR include exon 19 deletions or L858R substitution mutations. In a further embodiment, the mutations in EGFR include the T790M mutation.

[0034] In an embodiment, EGFR mutation-positive NSCLC is locally advanced EGFR mutation-positive NSCLC.

[0035] In an embodiment, EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC.

[0036] In an embodiment, EGFR mutation-positive NSCLC is unsuitable for radical surgery or radiotherapy.

[0037] There are numerous methods for detecting EGFR activating mutations, and those skilled in the art will recognize them. Tests provided by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories and / or tests approved by regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the National Medical Products Administration (NMPA) of China are suitable for use in these methods. These include both tumor tissue and plasma-based diagnostic methods. Generally, the EGFR mutation status is first evaluated using a tumor tissue biopsy sample from a human patient. If a tumor sample is not available or the tumor sample is negative, the EGFR mutation status can be evaluated using a plasma sample. Specific examples of suitable diagnostic tests for detecting EGFR mutations, particularly exon 19 deletions, L858R substitution mutations, and T790M mutations, include the Cobas™ EGFR Mutation Test v2 (Roche Molecular Diagnostics). Other examples of suitable diagnostic tests include FoundationOne CDx (Foundation Medicine), which can detect activating and resistant mutations in tissue samples; Guardant360 CDx (Guardant Health), which can detect activating and resistant mutations in plasma samples; and FoundationOne Liquid CDx (Foundation Medicine), which can detect activating mutations in plasma samples.

[0038] Thus, in embodiments, EGFR-mutated positive NSCLC includes activating mutations in EGFR (e.g., activating mutations in exons 18-21, such as exon 19 deletions, missense mutations in exon 21, and L858R substitution mutations; and resistance mutations such as the T790M mutation), and the EGFR mutation status of a 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 a test provided by an FDA-approved test and / or a CLIA-certified laboratory. In further embodiments, the diagnostic method uses the Cobas™ EGFR Mutation Test (v1 or v2) or FoundationOne CDx or the Guardant360 CDx or FoundationOne Liquid CDx.

[0039] In embodiments, the human patient is an EGFR TKI-naïve human patient. In embodiments, the human patient has previously received EGFR TKI treatment. 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-mutated positive NSCLC.

[0040] High or very high levels of MET amplification and / or overexpression in the tumor can be detected using various techniques known to those of skill in the art. For example, by applying fluorescence in situ hybridization assay (FISH) and / or immunohistochemistry assay (IHC) to a tumor tissue sample. MET amplification can also be detected by applying next-generation sequencing (NGS) to plasma and / or tumor samples.

[0041] In an embodiment, the cancer has a high or very high level of MET amplification determined by NGS. In an embodiment, the cancer has a high or very high level of MET amplification defined by ≧5 copies of MET (NGS5+) relative to the tumor ploidy by NGS.

[0042] In an embodiment, the cancer has a high or very high level of MET amplification and / or overexpression determined by FISH and / or IHC. In an embodiment, 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 an embodiment, the cancer has a high or very high level of MET amplification and / or overexpression determined by FISH and / or IHC using an FDA-approved test and / or a test provided by a CLIA-certified laboratory.

[0043] In an embodiment, cancer is defined by high or very high levels of MET amplification and / or overexpression having a MET gene copy number ≥6 (FISH6+) by FISH and / or ≥60% tumor cells (IHC60+) having strong (3+) membrane and / or cytoplasmic staining intensity by IHC; or defined by a MET gene copy number ≥7 (FISH7+) by FISH and / or ≥70% tumor cells (IHC70+) having strong (3+) membrane and / or cytoplasmic staining intensity by IHC; or defined by a MET gene copy number ≥8 (FISH8+) by FISH and / or ≥80% tumor cells (IHC80+) having strong (3+) membrane and / or cytoplasmic staining intensity by IHC; or defined by a MET gene copy number ≥9 (FISH9+) by FISH and / or ≥90% tumor cells (IHC90+) having strong (3+) membrane and / or cytoplasmic staining intensity by IHC; or defined by a MET gene copy number ≥10 (FISH10+) by FISH and / or ≥90% tumor cells (IHC90+) having strong (3+) membrane and / or cytoplasmic staining intensity by IHC, having high or very high levels of MET amplification and / or overexpression. In an embodiment, cancer has high or very high levels of MET amplification and / or overexpression defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+. In an embodiment, cancer has high or very high levels of MET amplification and / or overexpression defined by FISH10+. In an embodiment, cancer has high or very high levels of MET amplification and / or overexpression defined by IHC60+, IHC70+, IHC80+ or IHC90+. In an embodiment, cancer has high or very high levels of MET amplification and / or overexpression defined by IHC90+.

[0044] In an embodiment, the cancer is EGFR-mutant positive NSCLC and has high or very high level MET amplification and / or overexpression as defined by FISH10+ and / or IHC90+. In an embodiment, the cancer is EGFR-mutant positive NSCLC and has high or very high level MET amplification and / or overexpression as defined by FISH10+. In an embodiment, the cancer is EGFR-mutant positive NSCLC and has high or very high level MET amplification and / or overexpression as defined by IHC90+.

[0045] In an embodiment, the cancer has been found to have high or very high level MET amplification and / or overexpression prior to administration of a combination of an EGFR TKI and an inhibitor of c-MET.

[0046] A number of FISH and / or IHC assays are available for detecting MET amplification and / or overexpression and would be recognized by those of ordinary skill in the art. In an embodiment, the assay may 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), an example of a suitable IHC assay is the VENTANA MET (SP44) RxDx Assay (Ventana Medical Systems, Inc., Tucson, Arizona), and an example of a suitable NGS assay is the F1CDx (Foundation Medicine, Cambridge, MA).

[0047] This specification discloses a combination of an EGFR TKI and an inhibitor of c-MET as a first-line (1L) treatment (i.e., in EGFR TKI-naïve patients); as a second-line (2L) treatment (i.e., in patients who have previously received one line of EGFR TKI treatment); and as a third- or fourth-line (3-4L) 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 with or without subsequent chemotherapy).

[0048] In embodiments, the patient may have received one, two, or three lines of prior treatment, which must include an EGFR TKI as one of the prior lines of treatment, but may also include other EGFR TKIs, chemotherapy, or chemotherapy in combination with immuno-oncology (IO) agents in metastatic settings. In embodiments, the patient has been administered a third-generation EGFR TKI as one of the prior lines of treatment. In embodiments, the patient has been administered osimertinib as one of the prior lines of treatment. In embodiments, the patient has been administered a third-generation EGFR TKI as the most recent prior line of treatment. In embodiments, the patient has been administered osimertinib as the most recent prior line of treatment.

[0049] In embodiments, both the EGFR TKI and the inhibitor of c-MET are administered once daily (QD). In embodiments, the EGFR TKI is administered once daily (QD) and the inhibitor of c-MET is administered twice daily (BID).

[0050] In embodiments, the treatment provides an ORR of at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%.

[0051] In embodiments, the 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.

[0052] EGFR TKI The third-generation EGFR TKI is an inhibitor of EGFR with activating mutations that also significantly inhibits EGFR with the T790M mutation and does not significantly inhibit wild-type EGFR. Examples of third-generation TKIs include the compound of formula (I), osimertinib, AZD3759 (zolifertinib), lazertinib, nazartinib (EGF816), CO1686 (rociletinib), HM61713 (olmutinib), ASP8273 (nakutinib), PF-06747775 (mavertinib), avitinib (avibertinib), alflutinib (AST2818), CX-101 (olafertinib; RX-518), ormolutinib (HS-10296; almonertinib), and BPI-7711 (rezibertinib).

[0053] In one embodiment, the EGFR TKI is a third-generation EGFR TKI. In a further embodiment, the third-generation EGFR TKI is a compound of formula (I) as defined below. In a further 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, avibertinib or a pharmaceutically acceptable salt thereof, alflutinib 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 a further embodiment, the third-generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

[0054] Compound of formula (I) In one embodiment, the EGFR TKI is a compound of formula (I):

[0055]

Chemical Structure

[0056] In a further embodiment, there is provided a compound of formula (I) as defined above, wherein G is selected from indol-3-yl and indazol-1-yl; R 1 is selected from hydrogen, fluoro, chloro, 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; n is 0 or 1; or a pharmaceutically acceptable salt thereof.

[0057] Examples of the compounds of formula (I) include those described in International Publication No. WO 2013 / 014448, International Publication No. WO 2015 / 175632, International Publication No. WO 2016 / 054987, International Publication No. WO 2016 / 015453, International Publication No. WO 2016 / 094821, International Publication No. WO 2016 / 070816 and International Publication No. WO 2016 / 173438.

[0058] Osimertinib and pharmaceutical compositions thereof Osimertinib has the following chemical structure:

[0059]

Chemical Structure

[0060] 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 International Publication No. WO 2013 / 014448. Osimertinib is also known as AZD9291.

[0061] Osimertinib can be found in the form of its 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 (trademark).

[0062] Osimertinib mesylate is currently approved as an oral tablet formulation at a dose of 80 mg (expressed as the free base equivalent to 95.4 mg of osimertinib mesylate) once daily for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC. If a dose change is needed, a 40 mg once-daily oral tablet formulation (expressed as the free base equivalent to 47.7 mg of osimertinib mesylate) is available. The tablet core contains pharmaceutical diluents (such as mannitol and microcrystalline cellulose), disintegrants (such as low-substituted hydroxypropyl cellulose), and lubricants (such as sodium stearyl fumarate). The tablet formulation is described in International Publication No. WO 2015 / 101791.

[0063] Thus, in one embodiment, osimertinib or a pharmaceutically acceptable salt thereof is in the form of the mesylate salt, i.e., N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate.

[0064] In one embodiment, osimertinib or a pharmaceutically acceptable salt thereof is administered once a day. In a further embodiment, osimertinib mesylate is administered once a day.

[0065] In one embodiment, the total daily dose of osimertinib is about 80 mg. In a further embodiment, the total daily dose of osimertinib mesylate is about 95.4 mg.

[0066] In one embodiment, the total daily dose of osimertinib is about 40 mg. In a further embodiment, the total daily dose of osimertinib mesylate is about 47.7 mg.

[0067] In one embodiment, osimertinib or a pharmaceutically acceptable salt thereof is in tablet form.

[0068] 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 a further embodiment, the composition comprises one or more pharmaceutical diluents (e.g., mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (e.g., low-substituted hydroxypropyl cellulose) or one or more pharmaceutical lubricants (e.g., sodium stearyl fumarate).

[0069] In one embodiment, the composition is in tablet form, and 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 pharmaceutical diluents; (c) 2 to 15 parts of one or more pharmaceutical disintegrants; and (d) 0.5 to 3 parts of one or more pharmaceutical lubricants, all parts being parts by weight, and the sum of parts (a)+(b)+(c)+(d)=100.

[0070] In one embodiment, the composition is in the form of a tablet, and 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 pharmaceutically diluents, the pharmaceutically diluents including microcrystalline cellulose and mannitol; (c) 2 to 8 parts of a pharmaceutically disintegrant, the pharmaceutically disintegrant including low-substituted hydroxypropyl cellulose; (d) 1.5 to 2.5 parts of a pharmaceutically lubricant, the pharmaceutically lubricant including sodium stearyl fumarate, all parts being parts by weight, and the sum of parts (a) + (b) + (c) + (d) = 100.

[0071] In one embodiment, the composition is in the form of a tablet, and 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, all parts being parts by weight, and the sum of parts (a) + (b) + (c) + (d) = 100.

[0072] AZD3759 (zolifertinib) AZD3759 has the following chemical structure:

[0073]

Chemical formula

[0074] 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-piperazine carboxylate. AZD3759 is described in International Publication No. WO 2014 / 135876.

[0075] In one embodiment, AZD3759 or a pharmaceutically acceptable salt thereof is administered twice a day. In a further embodiment, AZD3759 is administered twice a day.

[0076] In one embodiment, the total daily dose of AZD3759 is about 400 mg. In a further embodiment, about 200 mg of AZD3759 is administered twice daily.

[0077] Lazertinib Lazertinib has the following chemical structure:

[0078]

Chem.

[0079] The free base of lazertinib is known by the chemical name 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 International Publication No. WO2016 / 060443. Lazertinib is also known by the names YH25448 and GNS-1480.

[0080] In one embodiment, lazertinib or a pharmaceutically acceptable salt thereof is administered once daily. In a further embodiment, lazertinib is administered once daily.

[0081] In one embodiment, the total daily dose of lazertinib is about 20 - 320 mg.

[0082] In one embodiment, the total daily dose of lazertinib is about 240 mg.

[0083] Avitinib Avinib has the following chemical structure:

[0084]

Chem.

[0085] The free base of avitinib is known by the chemical name: 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 U.S. Patent No. 2014038940. Avitinib is also known as abivertinib.

[0086] In one embodiment, avitinib or a pharmaceutically acceptable salt thereof is administered twice a day. In a further embodiment, avitinib maleate is administered twice a day.

[0087] In one embodiment, the total daily dose of avitinib maleate is about 600 mg.

[0088] Alflutinib Alflutinib has the following chemical structure:

[0089] [Chemical formula]

[0090] The free base of alflutinib is known by the chemical name: 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. Alflutinib is disclosed in International Publication No. 2016 / 15453. Alflutinib is also known as AST2818.

[0091] In one embodiment, alflutinib or a pharmaceutically acceptable salt thereof is administered once a day. In a further embodiment, alflutinib mesylate is administered once a day.

[0092] In one embodiment, the total daily dose of alflutinib mesylate is about 80 mg.

[0093] In one embodiment, the total daily dose of afatinib mesylate is about 40 mg.

[0094] CX-101 (olapatinib; RX-518) CX-101 has the following chemical structure:

[0095]

Chemical formula

[0096] 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 International Publication No. WO2015 / 027222. CX-101 is also known as RX-518 and olapatinib.

[0097] HS-10296 (almotinib; omoritinib) HS-10296 (almotinib; omoritinib) has the following chemical structure:

[0098]

Chemical formula

[0099] The free base of HS-10296 is known by the chemical name: N-[5-[[4-(1-cyclopropyl-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-phenyl]prop-2-enamide. HS-10296 is disclosed in International Publication No. WO2016 / 054987.

[0100] In one embodiment, the total daily dose of HS-10296 is about 110 mg.

[0101] BPI-7711 (Lenvatinib) BPI-7711 has the following chemical structure:

[0102]

Chemical formula

[0103] The free base of BPI-7711 is known by the chemical name: N-[2-[2-(dimethylamino)ethoxy]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide. BPI-7711 is disclosed in International Publication No. WO2016 / 94821.

[0104] In one embodiment, the total daily dose of BPI-7711 is about 180 mg.

[0105] Inhibitor of c-MET In embodiments, an inhibitor of c-MET is any molecule that binds to one or more c-MET (also known as mesenchymal-epithelial transition factor) isoforms and inhibits their activity.

[0106] In embodiments, the inhibitor of c-MET is selected from the group consisting of savolitinib (Orpathys®; AZD6094; HMPL-504; Volitinib) or a pharmaceutically acceptable salt thereof, capmatinib (Tabrecta®) or a pharmaceutically acceptable salt thereof, tepotinib (Tepmetko®) or a pharmaceutically acceptable salt thereof, glesatinib (SCC224) or a pharmaceutically acceptable salt thereof, and cabozantinib (Cometriq®, Cabometyx®) or a pharmaceutically acceptable salt thereof.

[0107] In an embodiment, the c-MET inhibitor is selected from the group consisting of savolitinib (Orpathys (registered trademark); AZD6094; HMPL-504; volitinib) or a pharmaceutically acceptable salt thereof, capmatinib (Tabrecta (registered trademark)) or a pharmaceutically acceptable salt thereof, and tepotinib (Tepmetko (registered trademark)) or a pharmaceutically acceptable salt thereof.

[0108] In an embodiment, the c-MET inhibitor is savolitinib (Orpathys (registered trademark); AZD6094; HMPL-504; volitinib) or a pharmaceutically acceptable salt thereof.

[0109] In an embodiment, the c-MET inhibitor is savolitinib (Orpathys (registered trademark); AZD6094; HMPL-504; volitinib).

[0110] Savolitinib (Orpathys (registered trademark); AZD6094; HMPL-504; volitinib) Savolitinib has the following chemical structure:

[0111] [Chemical formula]

[0112] The free base of savolitinib is known by the chemical name 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrrol-3-yl)triazolo[4,5-b]pyrazine. Savolitinib is described in International Publication No. WO2011079804 (Compound 270).

[0113] In one embodiment, savolitinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In a further embodiment, the composition comprises one or more pharmaceutical diluents (e.g., mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (e.g., low-substituted hydroxypropyl cellulose) or one or more pharmaceutical lubricants (e.g., magnesium stearate).

[0114] In one embodiment, the composition is in the form of a tablet.

[0115] In combination with an EGFR TKI such as osimertinib, savolitinib or a pharmaceutically acceptable salt thereof is generally administered to a subject at a daily dose of about 100 mg to about 1200 mg.

[0116] In some embodiments, savolitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 200 mg to about 800 mg. In one embodiment, savolitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg to about 600 mg.

[0117] In some embodiments, savolitinib or a pharmaceutically acceptable salt thereof is administered once daily (QD) to a subject. In some embodiments, savolitinib or a pharmaceutically acceptable salt thereof is administered twice daily (BID) to a subject

[0118] In one embodiment, savolitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 600 mg.

[0119] In another embodiment, savolitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg. In another embodiment, savolitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 600 mg. In another embodiment, savolitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg.

[0120] Capmatinib (Tabrecta®) Capmatinib has the following chemical structure:

[0121]

Chemical formula

[0122] Capmatinib is known by the chemical name 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide. Capmatinib is disclosed in U.S. Patent No. 7,767,675. In embodiments, capmatinib or a pharmaceutically acceptable salt thereof is administered once or twice daily. In a further embodiment, capmatinib hydrochloride is administered twice daily.

[0123] In embodiments, the total daily dose of capmatinib is about 800 mg (i.e., 400 mg twice daily). In embodiments, the total daily dose of capmatinib is about 600 mg (i.e., 300 mg twice daily). In embodiments, the total daily dose of capmatinib is about 400 mg (i.e., 200 mg twice daily).

[0124] Tepotinib (Tepmetko®) Tepotinib has the following chemical structure:

[0125]

Chemical formula

[0126] The free base of tepotinib is known by the chemical name 3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile. Tepotinib is disclosed in U.S. Patent No. 8329692. In embodiments, 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 embodiments, the total daily dose of tepotinib is about 450 mg.

[0127] Gurmetinib (SCC224) Gurmetinib has the following chemical structure:

[0128]

Chemical formula

[0129] The free base of gurmetinib is known by the chemical name 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. Gurmetinib is disclosed in International Publication No. WO 2014 / 201857. In embodiments, gurmetinib or a pharmaceutically acceptable salt thereof is administered once or twice daily. In a further embodiment, gurmetinib is administered once daily. In embodiments, the total daily dose of gurmetinib is about 400 mg. In embodiments, the total daily dose of gurmetinib is about 300 mg.

[0130] Cabozantinib (Cometriq®, Cabometyx®) Cabozantinib has the following chemical structure:

[0131]

Chemical formula

[0132] The free base of cabozantinib is known by the chemical name N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate. Cabozantinib is disclosed in U.S. Patent No. 7,579,473. In embodiments, cabozantinib or a pharmaceutically acceptable salt thereof is administered once or twice daily. In a further embodiment, cabozantinib (S)-malate is administered once daily. In embodiments, the total daily dose of cabozantinib is about 60 mg.

[0133] Further embodiments In one embodiment, an EGFR TKI for use in the treatment of cancer in a human patient is provided, the EGFR TKI being administered in combination with an inhibitor of c-MET, and the aforementioned cancer having high or very high levels of MET amplification and / or overexpression. In embodiments, the cancer is a lung cancer such as NSCLC. In still further embodiments, the NSCLC is EGFR mutant-positive NSCLC. In still further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH 10+ and / or IHC 90+.

[0134] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering a therapeutically effective amount of an EGFR TKI, the EGFR TKI being administered in combination with a therapeutically effective amount of an inhibitor of c-MET, and the aforementioned cancer having high or very high levels of MET amplification and / or overexpression. In embodiments, the cancer is a lung cancer such as NSCLC. In still further embodiments, the NSCLC is EGFR mutant-positive NSCLC. In still further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH 10+ and / or IHC 90+.

[0135] In one embodiment, there is provided a method of treating cancer in a human patient in need of such treatment, comprising administering to the human patient a first amount of an EGFR TKI and a second amount of an inhibitor of c-MET, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the cancer described above has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the cancer is a lung cancer such as NSCLC. In still further embodiments, the NSCLC is EGFR-mutant positive NSCLC. In still further embodiments, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0136] In one embodiment, there is provided the use of an EGFR TKI in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the EGFR TKI is administered in combination with an inhibitor of c-MET, and wherein the cancer described above has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the cancer is a lung cancer such as NSCLC. In still further embodiments, the NSCLC is EGFR-mutant positive NSCLC. In still further embodiments, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0137] In one embodiment, a combination of an EGFR TKI and an inhibitor of c-MET for use in the treatment of cancer in a human patient is provided, wherein the aforementioned cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naïve human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In still a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0138] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a therapeutically effective amount of an EGFR TKI in combination with a therapeutically effective amount of an inhibitor of c-MET, wherein the aforementioned cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naïve human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In still a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH10+ and / or IHC90+.

[0139] In one embodiment, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a first amount of an EGFR TKI and a second amount of an inhibitor of c-MET, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naïve human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In still a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0140] In one embodiment, there is provided the use of a combination of an EGFR TKI and an inhibitor of c-MET in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the cancer has high or very high levels of MET amplification and / or overexpression. In embodiments, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In further embodiments, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In further embodiments, the human patient is an EGFR TKI-naïve human patient. In further embodiments, the human patient has previously received EGFR TKI treatment. In further embodiments, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In still further embodiments, the cancer is a lung cancer such as NSCLC. In still further embodiments, the NSCLC is EGFR-mutant positive NSCLC. In still further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0141] In one embodiment, there is provided a combination of osimertinib or a pharmaceutically acceptable salt thereof and an inhibitor of c-MET for use in the treatment of cancer in a human patient, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient before the inhibitor of c-MET is administered to the human patient, and wherein the cancer has high or very high levels of MET amplification and / or overexpression. In embodiments, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In further embodiments, the cancer is a lung cancer such as NSCLC. In still further embodiments, the NSCLC is EGFR-mutant positive NSCLC. In still further embodiments, high or very high levels of MET amplification and / or overexpression are defined by FISH10+ and / or IHC90+.

[0142] In one embodiment, there is provided a method of treating cancer in a human patient in need of such treatment, comprising administering to the human patient a combination of a therapeutically effective amount of osimertinib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an inhibitor of c-MET, wherein the osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient before the inhibitor of c-MET is administered to the human patient, and wherein the aforementioned cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0143] In one embodiment, there is provided a method of treating cancer in a human patient in need of such treatment, comprising administering to the human patient a first amount of osimertinib or a pharmaceutically acceptable salt thereof and a second amount of an inhibitor of c-MET, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient before the inhibitor of c-MET is administered to the human patient, and wherein the aforementioned cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0144] In one embodiment, there is provided the use of a combination of osimertinib or a pharmaceutically acceptable salt thereof and an inhibitor of c-MET for the manufacture of a medicament for the treatment of cancer in a human patient, wherein the osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient before the inhibitor of c-MET is administered to the human patient, and wherein the aforementioned cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is a lung cancer such as NSCLC. In yet a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In yet a further embodiment, the high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0145] In one embodiment, there is provided an EGFR TKI for use in the treatment of cancer in a human patient, the treatment comprising i) the EGFR TKI and ii) separate, sequential, or simultaneous administration of an inhibitor of c-MET to the human patient, wherein the aforementioned cancer has high-level or very high-level 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 inhibitor of c-MET can be selected to ensure the generation of a combined therapeutic effect.

[0146] "Therapeutic effect" includes a therapeutic benefit and / or a prophylactic benefit. Prophylactic effects include delaying or precluding the occurrence of a disease or condition, delaying or precluding the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0147] In an embodiment, the administration of the EGFR TKI and the inhibitor of c-MET is sequential, and the EGFR TKI is administered before the inhibitor of c-MET.

[0148] In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the c-MET inhibitor is savolitinib 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 been administered osimertinib or a pharmaceutically acceptable salt thereof. In still a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is an EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0149] In one embodiment, there is provided a method of treating cancer in a human patient in need of such treatment, 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 an inhibitor of c-MET, wherein the aforementioned cancer has high-level or very high-level 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 savolitinib 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 been administered osimertinib or a pharmaceutically acceptable salt thereof. In still a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is an EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0150] In one embodiment, there is provided a method of treating cancer in a human patient in need of such treatment, comprising administering to the human patient (i) a first amount of an EGFR TKI and (ii) a second amount of an inhibitor of c-MET separately, sequentially, or simultaneously, wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the cancer has high or very high levels 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 inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naïve human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In still a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In still a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH 10+ and / or IHC 90+.

[0151] In one embodiment, there is provided the use of an EGFR TKI in the manufacture of a medicament for the treatment of cancer in a human patient, the treatment comprising the separate, sequential, or simultaneous administration to the human patient of i) an EGFR TKI and ii) an inhibitor of c-MET, wherein the aforementioned cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naïve human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In still a further embodiment, the cancer is a lung cancer such as NSCLC. In still a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In still a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0152] In one embodiment, there is provided an inhibitor of c-MET for use in the treatment of cancer in a human patient, the inhibitor of c-MET being administered in combination with an EGFR TKI, wherein the aforementioned cancer has high-level or very high-level MET amplification and / or overexpression.

[0153] In one embodiment, an inhibitor of c-MET for use in the treatment of cancer in a human patient is provided, the treatment comprising i) administration of an inhibitor of c-MET and ii) separate, sequential, or simultaneous administration of an EGFR TKI to the human patient, wherein the cancer has high-level or very high-level MET amplification and / or overexpression. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naïve human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the cancer is a lung cancer such as NSCLC. In yet a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In yet a further embodiment, high-level or very high-level MET amplification and / or overexpression is defined by FISH 10+ and / or IHC 90+.

[0154] In one embodiment, there is provided the use of an inhibitor of c-MET in the manufacture of a medicament for the treatment of cancer in a human patient, the treatment comprising i) an EGFR TKI and ii) separate, sequential, or simultaneous administration of an inhibitor of c-MET to the human patient, wherein the cancer has high or very high levels 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 inhibitor of c-MET is savolitinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naïve human patient. In a further embodiment, the human patient has previously received EGFR TKI treatment. In a further embodiment, the human patient has previously been administered osimertinib or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the cancer is a lung cancer such as NSCLC. In yet a further embodiment, the NSCLC is EGFR-mutant positive NSCLC. In yet a further embodiment, high or very high levels of MET amplification and / or overexpression are defined by FISH 10+ and / or IHC 90+.

[0155] In one embodiment, there is provided a method of treating locally advanced or metastatic NSCLC in a human patient in need of such treatment, 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 savolitinib, and wherein the locally advanced or metastatic NSCLC has high or very high levels of MET amplification and / or overexpression as defined by FISH 6+, FISH 7+, FISH 8+, FISH 9+ or FISH 10+ and / or IHC 60+, IHC 70+, IHC 80+ or IHC 90+, and wherein the locally advanced or metastatic NSCLC of the human patient has progressed during or after previous treatment with osimertinib or a pharmaceutically acceptable salt thereof.

[0156] In one embodiment, a method of treating locally advanced or metastatic NSCLC in a human patient in need of such treatment is provided, comprising administering a therapeutically effective amount of savolitinib to the human patient, wherein savolitinib is administered in combination with osimertinib or a pharmaceutically acceptable salt thereof, and wherein the aforementioned locally advanced or metastatic NSCLC is defined by high or very high levels of MET amplification and / or overexpression by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or IHC90+, and wherein the locally advanced or metastatic NSCLC of the aforementioned human patient has progressed during or after previous treatment with osimertinib or a pharmaceutically acceptable salt thereof.

[0157] In one embodiment, - a first pharmaceutical composition comprising an EGFR TKI and a pharmaceutically acceptable excipient; and - a kit is provided that includes a second pharmaceutical composition comprising an inhibitor of c-MET and a pharmaceutically acceptable excipient.

Examples

[0158] The following specific examples are provided for illustrative purposes only with reference to the accompanying drawings and should not be construed as limiting the teachings of this specification.

[0159] Study D5084C00007 (SAVANNAH) In the ongoing Phase 2 study D5084C00007 (SAVANNAH), the combination of osimertinib (80 mg QD) and savolitinib (300 mg QD, 300 mg BID or 600 mg QD) has been investigated to understand the performance of the combination in overcoming MET amplification and / or MET overexpression as a mechanism of resistance in patients with locally advanced or metastatic EGFRm+ NSCLC who have experienced disease progression after osimertinib therapy.

[0160] The identification of MET amplification and / or overexpression status in the SAVANNAH trial was primarily based on a prospective central trial of tumor biopsies collected after prior treatment with osimertinib, using two assays: MET FISH (Vysis MET FISH Probe Kit) and MET IHC (VENTANA MET (SP44) RxDx Assay). A positive MET result by either or both of the two assays qualifies patients for screening for enrollment in the trial. Per the inclusion criteria, patients are allowed to have received up to 3 lines of prior treatment, which must include osimertinib as one of the prior lines of treatment, but may also include other EGFR TKIs, chemotherapy, or chemotherapy in combination with an IO agent in the metastatic setting. The primary purpose of this trial is to determine efficacy.

[0161] In this trial, approximately 259 patients are planned to be enrolled and treated with osimertinib 80 mg QD in combination with either savolitinib 300 mg QD (approx. n = 196), savolitinib 300 mg BID (approx. n = 33), or savolitinib 600 mg QD (approx. n = 33). SAVANNAH is currently ongoing, but patient enrollment into the 300 mg QD dosing cohort is complete.

[0162] As of the data cut-off (DCO) in June 2021, a total of 253 patients had received at least one dose of investigational treatment with SAVANNAH. Of these 253 patients, 196 patients (87 2L patients [44.4%] and 109 ≥3L patients [55.6%]) were treated with an initial dose of 300 mg QD in combination with osimertinib (80 mg QD). 36 patients (18.4%) had received prior platinum-based chemotherapy and 12 patients (6%) had received prior PD-(L)1 therapy. Additionally, at this DCO, 27 patients (17 2L patients and 10 ≥3L patients) and 30 patients (8 2L patients and 22 ≥3L patients) were treated with savolitinib at initial doses of 300 mg BID and 600 mg QD, respectively, in combination with osimertinib (80 mg QD).

[0163] A total of 108 patients had received at least one dose of savolitinib 300 mg QD + osimertinib 80 mg QD and had high MET status (IHC90+ and / or FISH10+). 35 patients (32%) had recurrent disease and 38 patients (35%) had brain metastases at the start of the trial. 50 patients (46%) received 2L treatment, 37 patients (34%) received ≥3L treatment without prior chemotherapy in a metastatic setting, and 21 patients (19.4%) received ≥3L treatment with prior chemotherapy in a metastatic setting. 55 patients (50.9%) had one prior line of EGFR TKI and 51 patients (47.2%) had two prior lines of EGFR TKI. 99 patients (92%) had osimertinib as the line immediately preceding treatment at the start of the trial.

[0164] In the second interim analysis (DCO in October 2020), 137 patients (33 2L patients and 104 ≥3L patients) were treated with an initial dose of 300 mg QD in combination with osimertinib and had the opportunity to have at least two post-baseline Response Evaluation Criteria In Solid Tumors (RECIST) scans. The results of the objective response rate (ORR) and duration of response (DoR) confirmed from these patients are summarized in Table 1.

[0165]

Table 1

[0166] To better understand the relationship between the levels of MET amplification and / or overexpression and efficacy, exploratory analyses were performed in these 137 patients who progressed during or after osimertinib treatment. Analyses of ORR and median progression-free survival (PFS) based on the levels of MET overexpression detected by central MET IHC and FISH assays (Tables 2 and 3) showed a tendency for the response rate to improve with increasing levels of MET overexpression and amplification. Therefore, ≥10 copies of the MET gene (referred to as FISH10+) and tumor cells stained with ≥90% intensity of 3+ (referred to as IHC90+) were selected as the provisional optimal cut-offs for MET FISH and MET IHC.

[0167]

Table 2

[0168]

Table 3

[0169] Subsequently, the efficacy in the high biomarker group (FISH10+ and / or IHC90+) was further evaluated in a larger number of patients with longer follow-up. Patients received treatment with a starting dose of 300 mg of savolitinib QD in combination with osimertinib and had the opportunity to receive at least two post-baseline RECIST scans (DCO in June 2021; N = 193). Within this cohort, 108 patients met the criteria for FISH10+ and / or IHC90+ status. As summarized in Table 4, the efficacy in patients with FISH10+ and / or IHC90+ positive status (ORR 49.1%, DoR 9.6 months, PFS 7.1 months) was improved compared to all patients (ORR 32.1%, DoR 8.3 months, PFS 5.3 months), particularly compared to the subgroup without FISH10+ and IHC90+ status (ORR 9.1%, DoR 6.9 months, PFS 2.8 months).

[0170]

Table 4

[0171] Furthermore, with respect to PFS, Figure 1 shows a good separation of the Kaplan-Meier curves between patients with FISH10+ and / or IHC90+ status and patients without FISH10+ and / or IHC90+ status, further supporting an optimal cut-off for identifying the population to be treated.

[0172] As shown in Table 5, within 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.

[0173]

Table 5

[0174] Tumor responses are shown in Figure 2, which is a waterfall plot showing the best percent change in target lesions in patients with FISH10+ and / or IHC90+. Evaluable for the efficacy set was defined as dosed patients with measurable disease at baseline who received ≥2 RECIST scans during treatment. FISH10+, fluorescence in situ hybridization (MET copy number ≥10); IHC90+, 3+ immunohistochemical 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 the treatment of cancer in a human patient, wherein the EGFR TKI is administered in combination with an inhibitor of c-MET, and the cancer has high-level or very high-level MET amplification and / or overexpression. An EGFR TKI for use.

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

3. The EGFR TKI for use according to claim 1 or 2, wherein the cancer has high-level or very high-level 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 inhibitor of c-MET is separate, sequential, or simultaneous.

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

6. The EGFR TKI is a compound of formula (I): 【Chemical 1】 wherein 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, fluoro, chloro, methyl and cyano; R ２ is selected from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy and methyl; R ３ is 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]oct-2-yl, (3aR,6aR)-5-methylhexahydro-pyrrolo[3,4-b]pyrrol-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperidin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl]piperazin-1-yl; R ４ is selected from hydrogen, 1-piperidinomethyl and N,N-dimethylaminomethyl; R ５ is independently selected from methyl, ethyl, propyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro and cyclopropyl; X is CH or N; n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof. An EGFR TKI for use according to any one of claims 1 to 5.

7. G is selected from indol-3-yl and indazol-1-yl; R １ is selected from hydrogen, fluoro, chloro, 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; n is 0 or 1; or a pharmaceutically acceptable salt thereof, an EGFR TKI for use according to claim 6.

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

9. The EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof, the EGFR TKI for use according to claim 8.

10. The inhibitor of c-MET is selected from the group consisting of savolitinib (Orpathys (registered trademark); AZD6094; HMPL-504; volitinib) or a pharmaceutically acceptable salt thereof, capmatinib (Tabrecta (registered trademark)) or a pharmaceutically acceptable salt thereof, and tepotinib (Tepmetko (registered trademark)) or a pharmaceutically acceptable salt thereof, the EGFR TKI for use according to any one of claims 1 to 9.

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

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

13. The cancer is EGFR-mutant positive non-small cell lung cancer, the EGFR TKI for use according to any one of claims 1 to 12.

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

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

16. Use of an EGFR TKI in the manufacture of a medicament for the treatment of cancer in a human patient, wherein the EGFR TKI is administered in combination with an inhibitor of c-MET, and the cancer has high-level or very high-level MET amplification and / or overexpression 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 treatment, 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 an inhibitor of c-MET, and the cancer has high-level or very high-level MET amplification and / or overexpression 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, comprising administering to the human patient a first amount of an EGFR TKI and a second amount of an inhibitor of c-MET, wherein the first amount and the second amount together constitute a therapeutically effective amount, and the cancer has high-level or very high-level MET amplification and / or overexpression defined by FISH6+, FISH7+, FISH8+, FISH9+ or FISH10+ and / or IHC60+, IHC70+, IHC80+ or IHC90+.

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

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

21. The cancer is non-small cell lung cancer, and the inhibitor of c-MET is savolitinib (Orpatys (registered trademark); AZD6094; HMPL-504; volitinib) or a pharmaceutically acceptable salt thereof. An inhibitor of c-MET for use in the treatment of non-small cell lung cancer according to claim 19 or claim 20.

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