Use of an EGFR inhibitor of formula (I) in a method of treating a cancer having two or more EGFR mutations

Abstract

This disclosure relates to the use of an EGFR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancers having two or more EGFR mutations, wherein at least one of the mutations is a C797 mutation; preferably a C797S mutation. The EGFR inhibitors disclosed herein are compounds of formula (I): (I), or pharmaceutically acceptable salts, N-oxides, or solvates thereof.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 542,245, filed October 3, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure relates to the use of an EGFR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancers having two or more EGFR mutations, wherein at least one of the mutations is a C797 mutation; preferably a C797S mutation. The EGFR inhibitors disclosed herein are compounds of formula (I): (I), Or its pharmaceutically acceptable salts, N-oxides, or solvates. Background Technology

[0003] Lung cancer is the leading cause of cancer death worldwide. Metastatic non-small cell lung cancer (NSCLC) has recently benefited from two consecutive breakthroughs: identifying oncogene drivers, such as EGFR mutations, to develop targeted therapies, and understanding the cancer immune cycle to develop immune checkpoint inhibitors.

[0004] Epidermal growth factor receptor (EGFR) is overexpressed, dysregulated, or mutated in many epithelial malignancies, and EGFR activation appears to be important in tumor growth and progression. EGFR activation stimulates tumor growth and progression, including promoting proliferation, angiogenesis, invasion, metastasis, and inhibiting apoptosis.

[0005] EGFR mutations are a well-validated clinical target in non-small cell lung cancer (NSCLC). Osimertinib, a highly selective mutation-targeting covalent agent, is increasingly being used as first-line treatment for NSCLC patients with EGFR L858R mutations or exon 19 deletions (Soria et al., Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 378(2):113-125). Unfortunately, while a reasonable number of NSCLC patients with EGFR mutations initially respond to EGFR therapy, most of these patients eventually experience disease progression due to acquired resistance to osimertinib after approximately 9 to 14 months of treatment. The most common mutations leading to resistance include the C797 mutations C797S and C797G (Ercan et al., ClinCan Res 2015 21(17)3913-3923). Cysteine ​​797 is the site where roxitinib and osimertinib covalently bind (Zhou et al., Nature 2009; 462:1070-4).

[0006] In patient subgroups, the co-occurrence of L858R / C797x or ex19del / C797x mutations (“double mutations”) thus became a targeted resistance mechanism, highlighting the need for new therapies, particularly in patients with CNS metastases.The exact proportion of cancers that develop resistance to first-line osimertinib through the C797x mutation is still under investigation, with the latest data analysis showing a mutation rate as high as 12.5% ​​(Choudhury et al., Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers. J Thorac Oncol. 2023 18(4):463-475; Olsen et al., Real-World Clinical Outcomes after Genomic Profiling of Circulating Tumor DNA in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer. CurrOncol. 2022 29(7):4811-4826; Ramalingam et al., Mechanisms of acquired resistance to first-line Osimertinib: Preliminary data from the phase III FLAURA study. Annals Oncol. 2018 29(suppl.). 8):viii740; Ramalingam et al., Real-world Landscape of EGFR C797X Mutation as a Resistance Mechanism to Osimertinib in Non-smallCell Lung Cancer. J Thorac Oncol. 2022 17(9, Suppl.):S67-S68; Ramalingam et al., Real-world Landscape of EGFR C797X Mutation as a Resistance Mechanism to Osimertinib in Non-small Cell Lung Cancer. Abstracts, IASLC 2022 WorldConference on Lung Cancer, Vienna, Austria. 2022).

[0007] Currently, there are no effective treatment strategies to overcome EGFR inhibitor resistance mediated by L858R / C797x or ex19del / C797x mutations (double mutations). Theoretically, first-generation reversible inhibitors can maintain efficacy against C797S double-mutant EGFR proteins. However, designing a second-generation inhibitor with improved mutation selectivity compared to wild-type EGFR could further reduce adverse events associated with targeting wild-type EGFR inhibition. In addition, the relatively lack of brain exposure to first-generation inhibitors may limit durable clinical responses, especially in patients with brain metastases (Ballard et al., Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016 22(20):5130-5140).

[0008] Additional treatment is needed. Summary of the Invention

[0009] On one hand, this disclosure relates to the use of an EGFR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancers having two or more EGFR mutations, wherein at least one of the mutations is a C797 mutation; preferably a C797S mutation. The EGFR inhibitors disclosed herein are compounds of formula (I): (I) Or its pharmaceutically acceptable salts, N-oxides, or solvates, in Indicates a carbon-carbon single bond or a carbon-carbon double bond. n is an integer from 0 to 4, preferably n = 1. R1, R2, and R3 are each independently H or (C1-C6) alkyl, preferably H or methyl. R4 and R5 are each independently (C1-C6) alkyl groups, preferably methyl. A1 is a phenyl group, which is substituted or unsubstituted by one or more (preferably one or two) substituents selected from halogen atoms, (C1-C6) alkyl groups, and (C1-C6) alkoxy groups.

[0010] On the other hand, this disclosure relates to a method of treating cancer in a subject who has two or more EGFR mutations and requires such treatment, wherein the at least one mutation is a C797 mutation, preferably a C797S mutation, the method comprising administering an EGFR inhibitor or a pharmaceutically acceptable salt thereof to the subject.

[0011] The EGFR inhibitors disclosed in this article are compounds of formula (I): (I) Or its pharmaceutically acceptable salts, N-oxides, or solvates, in Indicates a carbon-carbon single bond or a carbon-carbon double bond. n is an integer from 0 to 4, preferably n = 1. R1, R2, and R3 are each independently H or (C1-C6) alkyl, preferably H or methyl. R4 and R5 are each independently (C1-C6) alkyl groups, preferably methyl. A1 is a phenyl group, which is substituted or unsubstituted by one or more (preferably one or two) substituents selected from halogen atoms, (C1-C6) alkyl groups, and (C1-C6) alkoxy groups.

[0012] Preferably, the EGFR inhibitor is a compound of formula (A): (A) In one implementation, the EGFR mutant also includes the mutation L858R or ex19Del.

[0013] In one embodiment, EGFR carries two mutations, i.e., EGFR is an EGFR double mutant. Preferably, EGFR has the L858R / C797 or ex19del / C797 double mutation, more preferably the L858R / C797S or ex19del / C797S double mutation.

[0014] In one implementation, the patient undergoes preliminary testing for the presence of two or more EGFR mutations, one of which is the C797 mutation; preferably, the C797S mutation. Upon confirmation of the presence of two or more EGFR mutations, an EGFR inhibitor or a pharmaceutically acceptable salt thereof is administered.

[0015] In one implementation, the patient has previously been treated with osimertinib, and specifically, the previous treatment with osimertinib has failed.

[0016] In one embodiment, the cancer is lymphoma, leukemia, myeloma, acute myeloid leukemia (AML), T-ALL, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, or adrenal cancer. Preferably, the cancer is lung cancer, more preferably non-small cell lung cancer (NSCLC). In particular, the cancer can be lung cancer that has metastasized to the CNS, especially NSCLC. More particularly, the cancer can be lung cancer that has been previously treated with osimertinib and has metastasized to the CNS, especially NSCLC.

[0017] In one embodiment, the EGFR inhibitor or a pharmaceutically acceptable salt thereof is combined with one or more other cancer treatments, preferably with at least one additional therapeutic agent. For example, the at least one additional therapeutic agent may be selected from other EGFR-targeting therapies, such as osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, cetuximab, panitumumab, AZD9291, CL387785, CO1686, or WZ4002, other HER2-targeting therapies, RAS pathway-targeting therapies, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeting therapies), farnesyltransferase inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators such as obataclax, cytotoxic chemotherapy agents, angiogenesis-targeting therapies, immune-targeting agents (including immunotherapy), and radiotherapy.

[0018] In one embodiment, the EGFR inhibitor or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with the at least one additional therapeutic agent.

[0019] In one embodiment, the EGFR inhibitor or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition. Attached Figure Description

[0020] Figure 1 Compound A exhibited high selectivity in biochemical assays. Ki of compound A and the benchmark first-generation +GFR inhibitor gefitinib was determined using a chelation-enhanced fluorescence (ChEF) assay with the AQT0001 peptide substrate and recombinant EGFR kinase domain protein. Data are presented as mean ± standard deviation. Compound A showed stronger inhibitory activity against the EGFR L858R / C797S double mutant than gefitinib. The residence time of compound A on the protein mutant was approximately 4.3 hours, compared to 14 minutes for gefitinib. Compound A showed superior selectivity for the L858R / C797S double mutant compared to gefitinib.

[0021] Figure 2 Compound A maintained potent potency and selectivity in the presence of C797S. Left figure: IC50 inhibition of proliferation of the Ba / F3 line expressing the EGFR construct by compound A. 50 Values ​​(CellTiterGlo, measured at 72 hours). Right figure: Mutant selectivity of compound A, osimertinib (C297 covalent), and gefitinib (first-generation reversible) against mutations in Ba / F3 cells expressing WT EGFR. Compound A maintained potent antiproliferative activity and selectivity in the presence of the C797S double mutation and was superior to the observed values ​​of the first-generation reversible inhibitor gefitinib (double mutation value is indicated compared to WT value).

[0022] Figure 3 Compound A's potent potency and selectivity extend to human cancer cells. Left figure: IC50 inhibition of the proliferation of the stated human cancer cell line by compound A. 50 Value (CellTitleGlo). Right figure: Selectivity of compounds A, osimertinib, and gefitinib against EGFR wild-type and EGF-dependent cell lines NCI-H2073 for mutant cell lines. Compound A showed better selectivity for common EGFR mutant cell lines than the observed selectivity of osimertinib or gefitinib.

[0023] Figure 4 Compound A selectively binds to the pEGFR target. The IC50 values ​​of compound A, osimertinib, and gefitinib for inhibition of pEGFR (phosphorylated EGFR, Tyr1068) are shown. 50 AlphaLISA value. Compared to the EGFR wild-type cell line NCI-H2073, compound A showed superior selectivity for all tested EGFR mutant cell lines compared to gefitinib (showing Ba / F3 double mutation selectivity).

[0024] Figure 5 Compound A is effective and well-tolerated in vivo. In ex19del or L858R human tumor xenograft mice, administration of compound A at BID of 5 to 15 mg / kg provided robust tumor growth inhibition (90% TGI or higher). All doses were well-tolerated. Its antitumor activity is comparable to or better than that of published clinically relevant doses of gefitinib.

[0025] Figure 6 Compound A inhibited pEGFR in a PC-9 (ex19del) PK / PD study. Pharmacodynamic readings of pEGFR were modulated from 5 to 15 mg / kg (single dose), with 15 mg / kg showing greater than 50% pEGFR inhibition within a 12-hour BID dosing window.

[0026] Figure 7 Compound A maintained its in vivo activity in C797S double-mutant xenograft tumors. A PC-9-derived cell line with the ex19del / C797S cis double mutation was constructed using CRISPR knock-in technology. In the presence of C797S, compound A maintained its tumor growth inhibitory effect in vivo at a dose of 15 mg / kg BID.

[0027] Figure 8 Compound A exhibits CNS penetration comparable to osimertinib. Following oral administration in rodents with intact blood-barriers, compound A showed good brain distribution with no delay compared to plasma distribution. Compound A demonstrated high in vitro permeability (ER 1.76 for Caco-2 at 1 μM) and low efflux (ER 0.95 for MDCK-MDR1 and 1.17 for MDCK-BCRP at 1 μM). The brain exposure Kc of compound A was calculated using rat brain slices. p,uu The value is similar to that of osimertinib obtained using the same method. Detailed Implementation

[0028] definition To facilitate understanding of the disclosure herein, several additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures described herein in organic chemistry, medicinal chemistry, and pharmacology are well-known and conventionally used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Every patent, application, published application, and other publication mentioned in this specification and its appendices is incorporated herein by reference in its entirety.

[0029] As used in this article, the term "acceptable" in relation to a formulation, composition, or ingredient means that it will not have a lasting harmful effect on the overall health of the subject receiving the treatment.

[0030] As used herein, the term “application” means administering, in any suitable manner, a therapeutically effective dose of a compound or composition disclosed herein to cells in a cell culture or in a patient (i.e., a subject).

[0031] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an amount of a chemical entity applied sufficient to alleviate one or more symptoms of the disease or condition being treated to a certain degree. The results include a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or the production of any other desired alterations to the biological system. For example, an "effective amount" for therapeutic use refers to the amount of a composition containing compounds disclosed herein required to provide a clinically significant improvement in the symptoms of a disease. In any individual case, the appropriate "effective" amount is determined using any suitable technique, such as dose escalation studies.

[0032] The term "excipient" or "pharmaceuticalally acceptable excipient" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceuticalally acceptable," meaning it is compatible with other components in the pharmaceutical formulation and suitable for use in contact with human and animal tissues or organs without causing excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice ofPharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nded.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0033] As used in this article, the term "epidermal growth factor receptor (EGFR) mutant" refers to EGFR with at least one disease-associated activating mutation. EGFR mutants may also include other mutations, including drug resistance mutations such as T790M and / or C797S. In particular, the term "EGFR double mutant" as used in this article refers to EGFR containing both an activating mutation (e.g., ex19del or L858R) and a resistance mutation (e.g., T790 mutation (e.g., T790M) or C797 mutation (e.g., C797S)). ex19del refers to an in-frame deletion occurring in exon 19 of EGFR (which encodes a partial kinase domain). These deletions primarily occur between codons 746 and 759. It is one of the most common EGFR mutations in lung cancer, occurring in approximately 40% of EGFR-positive NSCLC patients.

[0034] The term "non-small cell lung cancer" as used in this article includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma, and sarcomatoid carcinoma.

[0035] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not impair the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In other cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acidic group to a base to form a salt, such as ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), salts formed with organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, tris(hydroxymethyl)methylamine, etc., and salts formed with amino acids such as arginine and lysine, or by other previously determined methods. There are no particular limitations on the pharmaceutically acceptable salts provided they can be used in a drug. Examples of salts formed by the compounds described herein with bases include: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically examples of addition salts with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0036] The term "pharmaceutical composition" refers to a mixture of the compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. The pharmaceutical composition facilitates the administration of the compound to a living organism. Various methods of compound administration exist in the art, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0037] As used herein, the terms “subject,” “individual,” or “patient” are used interchangeably and refer to any animal, including mammals and primates (e.g., humans), such as mice, rats, other rodents, rabbits, dogs, cats, domestic pigs, pigs, cows, goats, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or condition to be treated.

[0038] As used herein, the term “treat” or “treatment” refers to a therapeutic or palliative measure. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial relief of symptoms associated with the disease or condition, reduction of disease severity, stabilization (i.e., non-exacerbation) of the disease state, delay or slowing of disease progression, improvement or palliative care of the disease state (e.g., one or more symptoms of the disease), and relief (whether partial or complete), whether detectable or undetectable. “Treatment” may also mean extended survival compared to expected survival without treatment.

[0039] Treatment methods for cancers carrying EGFR double mutations Patent application WO 2022 / 066734A1 discloses novel inhibitors of epidermal growth factor receptor (EGFR, ERBB1), particularly inhibitors of EGFR mutants. This disclosure is partly based on the findings that the compounds described herein, such as compounds of formula (I), such as compound A, exhibit both (i) relatively high potency and selectivity as inhibitors of EGFR double mutants, including L858R / C797x or ex19del / C797x mutations; and (ii) robust CNS penetration. Indeed, the compounds described herein have shown potent potency and selectivity against EGFR double mutants (e.g., EGFR L858R / C797S and ex19del / C797S double mutants), as well as robust CNS penetration. It is known that the C7997 mutation in EGFR confers resistance to osimertinib (Ercan et al., Clin Can Res 2015 21(17)3913-3923). The inhibitors of this invention specifically target EGFR mutants carrying the C797x combination of other resistance mutations, and are therefore particularly suitable for treating cancers resistant to osimertinib.

[0040] Therefore, a first aspect of this disclosure relates to an EGFR inhibitor or a pharmaceutically acceptable salt thereof for treating cancers having two or more EGFR mutations, wherein said EGFR inhibitor is a compound of formula (I): (I) Or its pharmaceutically acceptable salts, N-oxides, or solvates, in Indicates a carbon-carbon single bond or a carbon-carbon double bond. n is an integer from 0 to 4, preferably n = 1. R1, R2, and R3 are each independently H or (C1-C6) alkyl, preferably H or methyl. R4 and R5 are each independently (C1-C6) alkyl groups, preferably methyl. A1 is a phenyl group, which is substituted or unsubstituted by one or more (preferably one or two) substituents selected from halogen atoms, (C1-C6) alkyl groups, and (C1-C6) alkoxy groups.

[0041] Preferably, R1, R2, and R3 are H.

[0042] Preferably, R4 and R5 are methyl groups.

[0043] Advantageously, A1 is a phenyl group, which is substituted or unsubstituted by one or two substituents selected from halogen atoms and (C1-C6) alkoxy groups.

[0044] when When representing a carbon-carbon single bond, the compound of formula (I) can be in the form of (S)-type enantiomers, (R)-type enantiomers, or mixtures thereof, including racemic mixtures thereof. Preferably, the compound of formula (I) is in the form of (S)-type enantiomers.

[0045] Preferably, the EGFR inhibitor is a compound of formula (A): (A) In the above formula, (*) represents a stereochiral center. The method for synthesizing the compounds of this invention is disclosed in WO 2022 / 066734A1.

[0046] This disclosure also relates to a method of treating cancers with two or more EGFR mutations in patients in need, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof. This disclosure further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancers with two or more EGFR mutations.

[0047] In one embodiment, one of the EGFR mutations is the EGFR C797 mutation. As used herein, a “C797” or “C797x” mutation refers to any substitution of cysteine ​​residue 797 in the EGFR. Mutations of this residue known to alter the sensitivity of the EGFR to osimertinib include C797S and C797G. Preferably, one of the EGFR mutations is the C797S mutation.

[0048] More preferably, the EGFR mutant has an EGFR C797 mutation (optionally with a C797S mutation) and also contains an EGFR mutation L858R or ex19Del.

[0049] In particular, the EGFR mutant is an EGFR double mutant, meaning that there are two mutations affecting EGFR.

[0050] In a preferred embodiment, the EGFR mutant is the L858R / C797 or ex19del / C797EGFR mutant. Even more preferably, the EGFR mutant is the L858R / C797S or ex19del / C797SEGFR mutant.

[0051] In some embodiments, the cancer is lymphoma, leukemia, myeloma, acute myeloid leukemia (AML), T-ALL, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, or adrenal cancer. Preferably, the cancer is lung cancer. More preferably, the lung cancer is non-small cell lung cancer (NSCLC). The NSCLC may be adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma, or sarcomatoid carcinoma.

[0052] EGFR-mutant NSCLC is known to frequently metastasize to the central nervous system (CNS), leading to poor prognosis and limited treatment options. In particular, the treatment of CNS metastases is especially challenging due to the limited pathways for molecules to cross the blood-CSF and blood-brain barriers (Ahluwalia et al., Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Central Nervous System Metastases from Non-Small Cell Lung Cancer. Oncologist. 2018 23(10):1199-1209).

[0053] Surprisingly, the EGFR inhibitors described in this article exhibit robust CNS penetration, making them particularly suitable for treating NSCLC patients carrying EGFR double mutants that have metastasized to the CNS.

[0054] Therefore, the cancers treated by the methods disclosed herein can be NSCLC with EGFR double mutations, such as NSCLC with L858R / C797 or ex19del / C797 EGFR double mutations, especially NSCLC with L858R / C797S or ex19del / C797S EGFR double mutations, wherein the NSCLC has metastasized to the CNS.

[0055] In some implementations, the patient is first tested for two or more EGFR mutations, particularly the EGFRC797 mutation, optionally the C797S mutation, and combinations of EGFR mutations L858R or ex19Del. For example, samples from the patient (e.g., tissue samples, lung cancer biopsy samples, or liquid biopsy samples, such as blood or plasma samples used to detect tumor-derived DNA and / or circulating tumor cells or circulating exosomes) are tested for mutations. Suitable tissue sample acquisition methods include tissue biopsy, endobronchial biopsy, transbronchial biopsy, brushing cytology, irrigation cytology, fine-needle aspiration cytology, body fluid cytology, or bone biopsy. EGFR mutation detection can be performed using any suitable analytical technique, including real-time quantitative polymerase chain reaction (PCR), allele-specific PCR, or nucleic acid sequencing. Suitable tests include Therascreen® EGFR RGQPCR kit (Qiagen), Cobas® EGFR Mutation Test v2 (Roche), FoundationOne CDx™ (Foundation Medicine), Oncomine™ Dx Target Test (Thermo Fisher Scientific), Guardant360™ (Guardant Health), GeneStrat (Biodesix), OncoBEAM™ (SysmexInostics), ExoDx® Lung (T790M) (Exosome Diagnostics), and Biocept liquid biopsy. If a mutation is present, the patient is given a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0056] On the other hand, the patient has previously received a chemotherapy regimen. Preferably, the cancer has failed treatment with at least one previous chemotherapy regimen. For example, the cancer is cancer that has failed treatment with at least one previous osimertinib regimen. Indeed, for patients with EGFR-mutant cancers, particularly NSCLC, the available strategies are limited after disease progression on osimertinib treatment. The presence of EGFR C797S mutations has been described as one of the most common mechanisms for developing resistance to osimertinib exposure. Notably, through studies of the molecular signatures in progression, the presence of the EGFR sensitization mutation C797S has been reported to lead to resistance to osimertinib. Therefore, any compound that is effective against tumors exhibiting the C797S mutation is an excellent candidate for treating patients who have failed osimertinib treatment.

[0057] In one embodiment, the EGFR inhibitor disclosed herein is therefore used to treat cancer, wherein the treatment comprises administering the EGFR inhibitor to a patient who has previously been treated with osimertinib. This disclosure also relates to a method of treating cancer in a patient in need, wherein the method comprises administering the EGFR inhibitor to the patient, and the patient has previously been treated with osimertinib. This disclosure further relates to the use of the EGFR inhibitor in the preparation of a medicament for treating cancer, wherein the treatment comprises administering the EGFR inhibitor to a patient who has previously been treated with osimertinib. Preferably, the cancer has failed in a previous round of osimertinib treatment. The cancer may in particular be lung cancer, such as non-small cell lung cancer (NSCLC). In particular, the cancer may be lung cancer that has metastasized to the CNS, especially NSCLC. More particularly, the cancer may be lung cancer that has been previously treated with osimertinib and has metastasized to the CNS, especially NSCLC.

[0058] Treatment with the EGFR inhibitors disclosed in this article can also be combined with one or more other cancer treatments.

[0059] Cancer treatment can include, for example, surgery, chemotherapy, adjuvant therapy, radiation therapy, other targeted therapies, or combinations thereof.

[0060] For example, a compound of formula (I) (or a pharmaceutically acceptable salt thereof) may be combined with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional treatments or therapeutic agents (e.g., chemotherapeutic agents).

[0061] In particular, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) may be administered simultaneously, separately or sequentially with at least one additional therapeutic agent.

[0062] Non-limiting examples of additional therapeutic agents include: other EGFR-targeted therapies (i.e., first or second EGFR inhibitors), such as osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, cetuximab, panitumumab, AZD-9291, CL-387785, CO-1686, or WZ4002; other HER2-targeted therapies (i.e., first or second HER2 inhibitors); RAS pathway-targeted therapies; PARP inhibitors; other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapies (e.g., Trk inhibitors or multi-kinase inhibitors)); farnesyltransferase inhibitors; signal transduction pathway inhibitors; checkpoint inhibitors; apoptosis pathway modulators (e.g., oxacral); cytotoxic chemotherapy agents; angiogenesis-targeted therapies; immune-targeting agents (including immunotherapy); and radiation therapy.

[0063] In some implementations, the additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0064] Pharmaceutical Composition As is readily apparent, compounds of formula (I) or their pharmaceutically acceptable salts are typically administered to patients in the form of pharmaceutical compositions.

[0065] Therefore, this specification also provides a pharmaceutical composition comprising a compound of formula (I) as described above and at least one pharmaceutically acceptable excipient for the medical uses disclosed herein.

[0066] The form, route of administration, dosage, and administration regimen of a drug composition naturally depend on the condition to be treated, the severity of the disease, the patient's age, weight, and gender.

[0067] The pharmaceutical compositions of the present invention can be formulated for topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular, or subcutaneous administration.

[0068] Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable medium for use in injectable formulations. These mediums may in particular be isotonic, sterile saline solutions (sodium dihydrogen phosphate or disodium hydrogen phosphate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., or mixtures of such salts), or dry (especially lyophilized) compositions that, depending on the circumstances, can be prepared into injectable solutions by adding sterile water or saline.

[0069] The dosage used for application can be adjusted according to various parameters, especially according to the method of application, the relevant pathological conditions, or the required duration of treatment.

[0070] The active ingredient can be administered to animals or humans in the form of an administration unit mixed with a conventional pharmaceutical carrier. Suitable administration unit forms include oral administration, sublingual or buccal administration, parenteral administration (subcutaneous, intradermal, intramuscular, or intravenous), topical administration (to the skin and mucous membranes, including intranasal and intraocular administration), and rectal administration.

[0071] Such compositions can be in the form of solids, liquids, emulsions, lotions, or creams. As solid compositions, oral administration can be in the form of tablets, pills, powders (hard capsules or soft capsules), or granules. In these compositions, the active ingredient of this disclosure is mixed with one or more inert diluents (such as starch, cellulose, sucrose, lactose, or silica) in an argon gas stream. These compositions may also contain substances other than diluents, such as one or more lubricants (such as magnesium stearate or talc), colorants, coatings (coated tablets), or varnishes.

[0072] As a liquid composition for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs may be used, and may contain an inert diluent (such as water, ethanol, glycerin, vegetable oil, or paraffin oil). These compositions may contain substances other than diluents, such as wetting agents, sweeteners, thickeners, flavoring agents, or stabilizers.

[0073] Sterile compositions for parenteral administration are preferably aqueous or non-aqueous solutions, suspensions, or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils (particularly olive oil), injectable organic esters (e.g., ethyl oleate), or other suitable organic solvents can be used as solvents or media. These compositions may also contain adjuvants, particularly wetting agents, isotonic agents, emulsifiers, dispersants, and stabilizers. Sterilization can be performed by various methods, such as sterile filtration, addition of a sterilizing agent to the composition, radiation, or heating. Such compositions can also be formulated as solid sterile compositions that dissolve in sterile water or any other injectable sterile medium when used.

[0074] Compositions for rectal administration are suppositories or rectal capsules that, in addition to the active ingredient, contain excipients (such as cocoa butter, semi-synthetic glycerides, or polyethylene glycol).

[0075] Compositions for topical application may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops, or sprays.

[0076] Dosage depends on the desired effect, duration of treatment, and route of administration. Typically, a physician will determine the appropriate dosage based on the patient's age, weight, and all other specific factors.

[0077] The pharmaceutical compositions disclosed herein may also contain additional therapeutic agents. In particular, the pharmaceutical compositions disclosed herein may contain one or more of the following substances: other EGFR-targeting therapeutic agents (i.e., first or second EGFR inhibitors), such as osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, cetuximab, panitumumab, AZD-9291, CL-387785, CO-1686 or WZ4002; other HER2-targeting therapeutic agents (i.e., first or second HER2 inhibitors); RAS pathway-targeting therapeutic agents; PARP inhibitors; other kinase inhibitors (e.g., receptor tyrosine kinase-targeting therapeutic agents (e.g., Trk inhibitors or multi-kinase inhibitors)); farnesyltransferase inhibitors; signal transduction pathway inhibitors; checkpoint inhibitors; apoptosis pathway modulators (e.g., oxacral); cytotoxic chemotherapy agents; angiogenesis-targeting therapeutic agents; immune-targeting agents (including immunotherapy); and radiation therapy.

[0078] In some implementations, the additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0079] dose Dosage can vary depending on patient requirements, the severity of the condition being treated, and the specific compound used. Medical professionals can determine the appropriate dosage for a given situation. The total daily dose can be administered in divided doses throughout the day or via continuous administration.

[0080] In some embodiments, the compounds described herein are administered at doses of about 0.001 mg / kg to about 500 mg / kg (e.g., about 0.001 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 150 mg / kg; about 0.01 mg / kg to about 100 mg / kg; about 0.01 mg / kg to about 50 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 5 mg / kg; about 0.01 mg / kg to about 1 mg / kg; about 0.01 mg / kg to about 0.5 mg / kg; about 0.01 mg / kg to about 0.1 mg / kg; about 0.1 mg / kg to about 200 mg / kg; about 0.1 mg / kg to about 150 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 5 ... Administer at a dose of approximately 10 mg / kg; approximately 0.1 mg / kg to approximately 5 mg / kg; approximately 0.1 mg / kg to approximately 1 mg / kg; approximately 0.1 mg / kg to approximately 0.5 mg / kg.

[0081] Application plan The above dosages may be administered daily (e.g., once or twice or more), or non-daily (e.g., once every other day, once every two days, once every three days, once a week, twice a week, once every two weeks, or once a month).

[0082] In some embodiments, the application period of the compound described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In another embodiment, the discontinuation period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one implementation, a therapeutic compound is administered to an individual for a period of time, followed by another period of time. In another implementation, the therapeutic compound is administered for a first period of time, followed by a second period of time, during which administration is stopped, then a third period of time, during which administration of the therapeutic compound begins, followed by a fourth period of time, during which administration is stopped. In one aspect of this implementation, the administration period of the therapeutic compound is repeated within a defined or undefined period of time, followed by a period of cessation of administration. In another implementation, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In another implementation, the withdrawal period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

[0083] The present invention will now be described in detail with reference to the embodiments. However, the following embodiments are only for illustrative purposes and are obviously not limited to the following embodiments.

[0084] Example To characterize the potency and selectivity (compared to EGFR wild-type) of compound A as an inhibitor of the C797S active double mutation in vitro and in vivo, compound A was evaluated in vitro and in vivo in various engineered or endogenous single (ex19del or L858R) or double (ex19del / C797S or L858R / C797S) mutant systems. Furthermore, CNS exposure of compound A was characterized using the gold standard rat brain slice method to assess its free exposure in brain tissue.

[0085] Materials and methods: Compound A is an EGFR inhibitor of formula I(a). The potency of compound A against EGFR L858R and ex19del single mutants and / or the corresponding C797S double mutants was tested through a series of in vitro biochemical, cell signaling, and proliferation assays. Furthermore, the in vivo activity of compound A was tested in mice carrying human NSCLC cell line xenografts (NCI-H3255 (L858R) and PC-9 (ex19del)) and PC-9-derived ex19del / C797S double mutant knock-in xenografts. Free CNS penetration (Kp,uu) was determined in tumor-free mice and rats. Osimertinib and / or gefitinib were used as baseline molecules in the experiments.

[0086] result: Compound A is a novel ATP-competitive reversible EGFR inhibitor that exhibits potent and selective inhibition of the recombinant EGFR L858R / C797S EGFR mutant protein compared to wild-type EGFR, with an increased residence time for the mutant compared to the approved reversible EGFR inhibitor gefitinib. In proliferation assays using engineered Ba / F3 cells and human NSCLC cell lines, potent (high picomolar to low nanomolar) inhibition of L858R, ex19del, L858R / C797S, and ex19del / C797S mutants was observed. In engineered Ba / F3 cells and human cancer cells, selectivity greater than 150-fold compared to wild-type EGFR was demonstrated for all tested mutants, a level of selectivity higher than that observed in gefitinib. Pharmacodynamic analyses measuring EGFR pathway activation (pEGFR) also revealed the potent potency and dual mutant selectivity of Compound A. Compound A was well tolerated in mice at doses of 15 mg / kg BID or 50 mg / kg QD, and regression of EGFR single mutant xenografts was observed, accompanied by inhibition of the EGFR pathway. Notably, using a pair of syngeneic PC-9 (EGFR ex19del) NSCLC xenografts differing only in the presence of the C797S mutation, it was shown that the antitumor activity of compound A was not diminished in the presence of C797S. In pharmacokinetic studies measuring free CNS penetration in mice and rats, the Ka of compound A was [data missing]. p,uu The measured value was comparable to that of osimertinib, which served as a parallel baseline.

[0087] in conclusion Compound A exhibited potent biochemical inhibition of EGFR double mutant kinase activity and showed broader selectivity than the first-generation reversible compound gefitinib.

[0088] Compound A demonstrated greater potency and selectivity against the C797S double mutant compared to wild-type EGFR in proliferation and target binding assays. In double mutant cell lines, compound A was observed to have superior in vitro potency and selectivity compared to gefitinib.

[0089] Compound A exhibited potent in vivo antitumor activity in the tested single-mutant and double-mutant CDX models, and maintained its in vivo activity in the presence of the C797S mutation.

[0090] Compound A exhibits low efflux and good unbound exposure in brain tissue, with brain exposure comparable to osimertinib, offering the potential to address CNS metastases.

[0091] Preclinical data for compound A suggest that it is a potential best-in-class fourth-generation EGFR double mutant inhibitor.

Claims

1. The use of an EGFR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancers having two or more EGFR mutations. At least one of the mutations is the C797 mutation; preferably the C797S mutation, and The EGFR inhibitor mentioned above is a compound of formula (I): （I）， Or its pharmaceutically acceptable salts, N-oxides, or solvates, in Indicates a carbon-carbon single bond or a carbon-carbon double bond. n is an integer from 0 to 4, preferably n = 1. R1, R2, and R3 are each independently H or (C1-C6) alkyl, preferably H or methyl. R4 and R5 are each independently (C1-C6) alkyl groups, preferably methyl. A1 is a phenyl group, which is substituted or unsubstituted by one or more (preferably one or two) substituents selected from halogen atoms, (C1-C6) alkyl groups, and (C1-C6) alkoxy groups.

2. The EGFR inhibitor for use according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the EGFR inhibitor is a compound of formula (A): （A）。 3. An EGFR inhibitor for use according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the EGFR mutant further comprises a mutant L858R or ex19Del.

4. The EGFR inhibitor for use according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the EGFR carries two mutations.

5. The EGFR inhibitor for use according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the EGFR has an L858R / C797 or ex19del / C797 double mutation, preferably an L858R / C797S or ex19del / C797S double mutation.

6. The EGFR inhibitor for use according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, further comprising the step of pre-detecting the presence of two or more EGFR mutations in a patient, wherein one of said mutations is a C797 mutation; preferably a C797S mutation.

7. An EGFR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 6, said use comprising administering said EGFR inhibitor to a patient previously treated with osimertinib.

8. The EGFR inhibitor for use according to claim 7, or a pharmaceutically acceptable salt thereof, wherein prior treatment with osimertinib has failed.

9. An EGFR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 8, wherein the cancer is lymphoma, leukemia, myeloma, acute myeloid leukemia (AML), T-ALL, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, or adrenal cancer.

10. The EGFR inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the cancer is lung cancer, preferably non-small cell lung cancer (NSCLC).

11. The EGFR inhibitor for use according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the NSCLC is transferred to the CNS.

12. An EGFR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 11, wherein the use comprises combining the EGFR inhibitor or a pharmaceutically acceptable salt thereof with one or more other cancer treatments, preferably with at least one additional therapeutic agent.

13. The EGFR inhibitor for use according to claim 12, or a pharmaceutically acceptable salt thereof, wherein the at least one additional therapeutic agent is selected from other EGFR-targeting therapeutic agents, such as osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, cetuximab, panitumumab, AZD-9291, CL-387785, CO-1686 or WZ4002, other HER2-targeting therapeutic agents, RAS pathway-targeting therapeutic agents, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeting therapeutic agents), farnesyltransferase inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators such as oxacral, cytotoxic chemotherapeutic agents, angiogenesis-targeting therapeutic agents, immune-targeting agents, including immunotherapy, and radiotherapy.

14. An EGFR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 12 or 13, wherein the EGFR inhibitor or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with the at least one additional therapeutic agent.

15. An EGFR inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein the EGFR inhibitor or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition.

16. A method of treating cancer with two or more EGFR mutations in a subject requiring such treatment, the method comprising administering to the subject an effective amount of an EGFR inhibitor or a pharmaceutically acceptable salt thereof; The at least one mutation is the C797 mutation; preferably the C797S mutation, and The EGFR inhibitor mentioned above is a compound of formula (I): （I）， Or its pharmaceutically acceptable salts, N-oxides, or solvates, in Indicates a carbon-carbon single bond or a carbon-carbon double bond. n is an integer from 0 to 4, preferably n = 1. R1, R2, and R3 are each independently H or (C1-C6) alkyl, preferably H or methyl. R4 and R5 are each independently (C1-C6) alkyl groups, preferably methyl. A1 is a phenyl group, which is substituted or unsubstituted by one or more (preferably one or two) substituents selected from halogen atoms, (C1-C6) alkyl groups, and (C1-C6) alkoxy groups.

17. The method of claim 16, wherein the EGFR inhibitor is a compound of formula (A): （A）。 18. The method according to any one of claims 16 or 17, wherein the EGFR mutant further comprises the mutant L858R or ex19Del.

19. The method of claim 18, wherein the EGFR carries two mutations.

20. The method of claim 19, wherein the EGFR has a double mutation of L858R / C797 or ex19del / C797, preferably a double mutation of L858R / C797S or ex19del / C797S.

21. The method according to any one of claims 16 to 20, further comprising the step of pre-detecting the presence of two or more EGFR mutations in the patient, wherein one of the mutations is a C797 mutation; preferably a C797S mutation.

22. The method according to any one of claims 16 to 21, the method comprising administering the EGFR inhibitor to a patient previously treated with osimertinib.

23. The method of claim 22, wherein the prior treatment with osimertinib has failed.

24. The method according to any one of claims 16 to 23, wherein the cancer is lymphoma, leukemia, myeloma, acute myeloid leukemia (AML), T-ALL, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, or adrenal cancer.

25. The method of claim 24, wherein the cancer is lung cancer, preferably non-small cell lung cancer (NSCLC).

26. The method of claim 25, wherein the NSCLC is transferred to the CNS.

27. The method according to any one of claims 16 to 26, wherein the EGFR inhibitor or a pharmaceutically acceptable salt thereof is combined with one or more other cancer treatments, preferably with at least one additional therapeutic agent.

28. The method of claim 27, wherein the at least one additional therapeutic agent is selected from other EGFR-targeted therapeutic agents, such as osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, cetuximab, panitumumab, AZD-9291, CL-387785, CO-1686 or WZ4002, other HER2-targeted therapeutic agents, RAS pathway-targeted therapeutic agents, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents), farnesyltransferase inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators such as oxacral, cytotoxic chemotherapy agents, angiogenesis-targeted therapeutic agents, immune-targeting agents, including immunotherapy, and radiotherapy.

29. The method according to any one of claims 27 or 28, wherein the EGFR inhibitor or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with the at least one additional therapeutic agent.

30. The method according to any one of claims 16 to 29, wherein the EGFR inhibitor or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition.

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