Treatment methods for patients with non-small cell lung cancer exhibiting EGFR abnormalities

Abstract

A method for treating a subject having cancer with at least one abnormality in EGFR, wherein the subject is administered (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide (also known as diparereltinib and TAS6417) or a pharmaceutically acceptable salt thereof, to a subject that has been previously treated with a molecularly targeted therapy. The molecularly targeted therapy may be an EGFR-targeted therapy other than compound (1) or a non-EGFR-targeted therapy. The method may optionally involve administering an additional therapeutic agent to the subject.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Application Nos. 63 / 523,518, 63 / 523,572, both filed on Jun. 27, 2023, and 63 / 650,590 filed on May 22, 2024, each of which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] The present invention relates to a method for treating cancers having an abnormality in EGFR.

[0003] Description of Related Art In patients with advanced or metastatic NSCLC harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations, current lung cancer treatment guidelines recommend standard platinum-based chemotherapy as the first-line treatment. This regimen is preferred due to the low response rates observed with monotherapy of first-, second-, and third-generation EGFR-tyrosine kinase inhibitors (TKIs) in patients with EGFR ex20ins mutations. See National Comprehensive Cancer Network.NCCN guidelines.Non-small cell lung cancer version 3.2022.J Natl Compr Canc Netw.2022;20:497-530. Real-world evidence analyses of overall survival (OS) and progression-free survival (PFS) outcomes show that patients with advanced NSCLC harboring EGFR ex20ins mutations have better outcomes with platinum-based chemotherapy as first-line treatment compared to standard EGFR TKIs. However, the outcomes for these patients remain unsatisfactory regardless of subsequent therapy lines. See Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon20 insertion mutations and common EGFR mutations. Lung Cancer. 2021;162:154-161. Furthermore, cancer immunotherapy does not appear to provide the same benefit in patients with NSCLC harboring EGFR ex20ins mutations as it would in patients with advanced NSCLC without actionable mutations.See Remon J, Hendriks LEL, Cardona AF, Besse B. EGFR exon20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treat Rev. 2020;90:102105, Minchom A, Viteri S, Bazhenova L, et al. Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon20 insertion mutations who progressed after platinum-based chemotherapy. Lung Cancer. 2022;168:74-82.

[0004] Despite the recent accelerated / conditional approvals of amivantamab (US, EU, and Canada) and mobosertinib (US and China) for EGFR ex20ins patients whose locally advanced or metastatic disease has not been treated with platinum-based chemotherapy, there remains an unmet medical need for well-tolerated and effective treatment options that specifically target EGFR ex20ins mutations, particularly in the context of first-line treatment. Furthermore, due to the narrow therapeutic range between EGFR ex20ins inhibition and wild-type (WT) EGFR, currently available EGFR ex20ins-specific TKIs such as mobosertinib frequently cause rashes and diarrhea. Amivantamab, a bispecific antibody targeting EGFR and mesenchymal-epithelial transition factor (MET), requires intravenous administration and frequently causes infusion reactions (IRRs). While more effective for some patients, amivantamab treatment has the additional drawback of requiring intravenous administration and is associated with adverse events including rash, infusion-related reactions, infected skin around the nails, muscle and arthralgia, shortness of breath, nausea, fatigue, swelling of the hands, ankles, feet, face, or entire body, mouth pain, cough, constipation, vomiting, and changes in certain blood tests (e.g., decreased albumin levels, increased glucose levels, increased liver enzymes).

[0005] Therefore, despite recent advances in the development of EGFR ex20ins-targeted therapies, there remains a critical need for novel drugs that maximize clinical efficacy while achieving a more favorable safety profile.

[0006] Considering the above, there is a need for new treatment methods for patients with cancer that has EGFR abnormalities, particularly for patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations. [Overview of the Initiative]

[0007] Diparereltinib (CLN-081 / TAS6417) is a novel EGFR tyrosine kinase inhibitor (TKI) with broad activity against EGFR mutations (including ex20ins) and increased selectivity for ex20ins compared to wild-type (WT) EGFR. In cell-based assays using genetically engineered cell lines, diparereltinib potently inhibited intracellular phosphorylation of mutant EGFR, including EGFR with a wide range of ex20ins mutations. Its inhibitory activity was more potent against mutant EGFR than against WT EGFR, and diparereltinib exhibits significant antitumor activity in vivo against cancer xenografts with EGFR ex20ins mutations. See Udagawa H, Hasako S, Ohashi A, et al. TAS6417 / CLN-081 is a pan-mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical activity against clinically relevant EGFR mutations. Mol Cancer Res. 2019;17:2233-2243. The high specificity and selectivity of mutant EGFR (e.g., ex20ins mutant EGFR) to wild-type EGFR gives diparereltinib (TAS6417) a more promising side effect or adverse effect profile. Higher specificity and selectivity allow for the use of high doses of diparereltinib and longer-term administration without causing widespread adverse effects. The lower the impact on wild-type EGFR that is not related to cancer or tumors, the broader the therapeutic range of diparereltinib, offering a clear advantage over other EGFR-targeted therapies. Therefore, diparereltinib represents a significant improvement over existing therapies.

[0008] Therefore, one aspect of the present invention is to provide a method for treating a subject having cancer with an abnormality in EGFR.

[0009] Another aspect of the present invention is to provide a method for treating subjects having cancer having an EGFR exon 20 insertion mutation, including locally advanced and / or metastatic cancers.

[0010] Another aspect of the present invention is to provide a method for treating a subject having cancer with an EGFR exon 20 insertion mutation that has metastasized to the brain.

[0011] Another aspect of the present invention is to provide a method for treating a subject having cancer with an EGFR exon 20 insertion mutation that has already been treated with at least one TKI agent.

[0012] These and other embodiments, which will become apparent during the following detailed description, are achieved by our discovery that a treatment method involving the administration of both (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof to a subject, with or without the presence of additional therapeutic agents to patients who have previously received treatment with molecularly targeted therapies, is effective and can be used to treat cancers with EGFR abnormalities listed above, particularly non-small cell lung cancer. The present invention has the following embodiments:

[0013] A method for treating a subject having cancer having at least one abnormality in EGFR, comprising administering to the subject an effective amount of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indridine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof. The structure of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indridine-8-yl)acrylamide is shown below and is referred to herein as compound (1): [ka] The subject has previously been treated with systemic therapy consisting of at least one selected from the group comprising chemotherapy agents and molecularly targeted therapies.

[0014] (2) The method according to (1), wherein the cancer is a solid tumor.

[0015] (3) The method according to any one of (1) or (2), wherein the cancer is lung cancer.

[0016] (4) The method according to any one of (1) to (3), wherein the cancer is non-small cell lung cancer.

[0017] (5) The method according to (4), wherein the non-small cell lung cancer is non-squamous non-small cell lung cancer.

[0018] (6) The method according to any one of (1) to (5), wherein the cancer is selected from the group consisting of locally advanced cancer and cancer that has metastasized to the brain of the subject.

[0019] (7) The method according to any one of (1) to (6), wherein the cancer is locally progressive.

[0020] (8) The method according to any one of (1) to (7), wherein the cancer is unresectable.

[0021] (9) The method according to any one of (1) to (8), wherein the cancer has metastasized to the brain of the subject.

[0022] (10) The method according to any one of (1) to (9), wherein the cancer has EGFR amplification / overexpression.

[0023] (11) The method according to any one of (1) to (10), wherein the cancer has an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.

[0024] (12) The method according to any one of (1) to (11), wherein the cancer has an EGFR mutation in exon 20.

[0025] (13) The method according to any one of (1) to (12), wherein the cancer has an EGFR exon 20 insertion mutation.

[0026] (14) EGFR exon 20 insertion mutations include D770_N771insX, V769_D770insX, H773_V774insX, P772_H773insX, N771_P772insX, A763_Y764insX, V774_C775insX, D761_E762insX, A767_S768insX, S768_V769insX, Y764_V765insX, V765_M766insX, A763_Y764insFQEA, A767_S768insTLA, S768_V769insVAS, S768_V769ins AWT, V769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V769_D770insGVV, V769_D770insMASVD, V769_D770insASV, V769_D770 insGE, V769_D770delInsDGEL, D770_N771insSVD, D770_N771insNPG, D770_N771insKH, D770_N771insGNPH, D770_N771insAPW, D770_N771insD, D770_ N771insDG, D770delinsGY, D770_N771insGL, D770_N771insN, D770_N771insNPH, D770_N771insSVP, D770_N771insSVQ, D770_N771insMATP, D770_N7 71insG, D770_N771insY, D770_N771insGF, D770_N771insGT, delD770insGY, N771_P772insH, N771_P772insN, delN771insGY, delN771insGF, N771del insGY, N771_P772insRH, P772_H773insPR, P772_H773insYNP, P772_H773insDPH, P772_H773insDNP, P772_H773insQV, P772_H773insTPH, P772_H773i nsN, P772_H773insV, P772_H773insNP, P772_H773insNPH, H773_V774insH, H773_V774insNPH, H773_V774insPH, H773_V774insGNPH, H773_V774insG,The method according to (13), which is at least one selected from the group consisting of H773_V774insGH, H773_V774insAH, H773_V774delInsLM, H773_V774delInsTY, and V774_C775insHV.

[0027] (15) The method according to any one of (1) to (14), wherein the subject is determined to have the abnormality in EGFR before administration.

[0028] (16) The method according to any one of (1) to (15), wherein (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is orally administered to the subject.

[0029] (17) The method according to any one of (1) to (16), wherein (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice a day (BID).

[0030] (18) The method according to any one of (1) to (17), wherein (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-৮-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered daily to the subject for a treatment cycle lasting 21 days.

[0031] (19) The method according to any one of (1) to (18), wherein about 10 to about 500 mg of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject.

[0032] (20) The method according to any one of (1) to (19), wherein approximately 30 to approximately 300 mg per day of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject.

[0033] (21) The method according to any one of (1) to (20), wherein the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject in at least one form selected from the group consisting of tablets and capsules.

[0034] (22) The method of (21), wherein the tablet or capsule comprises a pharmaceutically acceptable carrier.

[0035] (23) The method according to any one of (1) to (22), further comprising administering an effective amount of an additional therapeutic agent to the subject.

[0036] (24) The method according to (23), wherein the additional therapeutic agent is at least one selected from the group consisting of chemotherapeutic agents, tyrosine kinase inhibitors, and immunotherapeutic agents.

[0037] (25) The method according to (24), wherein the chemotherapeutic agent is a platinum anticancer agent.

[0038] (26) The method according to any one of (1) to (25), wherein the systemic treatment is systemic treatment with a molecularly targeted drug selected from the group consisting of EGFR-targeted drugs other than compound (1) and non-EGFR-targeted drugs.

[0039] (27) The method according to (26), wherein the EGFR-targeting therapeutic agent other than compound (1) is at least one selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobocertinib, razertinib, sunbozertinib, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rosiletinib, vandetanib, lapatinib, durigotuzumab, panitumumab, zaltumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imugatuzumab, matsuzumab, and nimotuzumab.

[0040] (28) The method according to (27), wherein the EGFR-targeting therapeutic agent other than compound (1) is osimertinib.

[0041] (29) The method according to any one of (27) to (28), wherein the EGFR-targeting therapeutic agent other than compound (1) is afatinib.

[0042] (30) The method according to any one of (27) to (29), wherein the EGFR-targeting therapeutic agent other than compound (1) is gefitinib.

[0043] (31) The method according to any one of (27) to (30), wherein the EGFR-targeting therapeutic agent other than compound (1) is poziotinib.

[0044] (32) The method according to any one of (27) to (31), wherein the EGFR-targeting therapeutic agent other than compound (1) is sunvozertinib.

[0045] (33) The method according to any one of (27) to (32), wherein the EGFR-targeting therapeutic agent other than compound (1) is amivantamab.

[0046] (34) The method according to any one of (26) to (33), wherein the non-EGFR targeted therapeutic agent is at least one selected from the group consisting of crizotinib, ceritinib, alectinib, ensartinib, entrectinib, repotrectinib, belizatinib, alcotinib, folitinib, CEP-37440, TQ-B3139, PLB1003, zotizarquib, lorlatinib, contertinib, nivolumab, pembrolizumab, semiprimab, atezolizumab, durvalumab, bevacizumab, ipilimumab, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, and vinorelbine.

[0047] (35) The method according to (34), wherein the non-EGFR targeted therapeutic agent is nivolumab.

[0048] (36) The method according to any one of (34) to (35), wherein the non-EGFR targeted therapeutic agent is pembrolizumab.

[0049] (37) The method according to any one of (34) to (36), wherein the non-EGFR targeted therapeutic agent is cemiprimab.

[0050] (38) The method according to any one of (34) to (37), wherein the non-EGFR targeted therapeutic agent is atezolizumab.

[0051] (39) The method according to any one of (34) to (38), wherein the non-EGFR targeted therapeutic agent is durvalumab.

[0052] (40) The method according to any one of (1) to (39), wherein the systemic treatment is systemic treatment with a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dicycloplatin, heptaplatin, lovaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[0053] (41) The method according to (40), wherein the chemotherapeutic agent is cisplatin.

[0054] (42) The method according to any one of (40) to (41), wherein the chemotherapeutic agent is carboplatin.

[0055] (43) The method according to any one of (1) to (42), wherein the subject has previously received at least two systemic treatments for the cancer.

[0056] (44) The method according to any one of (1) to (43), wherein the subject has previously received at least three systemic treatments for the cancer.

[0057] (45) The method according to any one of (1) to (44), wherein the subject did not respond to the systemic treatment, or the subject had disease progression after administration of the systemic treatment.

[0058] (46) A method for treating a subject having cancer having at least one abnormality in EGFR, comprising administering to the subject an effective amount of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof, and an effective amount of a platinum anticancer agent.

[0059] (47) The method according to (46), wherein the cancer is a solid tumor.

[0060] (48) The method according to (46) or (47), wherein the cancer is lung cancer.

[0061] (49) The method according to any one of (46) to (48), wherein the cancer is non-small cell lung cancer.

[0062] (50) The method according to (49), wherein the non-small cell lung cancer is non-squamous non-small cell lung cancer.

[0063] (51) The method according to any one of (46) to (50), wherein the cancer is selected from the group consisting of locally advanced cancer and cancer that has metastasized to the brain of the subject.

[0064] (52) The method according to any one of (46) to (51), wherein the cancer is locally advanced.

[0065] (53) The method according to any one of (46) to (52), wherein the cancer is unresectable.

[0066] (54) The method according to any one of (46) to (53), wherein the cancer has metastasized to the brain of the subject.

[0067] (55) The method according to any one of (46) to (54), wherein the cancer has EGFR amplification / overexpression.

[0068] (56) The method according to any one of (46) to (55), wherein the cancer has an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.

[0069] (57) The method according to any one of (46) to (56), wherein the cancer has an EGFR mutation in exon 20.

[0070] (58) The method according to any one of (46) to (57), wherein the cancer has an EGFR exon 20 insertion mutation.

[0071] (59) The method according to any one of (46) to (58), wherein the subject has been determined to have the EGFR abnormality prior to the administration.

[0072] (60) The method according to any one of (46) to (59), wherein the subject has not previously received systemic treatment for the cancer.

[0073] The method according to any one of (46) to (60), wherein (61)(S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0074] The method according to any one of (46) to (61), wherein (62)(S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (BID).

[0075] The method according to any one of (46) to (62), wherein (63)(S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject daily for a therapeutic cycle lasting 21 days.

[0076] (64) The method according to any one of (46) to (63), wherein the platinum anticancer agent is administered intravenously to the subject.

[0077] (65) The method according to any one of (46) to (64), wherein the platinum anticancer drug is administered only on the first day of a 21-day treatment cycle.

[0078] (66) The method according to any one of (1) to (65), further comprising administering an effective amount of pemetrexed to the subject.

[0079] (67) The method of (66), wherein the pemetrexed is administered only on the first day of a 21-day treatment cycle.

[0080] (68) The method according to any one of (66) to (67), wherein the pemetrexed is administered intravenously to the subject.

[0081] (69) The method according to any one of (46) to (68), wherein the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof, and the platinum anticancer agent are administered over 1 to 10 treatment cycles, each treatment cycle lasting 21 days.

[0082] (70) The method according to any one of (46) to (69), wherein the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof, and the platinum anticancer agent are administered over four treatment cycles, each treatment cycle lasting 21 days.

[0083] (71) The method according to any one of (46) to (70), wherein the pemetrexed is administered over four treatment cycles, each treatment cycle lasting 21 days.

[0084] (72) The method according to any one of (46) to (71), wherein approximately 10 to approximately 500 mg of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.

[0085] (73) The method according to any one of (46) to (72), wherein approximately 30 to 150 mg per day of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject.

[0086] (74) The method according to any one of (1) to (73), wherein 100 mg of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (BID) for a therapeutic cycle lasting 21 days.

[0087] (75) The method according to any one of (46) to (74), wherein the platinum anticancer agent is at least one selected from the group consisting of cisplatin and carboplatin.

[0088] (76) The method according to any one of (46) to (75), wherein the platinum anticancer drug is cisplatin, and approximately 50 to approximately 100 mg / m2 of cisplatin is administered to the subject only on the first day of a 21-day treatment cycle.

[0089] (77) The method according to any one of (46) to (76), wherein the platinum anticancer agent is carboplatin, and carboplatin with an AUC of approximately 2.5 mg / mL / min to approximately 7.5 mg / mL / min is administered to the subject only on the first day of a 21-day treatment cycle.

[0090] (78) The method according to any one of (66) to (77), wherein pemetrexed at a dose of approximately 250 to approximately 750 mg / m2 is administered to the subject only on the first day of a 21-day treatment cycle.

[0091] (79) The method according to any one of (46) to (78), wherein the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject in at least one form selected from the group consisting of tablets and capsules.

[0092] (80) The method of (79), wherein the tablet or capsule comprises a pharmaceutically acceptable carrier.

[0093] The preceding paragraphs are provided for the purpose of providing an overview and are not intended to limit the scope of the following claims. The embodiments described, along with their further advantages, will be best understood by referring to the following detailed description when considered together with the accompanying drawings: [Brief explanation of the drawing]

[0094] [Figure 1] The graph shows plots of tumor volume over time in preclinical animal studies of various treatment regimens with compound (1)(TAS6417) and / or carboplatin, with a maximum dose of compound (1)(TAS6417) of 200 mg / kg. [Figure 2] The plots show the time course of body weight changes in preclinical animal studies of various treatment regimens with compound (1)(TAS6417) and / or carboplatin, with the maximum dose of compound (1)(TAS6417) being 200 mg / kg. [Figure 3A] Figure 3A shows a plot of the clinical activity of diparereltinib (compound (1), TAS6417) in EGFR ex20ins patients with NSCLC, based on target lesion assessment after baseline. (* indicates confirmed response, and E indicates previous EGFR-targeted Q:10 treatment.) [Figure 3B] Figure 3B shows a plot of the clinical activity of diparereltinib (compound (1), TAS6417) in EGFR ex20ins patients with NSCLC, based on target lesion assessment after baseline. Swimmers plots show the time to response and duration of treatment at different dose levels (EGFR, epidermal growth factor receptor; ex20ins, insertion of EGFR exon 20; NSCLC, non-small cell lung cancer). [Figure 4] This is a spider plot of the percentage change from baseline in the sum of target lesion diameters over time in the efficacy population (n=73), as assessed by the principal investigator. [Figure 5A]This image is from a gadolinium-enhanced MRI before treatment with diparereltinib (Figure 5A) (EGFR, epidermal growth factor receptor; ex20ins, EGFR exon 20 insertion; NSCLC, non-small cell lung cancer). [Figure 5B] This image is from an MRI scan with gadolinium enhancement after treatment with diparereltinib (Figure 5B) (EGFR, epidermal growth factor receptor; ex20ins, insertion of EGFR exon 20; NSCLC, non-small cell lung cancer). [Figure 6] A schematic diagram of the Phase 1 / 2 trial design is shown. A single-patient accelerated design was used for dose escalation from 30 to 100 mg twice daily. At the 100 mg dose level, the first patient experienced Grade 2 toxicity, and the trial was moved to a rolling 6 design. The low-dose cohort could be expanded in the rolling 6 design if this dose level achieved serum drug concentrations associated with response in the preclinical tumor model. This occurred at the initial dose level of 30 mg twice daily. The SRC decided to expand the cohort to higher dose levels to 6 patients and chose to expand only the 65 mg twice daily cohort. Based on safety considerations, the 100 and 150 mg dose levels were expanded. Dose level expansion to 13 patients was permitted based on the observation of a single response in the initial 6 patients at any dose level. The SRC chose to expand the dose levels to 65, 100, and 150 mg for 13 patients, but not for 30 or 45 mg. The expansion of the 100 mg dose level from 13 to 36 patients was based on the protocol-defined achievement of four or more responses. The 65 mg dose level also met this criterion but was not expanded at the SRC's discretion. DLT, Dose Limiting Toxicity; SRC, Safety Review Board. The 100 mg dose has a good balance between efficacy and adverse events. There is a tendency for more adverse events as the dose increases. [Figure 7] The Kaplan-Meier curves for PFS at different dose levels are shown (PFS, progression-free survival). [Figure 8]This is a waterfall plot showing the best percentage change from baseline in the sum of target lesion diameters by location of EGFR exon 20ins, as determined by routine clinical examinations and investigator responses (EGFR, Q:14 epidermal growth factor receptor; ORR, objective response rate, * indicates confirmed response). [Figure 9] The plots show the mean unbound plasma concentrations over time for dose levels of 30, 65, 100, and 150 mg. The 50% inhibitory concentrations are shown for cell lines expressing wild-type and cell lines expressing two types of exon 20 insertion mutations (EGFR, epidermal growth factor receptor; WT, wild-type). [Figure 10] The graph shows plots of tumor volume over time in preclinical animal studies of various treatment regimens with compound (1)(TAS6417) and / or carboplatin + pemetrexed, with a maximum dose of compound (1)(TAS6417) of 100 mg / kg. [Figure 11] The plots show mean body weight change throughout treatment for various preclinical animal studies of compound (1)(TAS6417) and / or carboplatin + pemetrexed, with the maximum dose of compound (1)(TAS6417) being 100 mg / kg. [Figure 12] The plots show the time course of tumor volume in preclinical animal studies of various treatment regimens with compound (1)(TAS6417) and / or carboplatin + pemetrexed, with a maximum dose of compound (1)(TAS6417) of 50 mg / kg. [Figure 13] The graph shows plots of tumor volume over time in preclinical animal studies of various treatment regimens with compound (1)(TAS6417) and / or carboplatin + pemetrexed, with a maximum dose of compound (1)(TAS6417) of 100 mg / kg. [Figure 14] The plots show mean body weight change throughout treatment for preclinical animal studies of various treatment regimens with compound (1) (TAS6417) and / or carboplatin + pemetrexed at various doses of carboplatin + pemetrexed and compound (1). [Figure 15] The graph shows plots of tumor volume over time in preclinical animal studies of various treatment regimens with continuous treatment with amibantamab or compound (1)(TAS6417), with a dose of compound (1)(TAS6417) of 200 mg / kg. [Figure 16] This is a summary of the entire patient statistics module C ami. [Figure 17] This is a summary of the best overall tumor response based on the investigator's assessment using RECITS v1.1. [Figure 18] This is a waterfall plot showing the best change from baseline in the target lesion. [Figure 19] This is a swim plot for the trial treatment period. [Figure 20] This is a Kaplan-Meier plot of progression-free survival based on RECITS v1.1. [Figure 21] This is a summary of treatment-related adverse events of any grade observed in ≥10% of patients. [Figure 22] This is a summary of Grade 3 treatment-related adverse events in ≥2 patients. [Modes for carrying out the invention]

[0095] Preferred examples of various definitions that fall within the scope of the invention are described in detail below in the above and below descriptions of this specification.

[0096] TAS6417 Compound (1), also known as diparereltinib and TAS6417, is a potent, highly selective EGFR-tyrosine kinase inhibitor (TKI) described in WO2018 / 079310, which is entirely incorporated herein by reference, and Hasako, S. et al. “TAS6417, A Novel EGFR Inhibitor Targeting Exon20 Insertion Mutations”, Mol Cancer Ther; 17(8), 2018, pp. 1648-1657). Biochemical assays have shown that compound (1) inhibits the in vitro phosphorylation activity of EGFR mutants having EGFR and exon 20 insertion mutations.

[0097] The chemical synthesis and chemical properties are described in U.S. Patent No. 9,650,386, which is incorporated herein by reference in its entirety.

[0098] Further descriptions of compound (1) can be found in WO2022 / 055895A1, as well as US2020 / 253975 and US2022 / 0072000, each of which is fully incorporated herein by reference.

[0099] Activation of TAS6417 In cell-based assays, compound (1) demonstrated strong cellular ability to inhibit phosphorylation of mutant EGFR containing widespread in-frame insertion mutations in exon 20 (A763_Y764insFQEA, V769_D770insASV, D770_N771insG, D770_N771insSVD, H773_V774insNPH, and H773_V774insPH). Compound (1) also showed moderate inhibition of WT EGFR.

[0100] Consistent with intracellular target inhibition, compound (1) demonstrated a more potent and selective inhibitory effect on the proliferation of cells expressing EGFR with exon 20 insertion mutations than on cells expressing WT EGFR.

[0101] Furthermore, compound (1) inhibited the growth of five cell lines with GI50 values ​​ranging from 1.92±0.21 nmol / L to 86.5±28.5 nmol / L from a panel of seven NSCLC cell lines possessing mutant EGFR (V769_D770insASV for LXF2478L cells, D770_N771insSVD for NCI-H1975 EGFR D770_N771insSVD for NCI-H1975 cells, delE746_A750 for HCC827 and PC-9 cells, and L858R+T790M for NCI-H1975). In contrast, KRAS mutant cell lines exhibiting EGFR-independent cell growth, NCI-H23 cells, and NCI-H460 cells did not respond to compound (1) (GI50 > 3000 nmol / L). CLN-081 suppressed the growth of NSCLC cells induced by EGFR exon 20 insertion (LXF2478 and NCI-H1975 EGFR D770_N771insSVD cells) through mechanisms related to the inhibition of phosphorylation of EGFR and its downstream molecules, as well as the induction of caspase 3 / 7.

[0102] In vivo antitumor efficacy studies showed that compound (1) exerted significant dose-dependent inhibitory and tumor regression effects in nude mouse and / or nude rat models with subcutaneous graft tumors expressing EGFR with exon 20 insertions (V769_D770insASV, D770_N771insSVD, and H773_V774insNPH). Pharmacodynamic (PD) marker analysis revealed that compound (1) exhibits potent and sustained in vivo inhibitory effects on the phosphorylation of EGFR and its downstream effectors in human lung cancer xenografts with EGFR exon 20 insertions, but does not affect skin tissue with WT EGFR. The antitumor effect of twice-daily administration of compound (1) to nude mice transplanted with human NSCLC cell line NCI-H1975 EGFR D770_N771insSVD was not inferior to that of once-daily administration of compound (1).

[0103] In cell-based assays, compound (1) demonstrated strong cellular activity in inhibiting the phosphorylation of mutant EGFR carrying mutations in exon 18 or exon 21 (G719A, G719S, G719C, E709K, E709A, L861Q), and its activity was higher than that of erlotinib and osimertinib. Compound (1) also showed strong inhibition of EGFR in combination with the acquired resistance mutation T790M and either an exon 18 mutation or an exon 21 mutation (G719A+T790M, L861Q+T790M) (the entire text of which is incorporated herein by reference WO2019 / 045036, Udagawa, H. et al. “TAS6417 / CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations” Mol Cancer Res 2019;17:2233-43).

[0104] Furthermore, compound (1) inhibited the growth of Ba / F3 cell lines with EGFR mutations in exon 18 (G719A, G719A+T790M) or exon 21 (L861Q, L861Q+T790M) with an IC50 in the range of 9.0 nmol / L to 37.5 nmol / L, significantly lower than the IC50 (597.3 nmol / L) required to inhibit Ba / F3 with wild-type EGFR. The selectivity index, defined as the ratio between the IC50 for WT EGFR-containing cell lines and the IC50 for mutant EGFR-containing cell lines, was significantly higher for compound (1) compared to erlotinib and afatinib. When the EGFR mutation included either G719A or L861Q in addition to T790M, the selectivity index for compound (1) was higher than that for osimertinib.

[0105] In vivo antitumor efficacy studies demonstrated that compound (1) exerted a dose-dependent significant tumor growth inhibitory effect in a nude mouse model with subcutaneous transplant tumors expressing EGFR with the G719A+T790M mutation. Importantly, the antitumor activity was not achieved at the expense of weight loss, fecal abnormalities, or skin abnormalities.

[0106] In cell-based assays, compound (1) demonstrated strong cellular activity in inhibiting the phosphorylation of mutant EGFR carrying mutations in exon 18 or exon 21 (G719A, G719S, G719C, E709K, E709A, L861Q), with activity higher than that of erlotinib and osimertinib. Compound (1) also showed strong inhibition against EGFR with the acquired resistance mutation T790M in combination with either an exon 18 or exon 21 mutation (G719A+T790M, L861Q+T790M).

[0107] In cell-based assays, compound (1), in combination with ex19del+T790M or L858R+T790M (i.e., L718Q+ex19del+T790M or L718Q+L858R+T790M), demonstrated strong cellular ability to inhibit phosphorylation of mutant EGFR possessing the L718Q mutation in exon 18, with both absolute activity and selectivity for baseline mutations (ex19del+T790M or L858R+T790M) higher than osimertinib, erlotinib, and afatinib (the whole of which is incorporated herein by reference WO2020 / 138400).

[0108] In cell-based assays, compound (1) is used in the following combinations: ex19del+T790M or L858R+T790M (i.e., L792H+ex19del+T790M, L792H+L858R+T790M, L792F+ex19del+T790M, L792F+L858R+T790M, L792Y+ex19del+T790M, L792Y+L858R+T790 In combination with M), it showed strong cellular ability to inhibit phosphorylation of mutant EGFR carrying mutations at L792 (L792H, L792F, L792Y) in exon 20, and both absolute activity and selectivity against baseline mutations (ex19del+T790M or L858R+T790M) were higher than osimertinib, erlotinib, and afatinib.

[0109] Compound (1) demonstrated favorable safety and tolerability, along with promising preliminary clinical efficacy, in patients with relapsed or metastatic EGFR ex20ins-mutated non-small cell lung cancer (NSCLC) who had previously been treated with other anticancer agents, including other TKIs, monoclonal antibodies, and ALK (anaplastic lymphoma kinase) agents. Objective responses were observed across the range of dose levels tested and across diverse ex20ins mutations. In the patient population that had received multiple prior treatments, compound (1) resulted in rapid and sustained tumor regression. While the data from this ongoing trial are mature, it is noteworthy that 24 out of 73 patients (33%) remained in the trial at the data cutoff.

[0110] The development of effective therapies targeting EGFR ex20ins is limited by EGFR-mediated toxicity, however, the safety profile of compound (1) observed to date appears to be consistent with its high in vitro selectivity for ex20ins variants against WT EGFR. TRAEs are generally reversible and manageable with standard supportive care. Diarrhea was observed in 30% of patients across all dose levels, with only two cases of grade 3 diarrhea, both tested at the highest dose level. Antidiarrheal prophylaxis was unnecessary, and symptoms were well managed with standard antidiarrheal therapy. Skin toxicity was more common, with 80% of patients experiencing rash across all dose levels, although these were also mostly of low grade. Only one patient (at the 150 mg dose level) experienced a grade 3 rash. Skin toxicity observed with compound (1) is well managed with conventional supportive care (topical antibiotics and / or corticosteroids, as well as oral antibiotics, antihistamines, or corticosteroids in a small number of patients).

[0111] The safety profile of compound (1) is better than that of other EGFR ex20-ins targeted therapies. Diarrhea occurred in 91% of patients treated with mobosertinib, 92% of patients treated with poziotinib, and 54% of patients treated with sunbosertinib, with over 20% of patients experiencing grade ≥3 diarrhea with mobosertinib and poziotinib.4,6,7 Amivantamab does not cause diarrhea as often, but skin toxicity, including rash (84%), is more common, and IRR occurs in 64% of patients.

[0112] Furthermore, skin and gastrointestinal toxicity rates were high, with 65% of patients requiring dose reduction from the initial dose of 16 mg / day with poziotinib. This type of EGFR-wild-type adverse event profile makes it difficult to obtain appropriate therapeutic indicators for TKIs in EGFR ins20 NSCLC, and this challenge also limits the clinical utility of afatinib and dacomitinib. With mobosertinib, which is similar to poziotinib, the most common side effect was gastrointestinal, with 92% of patients treated at 160 mg experiencing diarrhea of ​​any grade (16% grade ≥3) and 28% experiencing nausea. Rash was observed in 45%. Treatment-related adverse events led to dose reduction in 21% of patients and discontinuation of treatment in 10% of patients. Treatment with 160 mg of osimertinib daily led to higher rates of diarrhea (76% of any grade), fatigue (67% of any grade), and acneiform rash (38% of any grade) compared to typical treatment with 80 mg daily, but no cases of grade 3 gastrointestinal or cutaneous toxicity were observed. Skin rash was reported as a common side effect in 86% of patients with amivantamab, with grade 3 rash occurring in only 4%. Other common treatment-related adverse events were infusion-related reactions (66% (only 3% of which were grade ≥3), mainly due to the first infusion) and paronychia (42%), and a significant drawback of amivantamab is its need for intravenous administration.

[0113] In summary, these results indicate that compound (1) represents a more tolerable oral treatment option for patients with EGFR exon 20 insertion mutations than other currently available drugs. This promising safety profile may be due to increased selectivity for mutant EGFR (e.g., ex20ins mutant EGFR) compared to wild-type EGFR.

[0114] The ORR (38.4%) and mPFS (10 months) observed with compound (1), particularly the activity observed in the largest expanded cohort at 100 mg twice daily, suggest that its efficacy may be at least comparable to, if not exceeding, other EGFR ex20ins targeted agents, including both mobocertinib and amivantamab. In the CHRYSALIS trial, among 81 patients treated with amivantamab, the confirmed ORR was 40% and the mPFS was 8.3 months (95% CI, 6.5–10.9). Similarly, mobocertinib led to an ORR of 28% and an mPFS of several months. Furthermore, a response to compound (1) was observed in patients previously treated with ex20ins TKIs.

[0115] Compound (1), a novel oral irreversible pyrrolo-pyrimidine inhibitor of ex20ins mutant EGFR, demonstrated promising antitumor activity (as indicated by both ORR and PFS) in previously treated patients with EGFR ex20ins mutant NSCLC, as well as an acceptable safety profile and reduced WT EGFR-related toxicity. The risk-benefit profile of compound (1) is promising, and compound (1) may represent an alternative treatment option for these patients.

[0116] Due to low response rates, the 2017 lung cancer clinical practice guidelines do not recommend the use of EGFR-TKIs to treat patients with NSCLC embodied in EGFR ex20ins mutations; instead, these patients are encouraged to be treated with cytotoxic anticancer agents and immune checkpoint inhibitors. Ettinger DS,et al.,Non-Small Cell Lung Cancer,Version5.2017,NCCN Clinical Practice Guidelines in Oncology,J.Natl.Compr.Canc.Netw.,2017;15:504-535,Lee CK,et al.,Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A See Meta-Analysis, J. Thorac. Oncol., 2017;12:403-407, and Gainor JF, et al. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis, Clin. Cancer Res., 2016;22:4585-4593. There are currently no approved therapies for patients who have previously received exon20ins targeted therapy. However, the clinical benefits from combinations of these drugs are not yet fully understood. There is an unmet medical need for safe and effective treatment for patients with EGFR ex20ins mutations. Non-clinical studies have shown that CLN-081 / TAS6417 is not only a potent inhibitor of ex20ins mutations but also exhibits greater selectivity than WT EGFR.

[0117] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field to which the methods described herein belong. Any reference to a standard method, unless otherwise indicated, refers to the most recent available version of the method as of the filing date of this disclosure.

[0118] With respect to any method disclosed herein, including separate steps, the steps may be performed in any feasible order. Furthermore, any combination of two or more steps may be performed simultaneously, if necessary.

[0119] All headings are for the reader's convenience and should not be used to restrict the meaning of the text that follows them unless otherwise specified.

[0120] The words “preferred” and “preferred” refer to embodiments of the invention that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the enumeration of one or more preferred embodiments does not mean that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.

[0121] The term "comprises" and its variations are not intended to be restrictive when they appear in this specification and the claims. It will be understood that such terms implicitly include the steps or elements or groups of steps or elements described, but do not exclude any other steps or elements or groups of steps or elements.

[0122] "Consisting of" means including and being limited to what precedes the phrase "consisting of." Therefore, the phrase "consisting of" indicates that the enumerated elements are necessary or essential, and that other elements cannot be present. "Consisting essentially of" means including all elements enumerated before this phrase, and being limited to other elements that do not interfere with or contribute to the activity or action of the enumerated elements as identified in this disclosure. Therefore, the phrase "consisting essentially of" indicates that the enumerated elements are necessary or essential, but the other elements are optional and may or may not be present, depending on whether they substantially affect the activity or action of the enumerated elements.

[0123] Unless the context explicitly indicates otherwise, the singular forms “a,” “an,” and “the” refer to multiple objects. These articles refer to one or more (i.e., at least one). As used herein, the term “or” is generally used in its usual sense, including “and / or,” unless the content explicitly indicates otherwise. The term “and / or” means one or more of the items in the list joined by “and / or.” For example, “x and / or y” means any of the three element sets {(x), (y), (x,y)}. In other words, “x and / or y” means “either x or y or both.” As another example, “x, y, and / or z” means any of the seven element sets {(x), (y), (z), (x,y), (x,z), (y,z), (x,y,z)}. In other words, "x, y, and / or z" means "one or more of x, y, and z."

[0124] Where a range is given, the endpoint includes all numerical values ​​within that range (for example, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Furthermore, unless otherwise indicated or otherwise evident from the context and the understanding of those skilled in the art, a range can be assumed to be any specific value or subrange within the ranges described in different embodiments of this disclosure, up to one-tenth of the lower limit of that range, unless the context otherwise explicitly indicates. In this specification, the “maximum” numerical value (e.g., maximum 50) includes the numerical value (e.g., 50). The terms “in the range” or “within a range” (and similar statements) include the endpoint of the range described.

[0125] Throughout this specification, any reference to “one aspect,” “a certain aspect,” “a particular aspect,” or “several aspects” means that any particular feature, configuration, composition, or characteristic described in relation to an aspect is included in at least one aspect of this disclosure. Therefore, the use of such phrases in different parts of this specification does not necessarily refer to the same embodiment of this disclosure. Furthermore, any particular feature, configuration, composition, or characteristic may be combined in any preferred manner in one or more aspects.

[0126] Although the numerical ranges and parameters describing the broad scope of this invention are approximations, the numerical values ​​described in specific examples are reported as accurately as possible. However, all numerical values ​​inherently contain a range that inevitably arises from the standard deviations observed in their respective test measurements.

[0127] The term “exemplary” means to serve as an unrestrictive example, case, or illustration. As used herein, the terms “e.g.” and “for example” emphasize a list of one or more unrestrictive aspects, examples, cases, or illustrations.

[0128] As used herein, the term “substantially” refers to a qualitative state indicating the whole or nearly whole range or degree of the desired characteristic or property. It is rare, if any, for biological and chemical phenomena to progress toward completion and / or complete termination, or to achieve or avoid absolute results. Therefore, the term “substantially” is used herein to capture the inherent inability of many biological and chemical phenomena to completely terminate. For example, “substantially” could mean no more than about 20%, alternatively no more than about 10%, or alternatively no more than about 5% of the desired characteristic or property.

[0129] Unless otherwise indicated, all numbers used herein and in the claims to represent quantities, molecular weights, etc., of components should be understood in all examples to be modified by the term “about.” Where used herein in relation to measured quantities, the term “about” refers to the variation of the measured quantity that would be expected by a person skilled in the art who performs the measurement and takes care to a level commensurate with the purpose of the measurement and the accuracy of the measuring instrument used. Where used throughout this specification and in relation to numerical values, the term “about” indicates an acceptable interval of accuracy that is familiar to a person skilled in the art. Generally, such an interval of accuracy is + / -10%. Thus, unless otherwise indicated, the numerical parameters described in the specification and in the claims are approximations that may vary depending on the desired properties to be obtained by the invention. At the very least, and without attempting to limit the doctrine of equivalents to the claims, each numerical parameter should be interpreted in light of at least the reported significant number of digits and by applying the usual rounding techniques.

[0130] In this specification, "EGFR" refers to the human epidermal growth factor receptor protein, also known as ErbB-1 or HER1.

[0131] As used herein, "wild-type EGFR" refers to EGFR that does not have somatic mutations and specifically consists of the amino acid sequence represented by Sequence ID No. 1 (GenBank accession number: NP-005219.2).

[0132] The term "molecularly targeted therapy" refers to anticancer drugs that work by interfering with specific target molecules necessary for cancer-related functions such as carcinogenesis and tumor growth. Molecularly targeted therapies are distinguished from chemotherapeutic agents that nonspecifically interfere with all rapidly dividing cells. Molecularly targeted therapies can be small molecules (compounds) or antibodies. Examples of molecularly targeted therapies include, but are not limited to, kinase inhibitors, proteasome inhibitors, monoclonal antibodies, mTOR inhibitors, TNF inhibitors, and T cell inhibitors.

[0133] As used herein, “antagonist” and “inhibitor” are used interchangeably and refer to compounds or agents that have the ability to inhibit the biological function of a target protein or polypeptide, such as by inhibiting the activity or expression of that target protein or polypeptide. Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein or polypeptide. Some antagonists as used herein specifically interact with (e.g., bind to) a target protein or polypeptide, but compounds that inhibit the biological activity of that target protein or polypeptide by interacting with other members of its signaling pathway are also specifically included in this definition. Non-limiting examples of biological activity inhibited by antagonists include those related to tumor development, growth, or progression, or undesirable immune responses, such as those that appear in autoimmune diseases.

[0134] As used herein, “anticancer agent,” “antitemoid agent,” or “chemotherapeutic agent” refers to any agent useful for treating a tumorous condition. One class of anticancer agents includes chemotherapeutic agents. “Chemotherapy” means administering one or more chemotherapeutic agents and / or other agents to a cancer patient by various means, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, percutaneous, oral, or inhalation, or in the form of suppositories.

[0135] As used herein, “cell proliferation” or “cell growth” refers to the phenomenon in which the number of cells changes as a result of cell division. The term also encompasses cell growth in which the cell morphology changes in accordance with a proliferation signal (e.g., an increase in size).

[0136] As used herein, “selective inhibition” or “selectively inhibiting” applied to a biologically active drug refers to the ability of a drug to selectively reduce target signaling activity compared to off-target signaling activity, through direct or indirect interactions with the target. For example, a compound that selectively inhibits exon 20 mutant EGFR more than wild-type EGFR has at least about twice the activity against mutant EGFR (e.g., at least about three times, about five times, about ten times, about twenty times, about fifty times, or about 100 times) compared to the compound's activity against wild-type EGFR isoform.

[0137] As used herein, "in vivo" refers to an event occurring within the body of the subject. In vivo also includes events occurring in rodents, such as rats, mice, and guinea pigs.

[0138] As used herein, “in vitro” refers to an event that occurs outside the body of the subject. For example, an in vitro assay encompasses any assay performed outside the subject. In vitro assays include cell-based assays that use living or dead cells. In vitro assays also include cell-free assays that do not use intact cells.

[0139] As used herein, “therapeutic effect” encompasses the therapeutic benefits described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0140] The overall response rate (ORR) refers to the number and percentage of patients whose best overall response (BOR) is either a complete response (CR) or a partial response (PR). To qualify as a responder, a patient must have a complete or partial visit response confirmed by a second scan performed at least four weeks after the initial response criteria are met. The ORR is calculated separately using both the investigator's assessment of response and independent central review (ICR).

[0141] The present invention is defined in the claims. However, the following is a non-exclusive list of non-limiting exemplary embodiments. One or more features of these embodiments may be combined with one or more features of other examples, embodiments, or embodiments described herein.

[0142] A method of treating a specific type of cancer Compound (1) may be used directly or in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable” is used herein to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human tissue without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is commensurate with a reasonable benefit-risk ratio, within the bounds of appropriate medical judgment. The pharmaceutically acceptable salts of compound (1) are not particularly limited and include, for example, addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid; salts with alkali metals such as potassium and sodium; salts with alkaline earth metals such as calcium and magnesium; and salts with organic bases such as ammonium salts, ethylamine salts, and alginates. Pharmaceutically acceptable salts can generally be synthesized by conventional chemical methods, by reacting compound (1) with a suitable base or acid in a stoichiometric or quasi-stoichiometric amount (e.g., 0.5 equivalents) in water or an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) or a mixture thereof.

[0143] Compound (1) or a pharmaceutically acceptable salt thereof may also be in the form of a “solvate,” which refers to a physical association of a reference compound with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain examples, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate is separable. The solvent molecules in the solvate may exist in regular and / or irregular arrangements. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. The solvate encompasses both the solution phase and the separable solvate. Exemplary solvent molecules that can form solvates include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethyl acetate, glycerin, and acetone.

[0144] In this disclosure, the terms “treat,” “treating,” or “treatment” of cancer include any effect resulting in improvement of a condition, disease, disorder, or any improvement of its symptoms, such as reduction, decrease, regulation, stabilization, improvement, or elimination. Specifically, these terms include (1) stabilization, reduction (e.g., reduction of cancer cell population and / or tumor size by more than 10%, 20%, 30%, 40%, 50%, preferably more than 60%), or elimination of cancer cells; (2) inhibition of cancer cell division and / or cancer cell proliferation; (3) to some extent alleviation (or, preferably elimination) of one or more symptoms associated with, or partially caused by, unregulated or abnormal cell division; (4) increased disease-free, recurrence-free, progression-free, and / or overall survival, duration, or rate; (5) reduced hospitalization rate; (6) shortened hospital stay; (7) primary (1) Eradication, removal, or control of local cancer and / or metastatic cancer; (8) Stabilization or reduction of tumor or neoplasm growth (e.g., reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, preferably at least 80% compared to the initial growth rate); (9) Impairment of tumorigenesis; (10) Reduction of mortality; (11) Increase in response rate, duration of response, or number of responders or remissions; (12) Maintenance of tumor size, no increase or increase of less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%; (13) Reduction in the need for surgery (e.g., colectomy, mastectomy); and / or (14) Prevention or reduction of metastasis of cancer cells.

[0145] In some embodiments, the cancers that can be treated herein are EGFR-positive cancers. "EGFR-positive" means cancers in which EGFR protein abnormalities and / or EGFR gene abnormalities are detected / detectable. The EGFR protein / gene may be detected / detectable in its wild type or in altered form (e.g., mutation).

[0146] Examples of cancer types that can be treated include adenomas, carcinoid tumors, undifferentiated carcinomas, angiosarcomas, adenocarcinomas, gastrointestinal cancers (e.g., colorectal cancers including colon and rectal cancer ("CRC"), biliary tract cancers including gallbladder and biliary tract cancers (bile duct cancer), anal cancers, esophageal cancers, gastric cancers (stomach cancer), gastrointestinal carcinoid tumors (multiple), gastrointestinal stromal tumors (multiple) ("GIST"), liver cancers, duodenal cancers, and small intestinal cancers), lung cancers (e.g., non-small cell lung cancer ("NSCLC"), squamous cell lung cancer, large cell lung cancer, small cell lung cancer, invasive mucinous adenocarcinoma, mesothelioma, bronchial tumors, and other lung cancers (e.g., pleuropulmonary blastoma)), and urinary tract cancers (e.g., kidney cancer). Cancers (e.g., eye cancer, retinoblastoma, intraocular melanoma, hypopharyngeal cancer, pharyngeal cancer, laryngeal cancer, laryngeal papilloma, metastatic squamous cell carcinoma of unknown primary origin, nasal and paranasal sinus squamous cell carcinoma (SNSCC), oral cancers (mouth cancers (mouth cancers)Cancers (e.g., lip cancer, pharyngeal cancer, oropharyngeal cancer, sensory neuroblastoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, and salivary gland cancer), endocrine cancers (e.g., thyroid cancer, parathyroid cancer, multiple endocrine neoplasia syndrome, thymoma and thymic carcinoma), pancreatic cancers (including pancreatic ductal adenocarcinoma ("PDAC"), pancreatic neuroendocrine tumors, and islet cell tumors), breast cancers (extrahepatic ductal carcinoma in situ ("DCIS"), lobular carcinoma in situ ("LCIS"), triple-negative breast cancer, and inflammatory breast cancer) ), cancers of the male and female reproductive organs (e.g., cervical cancer, ovarian cancer, endometrial cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, gestational trophoblastic tumor ("GTD"), extragonadal germ cell tumor, extracranial germ cell tumor, germ cell tumor, testicular cancer and penile cancer), cancers of the brain and nervous system (e.g., astrocytoma, brainstem glioma, brain tumor, glioblastoma (GBM), craniopharyngotoma, central nervous system ("CNS") cancer, chordoma, ependymoma, embryonal tumor, neuroblastoma, paraganglioma, atypical teratoma, oligodactyly Gliomas, oligodendrons, oligodendrons, undifferentiated oligodendrons, gangliogliomas, central nervous system cell tumors, medulloblastomas, germ cell tumors, meningiomas, schwannomas, GH secretory pituitary adenomas, PRL secretory pituitary adenomas, ACTH secretory pituitary adenomas, non-functional pituitary adenomas, hematoblastomas, and epidermal tumors), skin cancers (e.g., basal cell carcinoma ("BCC"), squamous cell carcinoma ("SCC"), Merkel cell carcinoma, and melanoma), tissue and bone cancers (e.g., soft tissue sarcoma, rhabdomyosarcoma, rhabdomyosarcoma). Examples of cancers include, but are not limited to, tumors (fibrous histiocytoma of bone, Ewing's sarcoma, malignant fibrous histiocytoma of bone ("MFH"), osteosarcoma and chondrosarcoma), cardiovascular cancers (e.g., cardiac cancer and cardiac tumors), appendiceal cancer, childhood and adolescent cancers (e.g., pediatric adrenocortical carcinoma, median ductal carcinoma, hepatocellular carcinoma ("HCC"), hepatoblastoma and Wilms' tumor), and virus-induced cancers (e.g., HHV-8-related cancer (Kaposi's sarcoma) and HIV / AIDS-related cancers).

[0147] Cancers suitable for treatment include, but are not limited to, multiple myeloma, leukemia and lymphoma, and hematological and plasma cell malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes), such as myelodysplastic syndromes and myeloproliferative disorders. Leukemias include, but are not limited to, acute lymphoblastic leukemia ("ALL"), acute myeloid leukemia ("AML"), chronic lymphocytic leukemia ("CLL"), chronic myeloid leukemia ("CML"), acute monocytic leukemia ("AMoL"), hairy cell leukemia, and / or other leukemias. Lymphomas include, but are not limited to, Hodgkin lymphoma and non-Hodgkin lymphoma ("NHL"). In some embodiments, NHL is B-cell lymphoma and / or T-cell lymphoma. In some embodiments, NHL includes, but is not limited to, diffuse large B-cell lymphoma ("DLBCL"), small lymphocytic lymphoma ("SLL"), chronic lymphocytic leukemia ("CLL"), mantle cell lymphoma ("MCL"), Burkitt lymphoma, cutaneous T-cell lymphomas including mycosis fungoides and Sézary syndrome, AIDS-related lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma (Waldenström macroglobulinemia ("WM")), primary central nervous system (CNS) lymphoma, central nervous system malignant lymphoma, and / or other lymphomas.

[0148] Compound (1) or any pharmaceutically acceptable salt form thereof also possesses brain permeability. Therefore, cancers that can be treated include metastatic brain tumors, such as brain metastases of any of the above cancer types, including lung cancer, breast cancer, gastric cancer (stomach cancer), bladder cancer, or biliary tract cancer (including gallbladder cancer and bile duct cancer).

[0149] The therapeutic methods disclosed herein are particularly useful in the treatment of solid tumors (e.g., cancers with solid tumors), such as lung cancer (e.g., non-small cell lung cancer ("NSCLC"), invasive mucinous adenocarcinoma, etc.), breast cancer (e.g., extrahepatic ductal carcinoma in situ ("DCIS"), lobular carcinoma in situ ("LCIS"), etc.), gastric cancer, bladder cancer, biliary tract cancer, brain cancer (e.g., glioblastoma), colorectal cancer, pancreatic cancer, and ovarian cancer, as well as any of the above that have metastasized to the brain. NSCLC is the most common form of lung cancer and is histologically classified into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma. Of particular interest to this disclosure is lung cancer, specifically NSCLC. Of particular interest to this disclosure is non-squamous NSCLC.

[0150] The methods disclosed herein may also be used as a transtumor therapy for malignancies with EGFR abnormalities, for example, in the form of activation of constitutive ErbB-mediated pathways resulting from abnormal ligand binding (e.g., NRG1 fusion-driven tumors).

[0151] Subjects with one or more abnormalities in EGFR are candidates for treatment as described herein. EGFR abnormalities are important oncogenic drivers of certain types of cancer. For example, EGFR abnormalities can lead to the activation of various signaling pathways, including Ras and phosphoinositide 3-kinase (PI3K), and consequently contribute to various tumorigenetic processes.

[0152] In this disclosure, “abnormalities” in EGFR refer to gain-of-function changes such as protein overexpression, gene amplification (e.g., copy number changes), activating gene mutations / activating protein mutations (e.g., insertion mutations, point mutations, or deletion mutations), activating protein overexpression, activating chromosomal translocations / insertions / inversions, activating gene rearrangements or gene fusions (a subset of gene rearrangements), misregistration / dysregulation, etc. For example, cancers with EGFR abnormalities may express (i) amplified or overexpressed EGFR, including wild-type varieties; (ii) constitutively activated EGFR (including wild-type varieties) resulting from abnormal ligand binding, such as due to NRG1 abnormalities (e.g., NRG1 fusion-driven binding); (iii) alterations of EGFR due to, for example, activating gene and / or protein mutations; or (iv) a combination of abnormalities in which EGFR is amplified / overexpressed and altered, for example, through mutations in the EGFR gene and / or protein.

[0153] Unless otherwise specified, all references to EGFR amino acid sequence information are based on human wild-type EGFR isoform a, which is accessible from the National Center for Biotechnology Information (NCBI) protein database under accession numbers NP-005219.2, P00533.2, etc.

[0154] The isoforms of EGFR are known to those skilled in the art, and this disclosure also encompasses those isoforms. With respect to the changes (e.g., mutations) in EGFR discussed herein, it should be understood that the changes in isoforms may be located at positions different from those specified for EGFR, due to the deletion or insertion of amino acids in the isoform; nevertheless, the changes in isoforms correspond to positions specified for EGFR.

[0155] Abnormalities in EGFR can manifest as gene amplification and / or protein overexpression.

[0156] Abnormalities in EGFR can manifest as one or more mutations in the EGFR protein. Mutations in EGFR can be located in the tyrosine kinase domain of EGFR, including, but not limited to, one or more of the following regions: exon 18 (region 688–728), exon 19 (region 729–761), exon 20 (region 762–823), and exon 21 (region 824–875).

[0157] Mutations in EGFR exon 18 may include, but are not limited to, point mutations such as E709X or G719X (where X is any amino acid), as well as deletion and insertion mutations, such as deletions of glutamate at position 709 and threonine at position 710, and insertions of aspartate (DelE709_T710insD).

[0158] Mutations in EGFR exon 19 may include, but are not limited to, "classic" exon 19 deletion mutations involving at least three amino acid residues, as well as deletion / insertion mutations such as DelE746_A750 (deletion from glutamic acid at position 746 to alanine at position 750), DelL747_P753insS (deletion from leucine at position 747 to proline at position 753 and insertion of serine), DelE746_T751insA, DelE746_S752insD, DelL747_T751, and DelL747_A750insP.

[0159] Mutations in EGFR exon 20 may include, but are not limited to, point mutations, deletion mutations, and insertion mutations such as T790M, S768I, V769M, and H773R. In particular, compound (1) or its pharmaceutically acceptable salts have been found to be remarkably active in cancers with one or more EGFR exon 20 insertion mutations. EGFR exon 20 insertion mutations are found at relatively high prevalence in non-small cell lung cancer (NSCLC) and nasal sinus squamous cell carcinoma (SNSCC), are associated with novel resistance to currently clinically available EGFR inhibitors, and are therefore preferred targets for treatment as described herein.

[0160] EGFR exon 20 insertion mutations can be heterogeneous in-frame insertions of 1 to 7 amino acids (indicated as "insX") spanning approximately 15 amino acids (D761-C775) in exon 20, such as D761_E762insX (insertion of 1 to 7 amino acid residues "X" between aspartic acid at position 761 and glutamic acid at position 762), A763_Y764insX, Y764_V765insX, V765_M766insX, A767_S768insX, S768_V769insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, H773_V774insX, and V774_C775insX. Also, DelD770insX (deletion of aspartic acid at position 770 and insertion of 1-7 amino acids "X") and DelN771insX (Simon Vyse and Paul H. Huang, Targeting EGFR exon20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther. 2019 Mar 8;4:5). Specific examples of EGFR exon 20 insertion mutations include A763_Y764insFQEA, A763_Y764insTLA, Y764_V765insHH, A767_S768insASV, A767_S768insTLA, S768dupSVD, S768_V769insVAS, S768_V769insAWT, V769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V769_D770insGVV, and V769_D770insM ASVD, V769_D770insASV, V769_D770insGE, V769_D770delInsDGEL, V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insKH, D770_N771insGNPH, D770_N771insAPW, D770_N771insD, D770_N771insDG, D770delinsGY, D770_N771insGL, D770_N771insN, D770_N771insNPH,D770_N771insSVP, D770_N771insSVQ, D770_N771insMATP, D770_N771insG, D770_N771insY , D770_N771insGF, D770_N771insGT, D770_N771insSVG, DelD770insGY, DelD770insVG, N771 _P772insH, N771_P772insV, N771_P772insN, DelN771insGY, DelN771insTH, delN771insGF , N771delinsGY, N771_P772insRH, P772_H773insPR, P772_H773insYNP, P772_H773insDPH, P Examples include 772_H773insQV, P772_H773insTPH, P772_H773insN, P772_H773insV, P772_H773insNP, P772_H773insDNP, P772_H773insPNP, P772_H773insNPH, H773_V774insNPH, H773_V774insPH, H773_V774insGNPH, H773_V774insG, H773_V774insGH, H773_V774insAH, H773_V774insH, H773_V774delInsLM, H773_V774delInsTY, and V774_C775insHV, but are not limited to these. (Takayuki Kosaka et al.Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.Cancer Res.2017 May;77(10):2712-2721). ,

[0161] Preferred embodiments of the present disclosure involve treating subjects having cancer, and more specifically refer to non-small cell lung cancer (NSCLC) having an EGFR exon 20 insertion mutation, when such cancer is locally advanced or has metastasized to the brain.

[0162] Mutations in EGFR exon 21 may include, but are not limited to, the “classic” exon 20 activating mutation L858R, as well as point mutations such as L858X and L861X (where X is any amino acid), L833V, H835L, L838V, A839T, K846R, and L861Q.

[0163] Exemplary EGFR proteins containing multiple mutations that can be treated herein may include, but are not limited to, DelE746_A750 / T790M and T790M / L858R.

[0164] Mutations in the EGFR protein may be those described in Japanese Patent Application No. 2020-121525 (the contents of which are incorporated herein by reference in their entirety).

[0165] Abnormalities in EGFR can also be in the form of mutations resulting from one or more genetic changes in EGFR, such as gene amplification and / or EGFR gene rearrangement, as well as deletions of specific exons or exon portions in EGFR. Examples include, but are not limited to, EGFR variant I (EGFRvI; deletion of the N-terminal portion), EGFR variant II (EGFRvII; deletion of exons 14 and 15), EGFR variant III (EGFRvIII; deletion of exons 2-7), EGFR variant IV (EGFRvIV; deletion of exons 25-27), and EGFR variant V (EGFRvV; deletion of exons 25-28).

[0166] Of these, the gene rearrangement resulting in EGFRvIII expression is found at a high prevalence in glioblastoma (GBM), and its expression has also been identified in other cancers such as breast cancer and lung cancer (e.g., NSCLC). EGFRvIII arises from an 801-base pair in-frame deletion spanning exons 2–7, in which 267 amino acids are removed from the extracellular domain, thereby generating a junction site between exons 1 and 8 and a new glycine residue. These changes confer enhanced tumorigenic potential compared to unchanged EGFR, including increased growth rate, decreased apoptosis, increased angiogenesis, and increased invasiveness, mediated by several downstream signaling pathways including PI3K / Akt, Ras / Raf / MAPK, signaling and transcriptional activator 3 (Stat3), and nuclear factor kappa-B (NF-κB).

[0167] Given the high prevalence of EGFR amplification and EGFRvIII mutations in GBM, the lack of approved drugs targeting GBM with these EGFR genetic alterations, and the high brain permeability of compound (1) or a pharmaceutically acceptable salt thereof, preferred embodiments of the present disclosure include treating subjects having GBM with EGFR amplification and / or EGFRvIII mutations.

[0168] Abnormalities in EGFR can also be forms of constitutively activated EGFR (including wild-type varieties) due to abnormal ligand binding. One example is cancer with abnormalities in NRG1. “Abnormalities” in NRG1 refer to gain-of-function changes such as protein overexpression, gene amplification (e.g., copy number changes), activating gene mutations / activating protein mutations (e.g., insertion mutations, point mutations, or deletion mutations), activating chromosomal translocations / insertions / inversions, activating gene rearrangements or gene fusions (a subset of gene rearrangements), misregistration / dysregulation, and combinations thereof, which result in or contribute to the formation and / or development of cancer.

[0169] For example, abnormalities in NRG1 can manifest as NRG1 overexpression. Overexpression of NRG1 has been found to be associated with invasive tumor characteristics and poor prognosis in gastric cancer patients (Yun, S. et al. Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients; Gastric Cancer (2018) 21:225-236).

[0170] Another example is cancer with oncogenic gene fusions in NRG1. NRG1 gene fusions result in the irregular expression of the epidermal growth factor (EGF)-like domain of NRG1 on the cell surface, which functions as a ligand for ErbB3 (HER3) and induces the formation of heterodimers (most frequently ErbB2-ErbB3, but sometimes EGF receptor (EGFR; ErbB1) and ErbB4). This leads to pathological activation of phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), mitogen-activated protein kinase (MAPK), and other signaling pathways, resulting in abnormal cell proliferation. This binding event can occur in an autocrine or juxtacrine manner. Alternatively, in some cases, the EGF-like domain of NRG1 may be cleaved from its surface tether, resulting in paracrine binding to ErbB3. In any case, NRG1 fusion-positive cancers cause abnormal activation of EGFR and / or HER2, and therefore, in a preferred embodiment, this disclosure includes treating subjects having NRG1 fusion-driven tumors.

[0171] Cancers driven by one or more abnormalities in NRG1 may include, but are not limited to, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, biliary tract cancer, ovarian cancer, and gastric cancer.

[0172] Cancers driven by NRG1 gene fusion may include, but are not limited to, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, biliary tract cancer, and ovarian cancer.

[0173] NRG1 fusion can be formed from various fusion partners (hereinafter listed as X in X-NRG1), but the selection of fusion partners is not particularly limited. Examples of NRG1 fusion include, but are not limited to, DOC4-NRG1, CD74-NRG1, SLC3A2-NRG1, SDC4-NRG1, RBPMS-NRG1, WRN-NRG1, VAMP2-NRG1, ATP1B1-NRG1, ROCK1-NRG1, RALGAPA1-NRG1, TNC-NRG1, MDK-NRG1, DIP2B-NRG1, MRPL13-NRG1, DPYSL2-NRG1, PARP8-NRG1, ITGB1-NRG1, POMK-NRG1, APP-NRG1, CDH6-NRG1, ATP1B1-NRG1, and CLU-NRG1 (J. Laskin et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020). Dec;31(12):1693-1703).

[0174] Other growth factors that activate the ErbB receptor, which can lead to constitutive activation of abnormal ErbB-mediated pathways, include, but are not limited to, EGF, TGF-α, HB-EGF, amphiregulin, betacerlin, epigen, and epiregulin. Therefore, cancers having abnormal activation of any of these growth factors, which lead to abnormal activation of ErbB family receptors and downstream ErbB-mediated signaling pathways that contribute to carcinogenesis, can be treated herein.

[0175] While cancers of various stages and resectable properties may respond to the disclosed treatments, the methods described herein may be particularly useful in treating unresectable or advanced disease (stage III, "locally advanced") and metastatic disease (stage IV), "recurrent" cancer, "resistant" cancer, and "refractory" cancer (cancer that has not responded to previous medical treatments). "Recurrent" cancer is typically cancer that has recurred (come back) after a period in which it was not detectable. Cancer may recur in the same location as the original (primary) tumor or in a different location within the body. "Refractory" cancer may be presented as resistant / refractory from the outset. "Resistant" cancer may be presented after the acquisition of resistance / refractory by cancer cells in the course of previous therapy, and therefore may include recurrent cancers that initially respond to treatment but often recur in a more invasive / resistant form. Resistant cancer may also be described as "secondary resistance," "acquired resistance," or having similar terms. For example, the cancer may be a recurrent, resistant, or refractory EGFR-positive cancer, preferably a recurrent, resistant, or refractory cancer in which EGFR is genetically amplified and / or overexpressed. Examples of cancer types include, but are not limited to, recurrent, resistant, or refractory EGFR-positive NSCLC. Specifically, this disclosure relates to locally advanced and / or metastatic cancers of the brain in question.

[0176] Subjects with recurrent, resistant, or refractory cancer who have previously received at least one treatment regimen with one or more anticancer drugs may be treated with compound (1) or its pharmaceutically acceptable salts and platinum anticancer drugs. In some cases, recurrent, resistant, or refractory cancers may have acquired resistance to or refractory status from a previous treatment regimen. For example, subjects with EGFR-positive cancer who have been previously treated with one or more anticancer drugs and have not responded to or have relapsed from a previous treatment regimen may develop resistance / refractory status as a result of their cancer's exposure to anticancer drugs. Resistance / refractory status may manifest in cancer as EGFR abnormalities (e.g., overexpression and / or mutations), or any other cancer driver changes resulting in loss of function of tumor suppressor genes / proteins or gain-of-function changes of oncogenes / oncogene-coding proteins.

[0177] Previous treatment regimens may have been carried out using a variety of anticancer drugs, examples of which are described below. Embodiments of the Disclosure involve administering compound (1) or a pharmaceutically acceptable salt thereof to a subject having EGFR-positive cancer who has not previously received at least one systemic treatment with a molecularly targeted therapy. Embodiments of the Disclosure involve administering compound (1) or a pharmaceutically acceptable salt thereof to a subject having EGFR-positive cancer who has previously received at least one systemic treatment with a molecularly targeted therapy. In some embodiments, administration of compound (1) or a pharmaceutically acceptable salt thereof to a subject having EGFR-positive cancer who has previously received at least one systemic treatment is initiated after the systemic treatment has lost efficacy or effect, after disease recurrence, after disease progression, after the subject has not responded to treatment, or after a combination of these.Examples of systemic treatment with molecularly targeted therapies include one or more EGFR inhibitors (i.e., gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobosertinib, razertinib, sunbozertinib, flumonertinib, amibantamab, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib) Non-EGFR targeting agents such as ALK inhibitors (including EGFR inhibitors other than compound (1), such as nib, icotinib, neratinib, olmutinib, rosiletinib, vandetanib, lapatinib, durigotuzumab, panitumumab, zaltumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imugatuzumab, matsuzumab, and nimotuzumab), and crizotinib Examples of inhibitors include, but are not limited to, ceritinib, alectinib, ensartinib, entrectinib, repotrectinib, belizatinib, alcotinib, folitinib, CEP-37440, TQ-B3139, PLB1003, zotizarkib, lorlatinib, and contertinib; PD-1 / PD-L1 inhibitors (such as nivolumab, pembrolizumab, and semiprimab); PD-L1 inhibitors (such as atezolizumab and durvalumab); VEGF inhibitors (such as bevacizumab); CLTA-4 inhibitors (such as ipilimumab); patrizumab, deruxtecan, datopotamab; paclitaxel, albumin-bound paclitaxel; docetaxel; gemcitabine; vinorelbine; or combinations thereof. Systemic treatment does not include local treatments such as localized or limited tumor resection.

[0178] Before initiating treatment, it may be determined, as described above, whether the subject has one or more abnormalities in EGFR. Therefore, this method may involve a pre-screening step to determine whether the subject has EGFR abnormalities and is a good candidate for treatment. Abnormalities(s) can be determined by determining the subject's genotype from a family history of cancer(s) with abnormalities(s), by analyzing any biological sample from the subject, including blood or tumor samples taken from the subject using assays such as those described below, or from past records or previous tests performed on the subject. If the subject is determined to be EGFR-positive and has one or more abnormalities, such as those described in this disclosure, treatment with compound(1) or a pharmaceutically acceptable salt thereof is appropriate.

[0179] In one embodiment of the present invention, a step can be performed to detect whether the EGFR expressed by a malignant tumor patient has an exon 20 insertion mutation before administering compound (1).

[0180] Predictive biomarkers that may be used to identify individuals likely to respond to the treatments described herein include, but are not limited to, overexpression / amplification of EGFR at the DNA, RNA, or protein level in breast cancer, or other genetic alterations, such as insertions of EGFR exon 20 and other activating mutations in lung cancer (e.g., NSCLC), or mutations in EGFRvIII, amplification of EGFR, and / or methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter in brain cancer (e.g., GBM). Companion diagnostic (CDx) tests may be developed to analyze biological samples.

[0181] The presence of EGFR abnormalities (including abnormalities that cause protein activation via NRG1 fusion-driven EGFR, e.g., as described above) can be determined, for example, from previous tests performed on the subject during pre-screening, or according to known assays, including otherwise authorized or approved in vitro diagnostic (IVD) assays or assays for this purpose. Examples of these include, but are not limited to, next-generation sequencing (NGS) based gene panels, whole exome profiling, polymerase chain reaction (PCR), insight hybridization (ISH), immunohistochemistry (IHC), flow cytometry, or other assays that can determine EGFR abnormalities in tumor tissue or circulating tumor DNA (ctDNA), RNA, proteins, etc. For example, subjects without archived tumor tissue samples can be biopsied, and fresh tumor biopsies can be analyzed to confirm existing abnormalities.

[0182] The samples used to detect EGFR abnormalities are not particularly limited, as long as they are biological samples derived from malignant tumor patients, such as samples collected from malignant tumor patients and containing malignant tumor cells. Examples of biological samples include body fluids (blood, urine, etc.), tissues, their extracts, and cultures of collected tissues. Furthermore, the method of collecting the biological sample can be suitably selected according to the type of biological sample.

[0183] Biological samples are prepared by appropriate processing according to the detection method. Furthermore, reagents used for detection (e.g., reagents containing primers or probes) can be prepared by methods commonly used according to the detection method.

[0184] The term "effective dose" refers to a therapeutically or pharmaceutically effective amount. According to one embodiment of the present invention, the effective dose of a compound is sufficient to reduce or inhibit the activity of an enzyme or protein; or to achieve a biological or therapeutic effect, such as improving symptoms, alleviating a medical condition, slowing or delaying the progression of a disorder, or preventing a disease.

[0185] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid.

[0186] Terms such as “administer,” “administering,” and “administration” refer to methods that may be used to enable the delivery of the active ingredient to the desired site of biological action. The routes or forms of administration are as described herein. These methods include, but are not limited to, oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical / percutaneous, and rectal / vaginal administration. Those skilled in the art will be familiar with the available administration techniques. For compound (1), oral administration is preferred. For the platinum anticancer agent, intravenous injection is preferred. For the optional pemetrexed, intravenous injection is preferred.

[0187] As used herein, “co-administration,” “administered in combination,” and their grammatical equivalents encompass the administration of two or more drugs to a subject such that both drugs and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a single fixed-dose composition in which both drugs are present.

[0188] In this disclosure, "administration schedule" refers to a plan that shows the type, amount, duration, and procedure of drugs in drug therapy in chronological order, and indicates the dosage, method of administration, order of administration, and administration day for each drug. The designated administration day is determined before the start of drug administration. A series of administration schedules is called a "course," and administration is continued by repeating that course.

[0189] With respect to the administration schedule of this application, "continuous" means administration every day without interruption during the course of treatment. If the administration schedule follows an "intermittent" administration schedule, there may be one or more "rest days" or drug-free days in the course after one or more days of administration.

[0190] A "drug-free period" refers to a time when a drug is not administered according to a prescribed dosing schedule. For example, after several treatment courses, a controlled drug-free period may be prescribed as part of the dosing schedule, for instance, before resuming active treatment.

[0191] Dosage and duration of treatment vary depending on factors such as the bioavailability of the drug, mode of administration, drug toxicity, sex, age, lifestyle, weight, use of other drugs and nutritional supplements, disease stage, and the body's tolerance to the administered drug, and are then determined and adjusted accordingly. The appropriate dosage may vary from person to person. The appropriate dosage in any individual case can be determined using techniques such as dose escalation. An appropriate dosage may include a certain amount of compound (1). An appropriate dosage may also include a certain amount of an additional therapeutic agent (e.g., a platinum-based anticancer agent), as described below. These amounts may vary independently or together (e.g., a single dosage may be varied to maintain a specific ratio of compound (1) to the amount of the additional therapeutic agent).

[0192] Patients with cancer having at least one abnormality in EGFR can be treated with compound (1) or a pharmaceutically acceptable salt thereof at dose levels ranging from approximately 10 mg / day, 15 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 140 mg / day, 500 mg / day, 480 mg / day, 450 mg / day, 400 mg / day, 350 mg / day, 300 mg / day, 250 mg / day, 240 mg / day, 200 mg / day, and 150 mg / day. The dosage level may vary within ranges such as approximately 10 mg / day to approximately 500 mg / day, approximately 20 mg / day to approximately 300 mg / day, and approximately 30 mg / day to approximately 150 mg / day. In one embodiment, the dosage level is approximately 100 mg / day. The dosage level can be changed during the administration schedule. For example, administration can be started at a low dose for a while and then increased, or administration can be started at a high dose for a while and then decreased. The dosage can be reduced, but is not limited. The dosage may be reduced, for example, from 300 mg / day to 150 mg / day, from 300 mg / day to 100 mg / day, and from 100 mg / day to 50 mg / day.

[0193] Administration may be continuous (daily, 7 days a week) or intermittent (alternating between one or more administration days with one or more non-administration days, e.g., 4 days on / 3 days off), depending on pharmacokinetics and drug clearance / accumulation in a particular patient. The administration schedule should be selected using sound medical judgment. The dosage may be adjusted in response to the occurrence of side effects and symptoms, e.g., reduction from twice daily (BID) to once daily (QD). Daily administration is preferred. Administration can be every other day (QOD), once daily (QD), twice daily (BID), or three or more times per day (TID, etc.), with a preferred dose of approximately 60-300 mg / day, and most preferably approximately 200 mg / day.

[0194] If a patient experiences a clinically significant adverse event, such as a CTCAE V5.0 Grade 3 or higher, and / or otherwise unacceptable toxicity, administration of CLN-081 should be discontinued and supportive care should be provided as described in Table 11. Based on the severity and / or resolution of the adverse event, the study treatment may be discontinued or resumed, with or without dose reduction, according to the criteria detailed in Table 11. Recommended dose reductions are presented in Table 12.

[0195] The daily dose can be administered as a single dose or as multiple individual divided doses. For example, a patient may be given one tablet containing 50 mg of compound (1) or a pharmaceutically acceptable salt thereof once daily (QD) for a total dose of 50 mg / day. In another example, a patient may be given two tablets, each containing 50 mg of compound (1) or a pharmaceutically acceptable salt thereof, once daily (QD) for a total dose of 100 mg / day. In yet another example, a patient may be given one tablet containing 50 mg of compound (1) or a pharmaceutically acceptable salt thereof twice daily (BID) for a total dose of 100 mg / day. In yet another example, a patient may be given two tablets, each containing 50 mg of compound (1) or a pharmaceutically acceptable salt thereof, twice daily (BID) for a total dose of 200 mg / day. In another example, three tablets, each containing 10 mg of compound (1) or a pharmaceutically acceptable salt thereof, may be administered once daily (QD) for a total dose of 30 mg / day. In yet another example, three tablets, each containing 20 mg of compound (1) or a pharmaceutically acceptable salt thereof, may be administered twice daily (BID) for a total dose of 120 mg / day. Multiple individual divided doses may be equal in terms of the amount of compound (1) or a pharmaceutically acceptable salt thereof, or they may contain different amounts of compound (1) or a pharmaceutically acceptable salt thereof. For example, one tablet containing 50 mg of compound (1) or a pharmaceutically acceptable salt thereof may be administered to the patient as the first dose of the day, and two tablets, each containing 50 mg of compound (1) or a pharmaceutically acceptable salt thereof, may be administered to the patient as the second dose of the day (total dose of 150 mg / day).

[0196] Whether continuous or intermittent, administration continues over a specific treatment cycle, typically a cycle of at least 21 days, and can be repeated with or without rest periods. Longer or shorter cycles may also be used, such as 7, 14, 18, 24, 28, 35, 42 days, or any range in between. Treatment cycles may be repeated with or without rest periods, depending on the patient. Alternating consecutive day treatment cycles may be used. For example, a 7-day administration schedule may be used, with each period alternating between 4 days on and 3 days off. This schedule might include administration on days 1, 3, 5, 7, 8, 10, 12, 14, 15, 17, 19, 21, etc. Other schedules are possible depending on the presence or absence of adverse events, the cancer's response to treatment, and the patient's convenience. "Adverse event" refers to any undesirable or unintended illness or symptom that occurs in a patient to whom the drug has been administered. Whether or not there is a causal relationship with the drug is irrelevant.

[0197] High doses are usually administered intermittently, while doses up to approximately 500 mg are usually administered continuously (daily). Compound (1) may also be administered using an uptitration regimen, in which the subject is started with a low dose over a specific period (e.g., two weeks), and then the dose is gradually increased. The dose is increased until either the target dose or the maximum dose is reached, or the subject experiences an adverse event, at which point the increase is stopped, and the drug is reduced to the previous dose in which no adverse event was experienced or was not severe enough to require discontinuation of treatment. Subjects who experience an adverse event may also be managed by drug interruption (e.g., drug-free period) if deemed appropriate. Typical doses in a serial regimen may be 30, 45, 50, 60, 75, 100, 150, 200, 250, 300, 350, or 400 mg / day, but higher or lower doses may be used depending on the target response to treatment and the presence or absence of adverse events. If a dose is well tolerated, that dose can be increased. Serial administration may consist of one treatment cycle, for example, 21 days, after which the treatment cycle may be repeated as needed. In some embodiments, only one treatment cycle is performed. In some embodiments, up to 10 treatment cycles are performed. In general, any number of treatment cycles can be performed, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles. Drug-free periods may be included between any treatment cycles. A treatment regimen may include treatment cycles with drug-free periods and treatment cycles without drug-free periods.

[0198] Such continuous or intermittent administration is also applicable to combination therapies in which compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents (e.g., other anticancer agents).

[0199] The therapeutic methods described herein may involve the administration of compound (1) or a pharmaceutically acceptable salt thereof. The treatment may also include administration as adjuvant chemotherapy after surgical removal of the tumor to prevent recurrence of the tumor, as well as as neoadjuvant chemotherapy before surgery to surgically remove the tumor. In some cases, such as breast cancer, surgery may include mammary gland tumor removal, mastectomy, and breast reconstruction. In some cases, such as lung cancer, surgery may include lung resection, lobectomy, wedge resection, sleeve resection, and thoracoscopy. In some cases, such as brain tumors, surgery may include craniotomy, ventricular-peritoneal shunt, endoscopic third ventriculoscopy, and ventricular access catheter placement. The treatment may also include the administration of compound (1) or a pharmaceutically acceptable salt thereof as adjuvant therapy to prevent recurrence of the tumor in patients whose cancer has been eliminated by radiotherapy, or by other treatments such as surgery.

[0200] Subjects who have previously received a treatment regimen with one or more molecularly targeted therapies may be treated, i.e., compound (1) or a pharmaceutically acceptable salt thereof may be administered as a second-line, third-line, fourth-line, etc. Subjects who have previously been treated with EGFR-targeted therapies such as EGFR inhibitors may also be treated. EGFR inhibitors may be classified as EGFR tyrosine kinase inhibitors or anti-EGFR antibodies, such as those described herein, including afatinib, gefitinib, erlotinib, osimertinib, poziotinib, razertinib, sunbozertinib, flumonertinib, mobocertinib, lapatinib, neratinib, cetuximab, and dacomitinib. Examples of such compounds include, but are not limited to, panitumumab, vandetanib, DZD9008, BDTX-189, amibantamab, pembrolizumab, brigatinib, icotinib, olmutinib, rosiletinib, durigotuzumab, zaltumumab, depatuxizumab, depatuxizumab mafodotin, imugatuzumab, matsuzumab, nimotuzumab, and nesitumumab. Patients treated with the compounds(1) described herein or their pharmaceutically acceptable salts may or may not have been previously treated with other anticancer agents(s) other than EGFR inhibitors, examples of which are described below.

[0201] As described below, compound (1) or a pharmaceutically acceptable salt thereof may be specifically formulated for administration in solid or liquid form, including those adapted to the following: (1) oral administration, e.g., drenches (aqueous or nonaqueous solutions or suspensions), tablets or capsules, e.g., buccal, sublingual, and for systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue; (2) parenteral administration, e.g., sterile solutions or suspensions, or as sustained-release formulations, e.g., by subcutaneous, intramuscular, intravenous or epidural injection; (3) topical / transdermal administration, e.g., as creams, ointments, or controlled-release patches or sprays applied to the skin; (4) intravaginal or rectal administration, e.g., as pessaries, creams or foams; or (5) intranasal administration. In the case of compound (1) or a pharmaceutically acceptable salt thereof, oral formulations are preferred.

[0202] The formulation can be prepared by known formulation methods using pharmaceutically acceptable carriers, etc. A pharmaceutically acceptable carrier is a material, composition, or vivicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium talc, calcium stearate or zinc stearate, or stearic acid), or solvent encapsulation material, that is involved in transporting or carrying the compound of the subject from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository waxes; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, e.g., propylene glycol; (11) Polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) Esters, e.g., ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethyl alcohol; (20) pH buffers; (21) Polyesters, polycarbonates, and / or polyacid anhydrides; and (22) Other non-toxic, suitable substances used in pharmaceutical formulations, e.g., cyclodextrins, liposomes, micellars (such as bile acids).

[0203] Pharmaceutically acceptable carriers can be classified into various general-purpose agents such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, swelling agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and taste modifiers.

[0204] Examples of excipients include, but are not limited to, lactose, sucrose, D-mannitol, glucose, starch (corn starch), calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.

[0205] Examples of binders include, but are not limited to, water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid α-starch, liquid gelatin, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose (e.g., low viscosity hydroxypropylcellulose), hydroxypropylmethylcellulose (hypromellose), hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone.

[0206] Examples of disintegrants include, but are not limited to, low-substituted hydroxypropylcellulose, dried starch, partially pregelatinized starch, crystalline cellulose, carmellose sodium, carmellose calcium, D-mannitol, crospovidone, croscarmellose sodium, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose.

[0207] Examples of lubricants include, but are not limited to, hydrogenated oils, sucrose fatty acid esters, sodium lauryl sulfate, stearic acid, refined talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.

[0208] Examples of colorants include, but are not limited to, Food Yellow No. 5 dye, Food Blue No. 2 dye, Food Lake dye, ferric oxide, yellow ferric oxide, and titanium dioxide.

[0209] Examples of sweeteners / flavorings include, but are not limited to, aspartame, saccharin (as sodium saccharin, potassium saccharin, or calcium saccharin), cyclamate (as sodium salt, potassium salt, or calcium salt), sucralose, acesulfame K, thaumatin, neohesperidin, dihydrochalcone, ammonia-derived glycyrrhizin, dextrose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, wintergreen oil, peppermint oil, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, lemon, lime, and lemon-lime.

[0210] If necessary, oral formulations may be coated with an enteric coating or a coating to enhance the duration of effect by a method of preference. Examples of such coatings include hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyethylene glycol, and Tween80®.

[0211] Compound (1) or a pharmaceutically acceptable salt thereof is preferably formulated in the form of a solid dosage form for oral administration, such as capsules, tablets, pills, sugar-coated tablets, powders, granules, or lozenges, with film-coated tablets being preferred. Compound (1) or a pharmaceutically acceptable salt thereof may be mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate or dicalcium phosphate, and / or any of the following). (1) Fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) Binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) Humectants, e.g., glycerol; (4) Disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) Dissolution retarders, e.g., paraffin; (6) Absorption enhancers, e.g., quaternary ammonium compounds and surfactants (such as poloxamer and sodium lauryl sulfate); 7) Wetting agents, e.g., cetyl alcohol, glycerol monostearate, and nonionic surfactants (e.g., sorbitan fatty acid esters and polyalkoxylated sorbitan fatty acid esters, e.g., Tween80®), (8) Absorbents, e.g., kaolin and bentonite clay, (9) Lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (10) Colorants, and (11) Controlled release agents, e.g., crospovidone or ethylcellulose. In the case of capsules, tablets and pills, the formulation may also include buffers. Similar types of solid compositions may also be used as fillers in soft-shelled gelatin capsules and hard-shelled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0212] Tablets may be prepared by compression or molding with one or more optional adjuncts. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), a surfactant, or a dispersant. Molded tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine. Tablets and other solid dosage forms may be prepared by serration, coating, and shell (such as enteric coatings and other coatings well known in the pharmaceutical field) as needed. Examples of coating formulations include hypromellose, polyethylene glycol, titanium dioxide, and optionally a colorant. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using varying proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile. They may be formulated for immediate release and may be lyophilized, for example. These can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These formulations may also optionally contain an opacifier, and may be compositions that release the active ingredient(s) only or preferentially, and possibly delayed, to a specific portion of the gastrointestinal tract. Examples of usable embedding compositions include polymers and waxes. The active ingredient(s) may also be in microencapsulated form together with one or more of the excipients described above, if appropriate.

[0213] Compound (1) or a pharmaceutically acceptable salt thereof may be formulated for intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or parenteral administration by combining Compound (1) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders (which may contain sugars, alcohols, antioxidants, buffers, bacteriostatic agents, solutes to be isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners) that can be reconstituted into sterile injection solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers that can be used include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions may contain adjuvants such as preservatives, humectants, emulsifiers, dispersants, pH adjusters, stabilizers, and local anesthetics. Prevention of microbial activity against the subject compound can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. In addition, the inclusion of absorption-delaying agents such as aluminum monostearate and gelatin can lead to prolonged absorption of the injectable drug form.

[0214] Compound (1) or a pharmaceutically acceptable salt thereof may be combined with one or more additional therapeutic agents. Examples of additional therapeutic agents include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and antihormone agents, targeted therapies, and anti-angiogenic agents. Additional therapeutic agents may be anticancer agents. Many anticancer agents may be classified into one or more of these groups. Certain anticancer agents are classified herein into specific groups or subgroups, but many of these agents may also be enumerated in one or more other groups or subgroups, as is currently understood in the art. Where used herein, “combination” may refer to concurrent treatment (e.g., co-administration of the same or different regimens), overlapping treatment, sequential treatment, or a combination thereof. Sequential treatment may include treatment with compound (1) or a pharmaceutically acceptable salt thereof first, followed by treatment with one or more anticancer drugs, or treatment with one or more anticancer drugs first, followed by treatment with compound (1) or a pharmaceutically acceptable salt thereof. In sequential treatment, there may be a treatment gap, i.e., a period of time between the completion or discontinuation of the first treatment and the commencement of the second treatment.

[0215] The anticancer drugs are not particularly limited and include, for example, chemotherapeutic agents, mitotic inhibitors, plant alkaloids, alkylating agents, antimetabolites, platinum anticancer drugs, enzymes, topoisomerase inhibitors, retinoids, aziridines, antibiotics, hormones, antihormone agents, antiestrogens, antiandrogens, antiadrenal agents, androgens, targeted therapy agents, immunotherapy agents, biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, anti-PD-1 agents, anti-PD-L1 agents, colony-stimulating factors, immunomodulators, immunomodulatory imides (IMiDs), anti-CTLA4 agents, anti-LAG1 agents, anti-OX40 agents, GITR agonists, CAR-T cells, bispecific T cell-inducing antibodies (BiTEs), signal transduction inhibitors, Examples of such inhibitors include, but are not limited to, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, HER2 inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell cycle inhibitors, anti-angiogenic agents, matrix metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, HIF-1α inhibitors, HIF-2α inhibitors, fibroblast growth factor (FGF) inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF inhibitors, RAS inhibitors, gene expression regulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0216] Non-exclusive examples of chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, antimetabolites, platinum-based anticancer agents, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[0217] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes (e.g., cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel), demecorsin, epothilone, eribulin, etoposide (VP-16), etoposide phosphate, navelbine, noscapine, teniposide, taliblastine, vinblastine, vincristine, vindesine, vinflunin, and vinorelbine.

[0218] Non-limiting examples of alkylating agents include nitrogen mustards (e.g., chlorambucil, chlornafadin, colophosphamide, cytophosphan, estramustine, ifosfamide, mannomustine, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenesterine, prednimustine, tris(2-chloroethyl)amine, trophosphamide, and uracil mustard), alkyl sulfonates (e.g., busulfan, improsulfan, and biposulfan), and nitrosoureas (e.g., carmustine, chlorozotosine, Examples include fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07), ethyleneimines and methylamelamamines (e.g., altretamine, thiotepa, triethylenemelamine, triethylenethiophosphoramide, triethylenephosphoramide, and trimethylolomelamamine), ambamustine, bendamustine, dacarbazine, cyclophosphamide, etogluside, ilofluben, maphosphamide, mitobronitol, mitractol, pipobromane, procarbazine, temozolomide, treosulfan, and triadicone.

[0219] Non-limiting examples of antimetabolites include folate analogs (e.g., aminopterin, denopterin, edatrexate, methotrexate, pteropterin, larcitrexed, trimethrexate, and pemetrexed, of which pemetrexed is preferred), purine analogs (e.g., 6-mercaptopurine, 6-thioguanine, fludarabine, folodesine, thiamipurine, and thioguanine), and pyrimidine analogs (e.g., 5-fluorouracil (5-FU), tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine, trifluridine / tipiracil). Examples include tegafur hydrochloride, 6-azauridine, ancitabine, azacitidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifiuridine, doxifluridine, enocitabine, floxuridine, gallocitabine, gemcitabine, and sapacitabine), 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone, broxuridine, cladribine, cyclophosphamide, cytarabine, emiteflu, hydroxyurea, mercaptopurine, nerarabine, pentostatin, tegafur, and troxacitabine.

[0220] Non-exclusive examples of platinum-based anticancer drugs such as oxaliplatin, cisplatin, carboplatin, and nedaplatin. Of these, carboplatin is preferred.

[0221] Non-specific examples of enzymes include asparaginase and peg asparagase.

[0222] Non-exclusive examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrin, berotecan, eriptinium acetate, exatecan, indolocarbazole, irinotecan, lulutotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0223] Non-specific examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, rialozol, RII retinamide, and tretinoin.

[0224] Non-exclusive examples of aziridines include benzodopa, carbocone, metsuredopa, and uredopa.

[0225] Non-exclusive examples of antibiotics include intercalate antibiotics, anthracendions, anthracycline antibiotics (e.g., acralubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogalil, nogaramycin, pirarubicin, and barurubicin), 6-diazo-5-oxo-L-norleucine, acrasinomycin, actinomycin, ausramycin, azaserin, bleomycin, kakutinomycin, calicheamicin, carabicin, carminomycin, cardino Examples include phylline, chromomycin, dactinomycin, detrubicin, esorubicin, esperamicin, geldanamycin, marcelomycin, mitomycin, mitomycin C, mycophenolic acid, olibomycin, novanthron, peplomycin, porphyromycin, potophylromycin, puromycin, keramycin, rebeccamycin, rhodorubicin, streptonigrin, streptozocin, tanespimycin, tubercidine, ubenimex, dinostatin, dinostatin stimalamer, and zolubicin.

[0226] Non-exclusive examples of hormonal and antihormone agents include antiandrogens (e.g., abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide), antiestrogens (e.g., 4-hydroxytamoxifen, aromatase inhibitor 4(5)-imidazole, EM-800, phosfestrol, fulvestrant, keoxyfen, LY117018, onapristone, raloxifen, tamoxifen, toremifene, and trioxyfen), and antiadrenal agents (e.g., aminoglutethimide, dexaaminoglutethimide, mitotamide). Examples include steroids (and trilostane), androgens (e.g., carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone), Avalix, anastrozole, cerotorelix, deslorerin, exemestane, fadrozol, finasteride, formestan, histrelin (RL0903), human chorionic gonadotropin, lanreotide, LDI200 (Milkhaus), letrozole, leuprorelin, mifepristone, nafarelin, napoxidine, osaterone, prednisone, thyrotropin alfa, and triptorelin.

[0227] Non-exclusive examples of immunotherapeutic agents (i.e., immunotherapy) include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.

[0228] Non-exclusive examples of biological response modifiers include cytokine inhibitors (cytokines) such as interferons and interleukins, which include interferon alpha / interferon alpha (e.g., interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-nl, interferon alpha-n3, interferon alpha-con-1, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and leukocyte alpha-interferon), interferon beta (e.g., interferon beta-1a and interferon beta-1b), interferon gamma (e.g., natural interferon gamma-1a and interferon gamma-1b), aldesleukin, interleukin-1 beta, interleukin-2, oprelbequin, sonelmin, tasonelmin, and billysine.

[0229] Non-exclusive examples of tumor vaccines include APC8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin-17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolytic vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacillus Calmette-Guerin), and viral melanoma cell lysate vaccine (Royal Newcastle Hospital).

[0230] Non-exclusive examples of monoclonal antibodies include avagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER-2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), ipilimumab, lintuzumab, LYM-1-iodine-131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, and polymorphic epithelial mucin-yttrium 90 Examples include MAb (Antisoma), ranibizumab, rituximab, beltuzumab, patritumab deruxtecan, datopotamab, and trastuzumab.

[0231] Non-exclusive examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies (e.g., cemiprimab, nivolumab, and pembrolizumab), anti-PD-L1 agents or antibodies (e.g., atezolizumab, avelumab, and durvalumab), anti-CTLA-4 agents or antibodies (e.g., ipilumumab and tremelimumab), anti-LAG1 agents, and anti-OX40 agents.

[0232] Non-exclusive examples of colony-stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte-macrophage colony-stimulating factor, lenograstim, religistim, myrimostim, morglamostim, naltograstim, pegfilgrastim, and salglamostim.

[0233] Non-exclusive examples of additional immunotherapies include BiTE, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiD), mismatched double-stranded RNA (Ampligen), reximod, SRL172, and thymalfacin.

[0234] Examples of targeted therapies include monoclonal antibodies and small molecule drugs. Non-exclusive examples of targeted therapies include signaling inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, HER2 inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell cycle inhibitors, angiogenesis inhibitors, matrix metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factor (FGF) inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF inhibitors, RAS inhibitors, gene expression regulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0235] Non-exclusive examples of tyrosine kinase inhibitors include EGFR inhibitors, HER2 inhibitors, JAK inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factor (FGF) inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, BRAF inhibitors, RAS inhibitors, TYK2 inhibitors, c-MET inhibitors, RET inhibitors, and ROS1 inhibitors.

[0236] Non-exclusive examples of signal transduction inhibitors include tyrosine kinase inhibitors, multi-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, ronidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR and / or HER2 inhibitors (i.e., other than compound (1) or its salts).

[0237] Non-exclusive examples of EGFR inhibitors include EGFR small molecule antagonists (e.g., afatinib, brigatinib, erlotinib, gefitinib, lapatinib, neratinib, dacomitinib, vandetanib, and osimertinib), as well as antibody-based EGFR inhibitors (including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand). Antibody-based EGFR inhibitors include, for example, those described in Modjtahedi, H., et al., 1993, Br.J. Cancer 67:247-253, Teramoto, T., et al., 1996, Cancer 77:639-645, Goldstein et al, 1995, Clin. Cancer Res. 1:1311-1318, Huang, SM, et al., 1999, Cancer Res. 15:59(8):1935-40, and Yang, X., et al., 1999, Cancer Res. 59:1236-1243; monoclonal antibody Mab E7.6.3 (Yang, 1999 above); Mab Antibodies or antibody fragments having binding specificity for C225 (ATCC accession number HB-8508) or therefor; specific antisense nucleotides or siRNAs; afatinib, cetuximab, matsuzumab, necitumumab, nimotuzumab, panitumumab, and saltumumab.

[0238] Non-exclusive examples of HER2 inhibitors include HER2 tyrosine kinase inhibitors (e.g., afatinib, lapatinib, neratinib, and tucatinib) and anti-HER2 antibodies or their drug conjugates (e.g., trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, margetuximab, trastuzumab deruxtecan (DS-8201a), and trastuzumab duocalmazine).

[0239] Non-exclusive examples of histone deacetylase (HDAC) inhibitors include bellinostat, panobinostat, romidepsin, and vorinostat.

[0240] Non-exclusive examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.

[0241] Non-exclusive examples of cell cycle inhibitors, including CDK inhibitors, include abemaciclib, arbocidicib, palbociclib, and ribociclib.

[0242] Non-exclusive examples of anti-angiogenic agents (or angiogenesis inhibitors) include matrix metalloproteinase (MMP) inhibitors, VEGF inhibitors, EGFR inhibitors, TOR inhibitors (e.g., everolimus and temsirolimus), PDGFR kinase inhibitors (e.g., clenolanib), HIF-1α inhibitors (e.g., PX478), HIF-2α inhibitors (e.g., berzutifan and HIF-2α inhibitors described in WO2015 / 035223), fibroblast growth factor (FGF) or FGFR inhibitors (e.g., B-FGF and RG13577), hepatocyte growth factor inhibitors, KDR inhibitors, anti-Ang1 and anti-Ang2 agents, and anti-Tie2 kinase inhibitors. Examples include, but are not limited to, agents, Tek antagonists (US2003 / 0162712, US6,413,932), anti-Tweak agents (US6,727,225), ADAM disintegrin domains that antagonize integrin binding to their ligands (US2002 / 0042368), anti-eph receptors and / or anti-ephrin antibodies or antigen-binding regions (US5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, and 6,057,124), and antibodies or antigen-binding regions that specifically bind to anti-PDGF-BB antagonists and PDGF-BB ligands.

[0243] Non-exclusive examples of matrix metalloproteinase (MMP) inhibitors include MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, prinomast, RO32-3555, and RS13-0830. Examples of useful matrix metalloproteinase inhibitors include, for example, WO96 / 33172, WO96 / 27583, EP1004578, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, EP0606046, and EP093. As described in 1788, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO1999 / 007675, EP1786785, EP1181017, US2009 / 0012085, US5,863,949, US5,861,510, and EP0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity to inhibit MMP-1. More preferably, it selectively inhibits MMP-2 and / or MMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0244] Non-exclusive examples of VEGF and VEGFR inhibitors include bevacizumab, cedilanib, CEP7055, CP547632, KRN633, olanchinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonists (Borean, Denmark), and VEGF-TRAP®.

[0245] Other anti-angiogenic agents include 2-methoxyestradiol, AE941, alemtuzumab, alpha-D148 Mab (Amgen, US), alpha-statin, anecoltab acetate, angiocidin, angiogenesis inhibitor (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD9935, BAY RES2690 (Bayer, Germany), BC1 (Genoa Institute of Cancer Research, Italy), beroranib, benefin (Lane Labs, US), cabozantinib, CDP791 (Celltech Group, UK), chondroitinase AC, sirengitide, combretastatin A4 prodrug, CP564959 (OSI, US), CV247, CYC381 (Harvard University, US), E7820, EHT0101, Endostatin, Enzastaurin hydrochloride, ER-68203-00 (IVAX, US), Fibrinogen-E fragment, Flk-1 (ImClone Systems, US), Form of FLT1 (VEGFR1), FR-111142, GCS-100, GW2286 (GlaxoSmithKline, UK), IL-8, Ilostat, IM-862, Ilsogladine, KM-2550 (Kyowa Hakko, Japan), Lenalidomide, Lenvatinib, MAb alpha-5 beta-3 integrin, 2nd generation (Applied Molecular Evolution, USA and Medlmmune, US), MAb VEGF (Xenova, UK), Marimast, Masupin (Sosei, Japan), Metastatin, Motupolamine C, M-PGA, Ombrabrin, OXI4503, PI88, Platelet Factor IV, PPI2458, Ramucirumab, rBPI21 and BPI-derived anti-angiogenic agents (XOMA, US), Regorafenib, SC-236, SD-7784 (Pfizer, US), SDX103 (University of California at San Francisco)Examples include, but are not limited to, Diego (US), SG292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TBC-1635, tesevatinib, tetrathiomolybdate, thalidomide, thrombospondin 1 inhibitors, Tie-2 ligand (Regeneron, US), tissue factor pathway inhibitors (EntreMed, US), tumor necrosis factor-alpha inhibitors, tamstatin, TZ93, urokinase plasminogen activator inhibitors, bazimesan, vandetanib, vasostatin, batalanib, VE-cadherin-2 antagonists, xantrizole, XL784 (Exelixis, US), ziv-aflibercept, and ZD6126.

[0246] The anticancer agents (multiple) that may be combined with compound (1) may also be active agents that disrupt or inhibit the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway, or PD-1 and / or PD-L1 antagonists. Examples of these include, but are not limited to, RAF inhibitors, EGFR inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, or immunotherapies (including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1 agents, anti-PD-L-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTE).

[0247] Non-exclusive examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.

[0248] Non-exclusive examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.

[0249] Non-exclusive examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, laboxerutinib, urixerutinib, and ASTX029.

[0250] Non-exclusive examples of PI3K inhibitors include 17-hydroxywoltmannin analogs (e.g., WO06 / 044453), AEZS-136, alpelisib, AS-252424, buparisib, CAL263, copanlisib, CUDC-907, dactricib (WO06 / 122806), demethoxypyridine, duvelisib, GNE-477, GSK1059615, IC87114, idelalisib, INK1117, Examples include LY294002, Palomid529, Paxalisib, Perifosin, PI-103, PI-103 hydrochloride, Pictilisib (e.g., WO09 / 036,082, WO09 / 055,730), PIK90, PWT33597, SF1126, Sonolisib, TGI00-115, TGX-221, XL147, XL-765, Waltmannin, Taselicib (GDC-0032), and ZSTK474.

[0251] Non-exclusive examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408), Akt-1-1,2 (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408), API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12), lH-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700), indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963, Sarkar and Li (2004) J Nutr. 134 (12)). Suppl), 3493S-3498S), Perifosin, Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004), Phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97), Trisirivine (Yang et al. (2004) Cancer Res.64,4394-9), imidazooxazone compounds (including trans-3-amino-1-methyl-3-[4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (WO2012 / 137870)), afrecertib, capivacertib, 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4- Examples include triazolo[3,4-f][1,6]naphthyridine-3(2H)-one (MK2206) and its pharmaceutically acceptable salts, AZD5363, trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (TAS117) and its pharmaceutically acceptable salts, and patasertib.

[0252] Non-exclusive examples of TOR inhibitors include deforolimus, ATP competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30, and Torin1), TOR inhibitors in FKBP12 enhancers, rapamycin and its derivatives (including temsirolimus, everolimus, and WO9409010), rapalogs (e.g., those disclosed in WO98 / 02441 and WO01 / 14387 (e.g., AP23573, AP23464, or AP23841)), 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin, 40-epi(tetrazolyl)-rapamycin (also known as ABT578), AZD8055, 3 2-Deoxorapamycin, 16-Pentinyloxy-32(S)-Dihydrorapamycin, and other derivatives (as disclosed in WO05 / 005434), derivatives (US5,258,389, WO94 / 090101, WO92 / 05179, US5,118,677, US5,118,678, US5,100,883, US5,151,413, US5 Examples include those disclosed in 120,842, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and US5,256,790, as well as phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252).

[0253] Non-exclusive examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[0254] Non-exclusive examples of SHP2 inhibitors include JAB-3068, RMC-4630, TNO155, SHP-099, RMC-4550, and SHP2 inhibitors listed in WO2019 / 167000, WO2020 / 022323, and WO2021 / 033153.

[0255] Non-exclusive examples of RAS inhibitors include AMG510, MRTX849, LY3499446, JNJ-74699157 (ARS-3248), ARS-1620, ARS-853, RM-007, and RM-008.

[0256] Additional non-limiting examples of anticancer agents that may be suitable for use include: 2-ethylhydrazide, 2,2',2''-trichlorotriethylamine, ABVD, acegraton, acemannan, aldofosphamide glycoside, alfarazine, amifostin, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxin, antitumor-forming herbs, apadicon, algravin, arsenic trioxide, azathioprine, BAM002 (Novelos), bcl-2 (Genta), Bestrabusil, bilicodal, bisanthren, bromocriptine, brostarisin, bryostatin, and butionin. Ruhoximin, kallikrin, cell cycle nonspecific antitumor agents, cermoloukin, clodronate, clotrimazole, cytarabine oclosphate, DA3030 (Dong-A), defofamin, denileukin difutitox, dexrazoxane, diazicon, dichloroacetic acid, dilazep, discodermorid, docosanol, doxelcalciferol, ederfosine, eflornithine, EL532 (Elan), elfomithine, erusamitrusine, enyluracil, etanidazole, exislind, ferginol, folic acid supplements, e.g., frolinic acid(acid), gasitosine, gallium nitrate, gimeracil / oteracil / tegafur combination (S-1), glycopine, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha-fetoprotein, ibandronate, ibandronate, ICE chemotherapy regimen, imexone, iovenguan, IT-101 (CRLX101), lanikidal, LC9018 (Yakult), leflunomide, lentinan, levamisole + fluorouracil, lovastatin, rucanton, masopropyl, melarsoprol, metoclopramide, miltefosine, miproxyfen, mitogwazon, mitozolomid, mopidamol, motexafingadolinium, MX6 (Galderma), naloxone + pentazocine, nitracrine, noratexed, NSC631570 Octre Otide (Ukrain), Olaparib, P-30 protein, PAC-1, Palifermin, Pamidronate, Pamidronic acid, Pentosan polysulfate sodium, Fenamet, Picibanil, Pixantrone, Platinum, Podophyllic acid, Porfimer sodium salt, PSK (Polysaccharide-K), Rabbit anti-thymocyte polyclonal antibody, Rasbrien bodyment, Retinoic acid, Rhenium Re186 etidronate, Romultide, Samarium (153Sm) lexidronam, Schizophyllan, Phenylacetate sodium, Sparphosic acid, Spirogermanium, Strontium-89 chloride, Suramin, Swinesonin, Talaporfin, Taliquidal, Tazarotene, Tegafur-uracil, Temoporfin, Tenuazonic acid, Tetrachlorodecaoxide, Thrombopoietin, Ethyl etiopluris, Tirapazamin, TLC Examples include, but are not limited to, ELL-12, tositumomab-iodine-131, trifluridine and tipiracil combinations, troponin I (Harvard University, US), urethane, valspodar, verteporfin, zoledronic acid, and zoskidal.

[0257] Cisplatin can be administered at dose levels ranging from approximately 10 mg / m2, 15 mg / m2, 20 mg / m2, 30 mg / m2, 40 mg / m2, 50 mg / m2, 60 mg / m2, 80 mg / m2, 90 mg / m2, 250 mg / m2, 225 mg / m2, 200 mg / m2, 175 mg / m2, 150 mg / m2, 125 mg / m2, and 110 mg / m2. The dosage level may vary within the range of approximately 10 mg / m² to approximately 250 mg / m², approximately 20 mg / m² to approximately 150 mg / m², preferably approximately 50 mg to approximately 100 mg / m², preferably approximately 60 mg to approximately 90 mg / m², preferably approximately 70 mg to approximately 80 mg / m², more preferably approximately 72.5 mg to approximately 77.5 mg / m², and more preferably approximately 75 mg / m². The dosage level can be changed during the administration schedule. For example, administration can be started at a low dose for a while and then increased, or administration can be started at a high dose for a while and then decreased.

[0258] Cisplatin (or other platinum-based anticancer agents) can be administered continuously (daily, 7 days a week), intermittently (alternating between one or more administration days with one or more non-administration days, e.g., 4 days on / 3 days off), or once per cycle, depending on pharmacokinetics and the drug clearance / accumulation in a particular patient. The administration schedule should be selected using sound medical judgment. Once per cycle administration of cisplatin is preferred. Preferably, the once per cycle administration is performed on the first day of the treatment cycle. For a 21-day treatment cycle, the once per cycle administration is preferably performed only on the first day (day 1) of the treatment cycle.

[0259] The dose per cycle may be administered as a single dose or as multiple individual divided doses. For example, a single intravenous injection containing approximately 50–100 mg / m2 of cisplatin may be administered on the first day of the treatment cycle. In another example, three separate intravenous injections, each containing 20 mg / m2 of cisplatin, may be administered to the subject on that day, totaling 60 mg / m2 per day.

[0260] Whether continuous, intermittent, or once per cycle, administration continues over a specific treatment cycle, typically at least 21 days, and can be repeated with or without a rest period. Longer or shorter cycles, such as 7, 14, 18, 24, 28, 35, 42 days, or any range in between, may also be used. Treatment cycles may be repeated with or without a rest period, depending on the patient.

[0261] Carboplatin can be administered at dose levels ranging from approximately AUC 1.0 mg / mL / min to approximately AUC 1.5 mg / mL / min, approximately AUC 2.0 mg / mL / min, approximately AUC 2.5 mg / mL / min, approximately AUC 3.0 mg / mL / min, approximately AUC 3.5 mg / mL / min, approximately AUC 4.0 mg / mL / min, approximately AUC 4.5 mg / mL / min, up to approximately AUC 10.0 mg / mL / min, up to approximately AUC 9.5 mg / mL / min, up to approximately AUC 9.0 mg / mL / min, up to approximately AUC 8.5 mg / mL / min, up to approximately AUC 8.0 mg / mL / min, up to approximately AUC 7.5 mg / mL / min, up to approximately AUC 7.0 mg / mL / min, up to approximately AUC 6.5 mg / mL / min, up to approximately AUC 6.0 mg / mL / min, and up to approximately AUC 5.5 mg / mL / min. The dosage level may vary within ranges such as approximately AUC 1 mg / mL / min to approximately AUC 10 mg / mL / min, approximately 2.5 mg / mL / min to approximately AUC 7.5 mg / mL / min, and approximately 4.5 mg / mL / min to approximately AUC 5.5 mg / mL / min. Preferably, carboplatin is administered at a dose level of AUC 5.0 mg / mL / min. The dosage level can be changed during the administration schedule. For example, administration can be started at a low dose for a while and then increased, or administration can be started at a high dose for a while and then decreased.

[0262] The administration of carboplatin (or other platinum-based anticancer agents) can be continuous (daily, 7 days a week), intermittent (alternating between one or more administration days with one or more non-administration days, e.g., 4 days on / 3 days off), or once per cycle, depending on pharmacokinetics and the drug clearance / accumulation in a particular patient. The administration schedule should be selected using sound medical judgment. Once per cycle administration of cisplatin is preferred. Preferably, the once per cycle administration is performed on the first day of the treatment cycle. For a 21-day treatment cycle, the once per cycle administration is preferably performed only on the first day (day 1) of the treatment cycle.

[0263] The dose per cycle may be administered as a single dose or as multiple individual divided doses. For example, a single intravenous injection sufficient to deliver an AUC of 5 mg / mL / min may be administered over a period of 15 to 60 minutes.

[0264] Whether continuous, intermittent, or once per cycle, administration continues over a specific treatment cycle, typically at least 21 days, and can be repeated with or without a rest period. Longer or shorter cycles, such as 7, 14, 18, 24, 28, 35, 42 days, or any range in between, may also be used. Treatment cycles may be repeated with or without a rest period, depending on the patient.

[0265] Pemetrexed can be administered at dose levels ranging from approximately 50 mg / m2, 75 mg / m2, 100 mg / m2, 150 mg / m2, 200 mg / m2, 250 mg / m2, 300 mg / m2, 350 mg / m2, 400 mg / m2, 425 mg / m2, 450 mg / m2, 475 mg / m2, up to 1000 mg / m2, up to 950 mg / m2, up to 900 mg / m2, up to 850 mg / m2, up to 800 mg / m2, up to 750 mg / m2, up to 700 mg / m2, up to 650 mg / m2, up to 600 mg / m2, and up to 550 mg / m2. The dosage level may vary within ranges such as approximately 50 mg / m² to 100 mg / m², approximately 250 mg / m² to 750 mg / m², and approximately 450 mg to 550 mg / m². Preferably, pemetrexed is administered at a dose of 500 mg / m². The dosage level can be changed during the administration schedule. For example, administration can be started at a low dose for a while and then increased, or administration can be started at a high dose for a while and then decreased.

[0266] Pemetrexed administration may be continuous (daily, 7 days a week), intermittent (alternating between one or more administration days with one or more non-administration days, e.g., 4 days on / 3 days off), or once per cycle, depending on pharmacokinetics and the drug clearance / accumulation in a particular patient. The administration schedule should be selected using sound medical judgment. Once per cycle administration of pemetrexed is preferred. Preferably, the once per cycle administration is performed on the first day of the treatment cycle. For a 21-day treatment cycle, the once per cycle administration is preferably performed only on the first day (day 1) of the treatment cycle.

[0267] The dose per cycle may be administered as a single dose or as multiple individual divided doses. For example, a single intravenous injection containing approximately 450–550 mg / m2 of pemetrexed may be administered on the first day of the treatment cycle.

[0268] Whether continuous, intermittent, or once per cycle, administration continues over a specific treatment cycle, typically at least 21 days, and can be repeated with or without a rest period. Longer or shorter cycles, such as 7, 14, 18, 24, 28, 35, 42 days, or any range in between, may also be used. Treatment cycles may be repeated with or without a rest period, depending on the patient.

[0269] In some embodiments, the additional therapeutic agent is amivantamab. Amivantamab can be administered in dose levels ranging from approximately 350 mg, 500 mg, 700 mg, 1000 mg to 1050 mg, up to 1400 mg, up to 1500 mg, up to 1750 mg, up to 1900 mg, and up to 2100 mg. The dose levels may vary within ranges such as approximately 350 mg to 700 mg, 1050 to 1400 mg, 1400 mg to 1750 mg, and 1750 to 2100 mg. The dose levels can be changed during the administration schedule. For example, administration can be started at a low dose for a while and then increased, or administration can be started at a high dose for a while and then decreased. Amivantamab can be administered at infusion rates of approximately 20 mL / hour, 35 mL / hour, 50 mL / hour, up to approximately 65 mL / hour, up to approximately 75 mL / hour, up to approximately 85 mL / hour, up to approximately 125 mL / hour, and up to approximately 150 mL / hour.

[0270] Amivantamab can be administered continuously (daily, 7 days a week), intermittently (alternating between one or more administration days with one or more non-administration days, e.g., 4 days on / 3 days off, once a week), or once per cycle, depending on pharmacokinetics and the drug clearance / accumulation in a particular patient. The administration schedule should be selected using sound medical judgment.

[0271] Amivantamab can be administered as a single dose or as multiple individual divided doses. For example, in the first week of amivantamab treatment, amivantamab may be administered in two doses at least one day apart, but still within a 7-day period. For example, on the first day, the first dose of amivantamab may be administered, for example, containing 350 mg, 500 mg, or 700 mg of amivantamab. On the second day, the second dose of amivantamab may be administered, for example, containing 700 mg, 1050 mg, or 1400 mg of amivantamab.

[0272] A typical exemplary dosing schedule for amivantamab includes a weekly dose of 1050 mg, with the first week's infusion divided into two days, with day 1 receiving 350 mg of amivantamab and day 2 receiving 700 mg of amivantamab. Another typical exemplary dosing schedule for amivantamab includes a weekly dose of 1400 mg, with the first week's infusion divided into two days, with day 1 receiving 350 mg of amivantamab and day 2 receiving 1050 mg of amivantamab. Typical dosing schedules include weekly dosing for four weeks or in four-week cycles, or weekly dosing every two weeks or more following four weeks of weekly dosing (e.g., until disease progression or unacceptable toxicity occurs). Weeks 5 and / or 6 may be drug-free periods. Subsequent cycles may not require the initial week's dose to be divided as described above. Subsequent cycles may be repeated indefinitely (e.g., until disease progression or unacceptable toxicity occurs). The occurrence of an adverse reaction may lead to, result in, or be mitigated by a reduction in the dose in subsequent weeks or treatment cycles. For example, an initial dose of 1050 mg may be reduced to 700 mg, and then to 350 mg. An initial dose of 1400 mg may be reduced to 1050 mg, then to 700 mg, and then to 350 mg. Amivantamab may be administered according to the drug label.

[0273] In some embodiments, prior treatment with amibantamab is carried out as described above.

[0274] Where used in this disclosure, the terms “combination,” “combined,” or variations thereof are intended to define a treatment method involving the use of a combination of two or more compounds / drugs. These terms may refer to compounds / drugs administered as part of the same overall dosing schedule. The individual doses of the two or more compounds / drugs may differ. Combination therapy is intended to encompass the sequential administration of these compounds / drugs, i.e., the administration of each compound / drug at different times, as well as the administration of these compounds / drugs or at least two of the compounds / drugs substantially simultaneously. Substantially simultaneous administration can be achieved, for example, by administering a single dosage form containing a fixed ratio of each compound / drug to a target, or by administering each compound / drug to a target in multiple single dosage forms. Sequential or substantially simultaneous administration of each compound / drug can be achieved by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption via mucosal tissue (e.g., the cheek). Compounds / drugs may be administered via the same or different routes. For example, the first compound / drug in the selected combination may be administered by intravenous injection, while the other compounds / drugs in the combination may be administered orally. Alternatively, for example, all compounds / drugs may be administered orally, or all compounds / drugs may be administered by intravenous injection.

[0275] Combination therapy may also encompass the administration of the above-mentioned compounds / drugs in further combination with other biologically active ingredients and non-pharmacological therapies (e.g., surgery or radiation therapy). If combination therapy further includes non-pharmacological therapy, the non-pharmacological therapy may be administered at any appropriate time, as long as the beneficial effects of the synergistic action of the combination of the compound / drug and the non-pharmacological therapy are achieved. For example, where appropriate, beneficial effects may still be achieved even if the non-pharmacological therapy is temporarily removed from the administration of the compound / drug, perhaps for several days or even several weeks.

[0276] Techniques for administering radiotherapy are known in the art and these techniques can be used in the combination therapies described herein. Administration of compound (1) in this combination therapy can be determined as described herein. Radiotherapy can be administered through one of several methods, or a combination of methods including, but not limited to, external beam radiotherapy, brachytherapy, implant radiotherapy, stereotactic radiotherapy, whole body radiotherapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiotherapy delivered by a spatially restricted radioactive material inserted into the body near the tumor or other proliferative tissue disease site. This term is intended to include exposure to radioisotopes such as, but not limited to, At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu. Suitable radiation sources for use as the cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic light rays. The radioactive material can also be a fluid made from any solution of radionuclide(s) (e.g., a solution of I-125 or I-131), or the radioactive fluid can be generated using a suitable fluid slurry containing small particles of a solid radionuclide such as Au-198, Y-90, etc. Further, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0277] The technology described in this specification and its advantages will be better understood by referring to the following examples. These examples are provided to describe specific implementations of the technology. By providing these specific examples, it is not intended to limit the scope and spirit of the technology. It will be understood by those skilled in the art that the subject matter defined by the claims appended to this specification, as well as any variations, modifications, or equivalents of those claims, encompasses the entire scope of the technology described herein.

Examples

[0278] Example 1: Evaluation of the efficacy of TAS6417 in a xenograft model with an EGFR exon 20 insertion mutation (insSVD).

[0279] Method: H1975insSVD was transplanted into the flanks of male BALB / cA Jcl-nu mice at 5×106 cells / mouse. TAS6417 was orally administered daily at 100 mg / kg. Carboplatin (CBDCA) was intravenously administered at 50 mg / kg and 70 mg / kg on days 1 and 8.

[0280] Vehicle and compound: TAS6417 was mixed in 0.1 mol / L hydrochloric acid to form a suspension. CBDCA was mixed in physiological saline to form a suspension.

[0281] Example 2: Body weight change As an index of toxicity, the body weight change rate (BWC) for each group was calculated by the following formula. Then, the average BWC was calculated from the BWC data of individual animals and plotted on a graph against the number of days after grouping. BWC (%) = [(body weight on day n) - (body weight on day 0)] / (body weight on day 0) × 100

[0282] The efficacy of combining CBDCA with TAS6417 was investigated compared to TAS6417 monotherapy. H1975ins SVD cells were transplanted into the flanks of mice. The efficacy of combining CBDCA with TAS6417 was observed in this xenograft model (Figure 1). TAS6417 in combination with CBDCA resulted in a significant reduction in tumor growth compared to TAS6417 monotherapy (Aspin-Welch trial, p<0.05). This combination setting showed similar weight changes as TAS6417 monotherapy (Figure 2).

[0283] Table 1 below presents the results from preclinical animal studies of various treatment regimens with compound (1)(TAS6417) and / or carboplatin at various maximum doses of compound (1)(TAS6417). Figure 1 shows plots of tumor volume presented in Table 1 below, along with additional time points between day 1 and day 15.

[0284] As can be seen, carboplatin alone did not inhibit the increase in tumor volume. However, administration of compound (1)(TAS6417) in conjunction with or in combination with carboplatin resulted in dramatically smaller tumor volumes after 15 days. Furthermore, when compound (1)(TAS6417) was administered in combination with carboplatin at a dose of 100 mg / kg, tumor volume was statistically significantly reduced (indicated by square brackets and asterisks in Figure 1). These data demonstrate the remarkable effect of administering both together. There was no significant difference between TAS6414+CBDCA for 50 mg CBDCA and TAS6414+CBDCA for 70 mg CBDCA. Each combination showed a remarkable effect compared to monotherapy.

[0285] Figure 2 shows a plot of mean body weight change over the entire treatment period for preclinical animal studies. Reasonable stability of body weight over the entire treatment period indicates that none of the regimens resulted in increased or unacceptable levels of toxicity. [Table 1]

[0286] Example 3: Phase 1 / 2a Test Test design This international, multicenter Phase 1 / 2a trial (Clinical-Trials.gov identifier: NCT04036682) evaluated the safety, tolerability, antitumor activity, and pharmacokinetics of compound (1) in patients with relapsed or metastatic NSCLC with EGFR ex20ins mutations. The trial was commissioned by Cullinan Pearl Corporation, an investment of Cullinan Oncology Inc.

[0287] Compound (1) was administered orally twice daily without food for a continuous 21-day treatment cycle. Tumor assessments were performed at baseline, at week 6, every 9 weeks up to week 42, and every 12 weeks thereafter. Brain imaging was required for patients with a history of central nervous system (CNS) metastases at each reclassification. Treatment was continued until disease progression, unacceptable adverse events, withdrawal of consent, or discontinuation at the discretion of the principal investigator. Treatment may be continued beyond disease progression observed by radiation in patients with continued clinical benefit. Safety assessments, including clinical and laboratory evaluations, were performed at baseline and at regular intervals during treatment. The severity of adverse events (AEs) was assessed by National

[0288] Adverse events were graded according to the Japanese Cancer Society's Common Terminology Criteria for Adverse Events, version 5.0. Dose-limiting toxicity (DLT) was defined based on treatment-related adverse events (TRAEs) observed during the first 21-day treatment cycle, although delayed events may be judged as dose-limiting by the Safety Review Committee (SRC).

[0289] The dose escalation was initiated with a single-patient accelerated escalation design, transitioning to a rolling 6 design at the first occurrence of a Grade ≥2 TRAE during Cycle 1 (Figure 6). Consecutive cohorts were treated with Compound 1 at 30, 45, 65, 100, and 150 mg twice daily, transitioning to the rolling 6 design at the 100 mg dose level. The protocol (online only) allowed for expansion enrollment of up to 6 patients in any cohort with an acceptable safety profile. For these cohorts where at least 1 / 6 patients achieved a confirmed partial response (PR), enrollment could be expanded to a total of 13 patients, and for cohorts where 4 / 13 patients achieved a confirmed PR, enrollment could be expanded to a total of up to 36 patients.

[0290] Eligibility Criteria Eligible patients were 18 years of age or older, had histologically or cytologically confirmed recurrent and / or metastatic NSCLC, and had confirmed EGFR ex20ins mutations by local testing in a Clinical Laboratory Improvement Amendments, CLIA-certified, or equivalent laboratory. Central confirmation of EGFR ex20ins was not required. During screening, archived tumor tissue and circulating tumor deoxyribonucleic acid were collected for molecular profiling.

[0291] Previous platinum-based chemotherapy was required unless contraindicated or refused by the patient, and there was no limit on the number of previous therapies. Previous EGFR inhibitors were permitted, but previous ex20ins-specific TKIs were permitted only in the accelerated escalation cohort. Other requirements included the presence of measurable disease according to the Response Evaluation Criteria in Solid Tumors, a general status of 0-1 according to 11 Eastern Cooperative Oncology Groups, and adequate renal, hepatic, cardiac, and hematological function. Patients with asymptomatic brain metastases who were stable on radiation were eligible. Exclusion criteria included spinal cord compression, a history of drug-induced pneumonia, or active infection.

[0292] Pharmacokinetic analysis In the dose-escalation cohort, blood was collected after the first dose on day 1 of cycle 1 (C1D1) and day 15 of cycle 1 (C1D15) to quantify the plasma concentration of compound 1. During dose expansion, blood was collected on C1D1. PK data are included at the PK data cutoff in November 2021. The concentration of compound 1 was determined using a validated liquid chromatography-tandem mass spectrometry assay. Details of the PK analysis are available below.

[0293] statistical analysis At the data cutoff point, all patients treated with compound 1 are included in the safety population. All enrolled patients considered evaluable for response at the data cutoff point are included in the efficacy population. Patients who received compound 1 at least once were included in the PK analysis.

[0294] Exam monitoring All patients submitted written informed consent for study participation. The study was conducted in accordance with the guidelines of the standards for the conduct of clinical trials and the principles of the Declaration of Helsinki and was reviewed and approved by the institutional review board at each participating site. The conduct of the study was monitored by an SRC composed of the principal investigator, an independent reviewer, and a representative of the sponsor.

[0295] Results Patients A total of 91 patients were screened, 73 patients were enrolled, and as of the data cutoff on May 9, 2022, were treated with Compound 1. All 73 patients were included in both the safety population and the efficacy population. All patients initiated treatment with Compound 1 between December 23, 2019, and October 21, 2021.

[0296] During dose escalation, 8 patients were treated at 30 mg twice daily, 1 patient at 45 mg twice daily, 14 patients at 65 mg twice daily, 13 patients at 100 mg twice daily, and 11 patients at 150 mg twice daily. After the first 11 patients treated at 150 mg twice daily had an excessive number of dose reductions (3 patients) and drug discontinuation (3 patients), as well as events meeting the DLT criteria outside the 21-day DLT assessment period, the SRC halted enrollment at 150 mg twice daily. Subsequently, the 100 mg twice-daily dose level entered the Phase 2a expansion with 36 patients planned according to the protocol. The original additional 3 patients screened at the 150 mg dose level were enrolled at the 100 mg dose level after closure of the 150 mg dose level, and a total of 39 patients were treated at 100 mg twice daily.

[0297] Demographic information is summarized in Table 2. The registered T1 patients (32 [44%] males, 41 [56%] females) had a median age of 64 years (range, 36–82 years) and a median number of previous systemic therapies of 2 (range, 1–9), with 66% having ≥2 previous regimens (Table 2). All patients had adenocarcinoma histological features and documented EGFR ex20ins mutations, representing widespread and distinct ex20ins mutations (Table 5 below). Of the 73 patients, 70 (96%) had previously received platinum-based chemotherapy, and 3 patients were previously untreated (ineligible for or refused chemotherapy). Of the 73 patients, 29 (40%) had previously taken EGFR inhibitors, with 13 / 73 (18%) having previously received osimertinib and 3 / 73 (4%) having previously received poziotinib or mobosertinib (Table 2). None had taken amivantamab. Forty patients (55%) had taken immune checkpoint inhibitors (ICIs), and ICIs were part of the most recent treatment regimen in 22 patients (30%). [Table 2]

[0298] safety TEAEs (Treatment-Onset Adverse Events) of any grade were observed in 73 / 73 (100%) of patients treated across all dose levels, and grade ≥3 TEAEs were observed in 39 / 73 (53%) of patients (see Table 6 for details). TRAEs of any grade occurred in 72 / 73 (99%) of patients treated across all dose levels, and grade ≥3 TRAEs occurred in 17 / 73 (23%) of patients (Table 3). The most common TRAEs of any grade occurring in ≥15% of patients included rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%), anemia (19%), dry skin (18%), and nausea (16%, Table 3). Anemia (10%) was the only grade ≥3 TRAE observed in ≥5% of patients (Table 7). [Table 3]

[0299] Fifty-eight patients (80%) experienced treatment-related rashes, with 70% being grade 1, 28% grade 2, and 2% grade 3. Twenty-two patients (30%) developed diarrhea, with 68% being grade 1, 23% grade 2, and 9% grade 3. Patients treated with a single dose of 100 mg of the compound twice daily or less did not experience diarrhea or rash of grade ≥3. Prophylactic antidiarrheal treatment was not necessary, and both diarrhea and rash were generally managed with conventional supportive medications.

[0300] DLTs occurred in 0 / 8, 0 / 1, 1 / 14, 1 / 39, and 4 / 11 patients at the 30, 45, 65, 100, and 150 mg dose levels, respectively (Table 8). Due to drug-related adverse events, 10 out of 73 patients (14%) required dose reduction, and 6 out of 78 patients (8%) discontinued compound 1. Six treatment-related discontinuations (2 each at 65, 100, and 150 mg) were due to pneumonia (n=2), hepatotoxicity, fatigue (2), and an allergic reaction (1). Overall, there were four cases of pneumonia that were thought to be potentially related to compound 1. Dose reductions occurred in 2 / 13, 5 / 39, and 3 / 11 patients at the 65, 100, and 150 mg twice daily dose levels. Reasons for dose reduction included rash in 3 patients and treatment (1 patient each). No drug-related deaths were observed. Of the 73 patients, 49 (67%) had discontinued treatment at the data cutoff point, while 24 out of 73 (33%) continued treatment.

[0301] Effectiveness Objective responses (ORs) were observed across the entire range of the tested compound dose, including the initial dose of 30 mg twice daily (Table 4, Figures 3A–3B). Confirmed ORs occurred in 28 / 73 patients (38.4%; 95% CI, 27–49) across all dose levels and in 16 / 39 patients (41%; 95% CI, 25–56) treated with 100 mg twice daily. The median time to response was 1.5 months (range, 1.5–6.2). Of the 73 patients, 54 (74%) experienced tumor regression at their first 6-week disease assessment (Figure 4), including 24 / 73 (33%) patients with OR and 43 / 73 (59%) patients (F2) with disease stable (SD) at the initial scan.

[0302] [Table 4]

[0303] With a median follow-up period of 11 months, the median duration of response (mDOR) was 10 months (95% CI, 6 to uncalculable [NC]) across all dose levels. At the data cutoff, mDOR had not been reached in 16 patients treated with 100 mg twice daily or 12 patients treated with doses of ≤65 mg twice daily. The median progression-free survival (mPFS) was 10 months (95% CI, 6 to 12) across all dose levels, 12 months (95% CI, 5 to NC) for 100 mg twice daily, and 8 months (95% CI, 5 to 13) for patients treated with doses of ≤65 mg twice daily (Figure 7).

[0304] Of 26 patients who took compound 1 after previous EGFR (non-ex20ins) inhibitors, 8 (31%) experienced a partial response (PR), 13 (50%) had stable disease (SD), and 2 (8%) experienced disease progression (Figures 3A-3B). Of 3 patients previously treated with another ex20ins-targeted TKI (posiotinib, mobosertinib, or both), 2 had a PR and 1 had SD (Figures 3A-3B). In exploratory analysis, the adverse response rate (ORR) was 41.5% among patients with near-loop exon 20 implantation (n=52) and 22% among patients with far-loop implantation (n=9, Figure 8).

[0305] Preclinical studies suggested that compound 1 may not efficiently cross the normal rodent blood barrier; however, cases of intracranial activity were observed in patients with CNS target lesions. Eighteen patients had non-targeted CNS disorders, and three had CNS target lesions. Of the three patients with measurable target CNS lesions, one had both systemic and intracranial partial responses (Figures 5A and 5B), one had systemic and intracranial F3 stable disease (SD), and one had CNS progression as the best response (details below).

[0306] Pharmacokinetics PK was evaluable for 47 patients after the initial dose of C1D1, and PK for C1D15 was evaluable for 24 patients (Figure 9 and Table 9). After fasting administration of compound 1, the median time to Cmax (Tmax) was within the range of 0.5–1.5 hours after the dose of C1D1 or C1D15. Both Cmax and area under the plasma concentration-time curve (AUC) increased in dose-related proportions and showed moderate to high variability, with between-subject variability (%) ranging from 24% to 86% over both days. The elimination half-life of compound 1 was 3–4 hours after 14 days of repeated twice-daily administration. No significant accumulation was observed after 14 days, based on the D15 / D1 ratio of AUCTAU. The mean range was 1.05–1.25.

[0307] Patients eligible for response included those with measurable disease at baseline and those with either at least one tumor assessment at treatment or clinical progression prior to the tumor assessment at the first treatment. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities version 24.0. Responses in individual patients were determined based on the assessment of the treating investigator using the Solid Tumor Response Evaluation Criteria, version 1.1. Objective response (OR) was confirmed by at least one sequential tumor assessment obtained at least 4 weeks after the original scan documenting the response. The ORR was calculated as [[(number of patients: 1 with complete response, 4 with partial response [PR])]3 = 100%]. The efficacy of diparereltinib was evaluated at all dose levels entering the Phase I dose expansion phase using the Simon 2-stage design.

[0308] This analysis included patients treated in both the dose-escalation cohort and the Phase I dose-expansion cohort at a given dose level. The null hypothesis was a 10% ORR, which was tested against the alternative hypothesis of an ORR ≥ 40%. If zero responses were observed in the first six patients at a given dose level, no further patients were recruited at that dose level. Otherwise, seven additional patients could be recruited, and if four or more responses were observed in total, the null hypothesis was rejected. This design yields a one-sided Type I error of <5% and >80% power when the true response rate is 40%. For the dose levels entering Phase 2a dose-expansion, an additional 23 patients could be recruited. If a total of 36 patients were enrolled at a dose level, the lower and upper limits of the 90% confidence interval for ORR are within 15% of the point estimate.

[0309] The median duration of response was estimated using the Kaplan-Meier method and defined as the interval between the earliest response date and the date of disease progression or death due to any cause. The median progression-free survival was estimated using the Kaplan-Meier method and defined as the interval between the first administration date of the study treatment and the first documented disease progression or death due to any cause (whichever comes first). The median duration of follow-up was determined by a simple frequentist median.

[0310] PK analysis Pharmacokinetic parameters (maximum observed plasma concentration [Cmax], area under the plasma-time concentration curve from time 0 to the final observation point [AUClast], area under the plasma concentration-time concentration curve over a 12-hour dosing interval [AUCTAU], terminal phase half-life [t1 / 2], and accumulation ratio [AR]) were estimated by non-compartmental analysis Q:11 (Phoenix WinNonlin Build 8.0.0.3176; ICON plc, Dublin, Ireland).

[0311] safety Treatment-related serious adverse events included pneumonia (n=2), diarrhea (n=1), and hypersensitivity reactions (n=1).

[0312] According to the investigator's assessment, there were four cases of potentially diparereltinib-related pneumonia (one on 65 mg twice daily, one on 150 mg twice daily, and two on 100 mg twice daily). One case of grade 1 pneumonia resolved after dose retention and resumption of corticosteroid and diparereltinib treatment at the same dose; another patient with a history of osimertinib-induced pneumonia also experienced grade 2 pneumonia with diparereltinib; and one patient who discontinued pembrolizumab and chemotherapy for disease progression (PD) approximately one month prior to enrollment in the trial experienced grade 3 pneumonia with diparereltinib. In the fourth patient, the grade 3 pneumonia was initially thought to be potentially related to dipareretinib, but based on a positive bronchoalveolar lavage, it was diagnosed as Pneumocystis iroveti pneumonia. After treatment, it was ultimately determined by the sponsor to be unrelated to the study treatment.

[0313] There were four cases of grade 3 or 4 ALT / AST elevation (one case with ≤65 mg twice daily, two cases with 100 mg twice daily, and one case with 150 mg twice daily), all of which were patients who discontinued pembrolizumab therapy within 50 days of starting diparereltinib therapy. Only one patient had measurable liver metastases. Two of the four patients discontinued diparereltinib due to elevated AST / ALT levels.

[0314] Reasons for discontinuing treatment included disease progression (PD) (30 / 49 patients, 61%), adverse events (AEs) (12 / 49 patients, 25%), withdrawal of consent (3 / 49 patients, 6%), other reasons (2 / 49 patients, 4%), and deterioration of general condition and death (4 / 49 patients, 8%).

[0315] clinical activity The median number of cycles administered was 11 (range, 2–32), 11 (2–33), and 10 (1–17) for patients treated with doses of 65 mg or less twice daily, 100 mg twice daily, and 150 mg twice daily, respectively.

[0316] PRs were observed across a diverse range of epidermal growth factor receptor exon 20 insertion mutations (ex20ins). In this study, near-loop mutations were the most common mutation subtype, followed by far-loop mutations and helical region mutations, accounting for 52, 9, and 2 patients, respectively. Ten patients had mutation sites that were not reported by polymerase chain reaction assays. One patient had different ex20ins mutations identified in two different tumor specimens and was included in the unconfirmed group. In an exploratory analysis of response rates by mutation subtype, the response rates were 41.5%, 22%, and 0% for near-loop, far-loop, and helical region mutations, respectively (Figure 8). The response rate for the unconfirmed group was 40%.

[0317] Eighteen patients had non-targeted central nervous system (CNS) disorders, and three patients had CNS target lesions. Of the three patients with measurable target lesions in the brain, one patient (treated at a dose level of 100 mg) achieved both systemic and intracranial responses in cycle 6 and remained in a partial response (PR) in cycle 16 at the data cutoff (Figures 5A-5B). The second patient (Q:12, treated at 100 mg) had disease stability both systemically and intracranially one year after treatment. The third patient (treated at 150 mg) progressed with new lesions in the CNS in cycle 3. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0318] Example 4: Evaluation of the efficacy of TAS6417 in combination therapy in xenograft models with EGFR exon 20 insertion mutations (insSVD).

[0319] Methods: H1975insSVD was transplanted into the flanks of male BALB / cA Jcl-nu mice at a rate of 8 × 10⁶ cells / mouse. TAS6417 was administered orally at 100 mg / kg daily. CBDCA and pemetrexed were administered intravenously at 60 mg / kg and 50 mg / kg on days 1 and 15, respectively.

[0320] A suspension was prepared by mixing the vehicle and compound TAS6417 in 0.1 mol / L hydrochloric acid. A suspension was prepared by mixing CBDCA and pemetrexed in physiological saline.

[0321] Example 5: Body weight changes in xenograft models with EGFR exon 20 insertion mutations (insSVD).

[0322] As an indicator of toxicity, the BWC rate for each group was calculated using the following formula. Subsequently, the average BWC was calculated from the BWC data of individual animals and plotted on a graph against the number of days after grouping. BWC(%) = [(Weight on day n) - (Weight on day 0)] / (Weight on day 0) × 100

[0323] The efficacy of combination therapy with CBDCA / pemetrexed and TAS6417 was investigated compared to TAS6417 monotherapy. H1975ins SVD cells were transplanted into the flanks of mice. The efficacy of combination therapy with CBDCA / pemetrexed and TAS6417 was observed in this xenograft model (Figure 10). TAS6417 in combination with CBDCA / pemetrexed resulted in a significant reduction in tumor growth compared to TAS6417 monotherapy (Aspin-Welch trial, p<0.05). This combination setting showed similar weight changes as TAS6417 monotherapy (Figure 11).

[0324] Table 10 below presents the results from preclinical animal studies of various treatment regimens with compound (1) (TAS6417) and / or CBDCA / pemetrexed. The tumor volume plots presented in Table 10 below, as well as additional time points between day 1 and day 22, are shown in Figure 10.

[0325] As can be seen, CBDCA / pemetrexed did not inhibit the increase in tumor volume. However, administration of compound (1)(TAS6417) along with or in combination with CBDCA / pemetrexed resulted in dramatically smaller tumor volume after 22 days. Furthermore, when compound (1)(TAS6417) was administered in combination with CBDCA / pemetrexed at a dose of 100 mg / kg, tumor volume was statistically significantly reduced (indicated by square brackets and asterisks in Figure 10). These data demonstrate the remarkable effect of administering both together.

[0326] Figure 11 shows a plot of mean body weight change over the entire treatment period for preclinical animal studies. Reasonable stability of body weight over the entire treatment period indicates that none of the regimens resulted in increased or unacceptable levels of toxicity. [Table 10]

[0327] Example 6: Evaluation of the efficacy of TAS6417 in combination with EGFR exon 20 insertion mutations (insNPH) in an allograft model.

[0328] Methods: NIH / 3T3 EGFR H773_V774insNPH was transplanted into the flanks of male BALB / cA Jcl-nu mice at a rate of 5 × 10⁶ cells / mouse. TAS6417 was administered orally at 100 mg / kg daily. CBDCA and pemetrexed were administered intravenously at 60 mg / kg and 50 mg / kg, respectively, on day 1.

[0329] A suspension was prepared by mixing the vehicle and compound TAS6417 in 0.1 mol / L hydrochloric acid. A suspension was prepared by mixing CBDCA and pemetrexed in physiological saline.

[0330] Example 7: Body weight changes in an allograft model with EGFR exon 20 insertion mutations (insNPH).

[0331] As an indicator of toxicity, the BWC rate for each group was calculated using the following formula. Subsequently, the average BWC was calculated from the BWC data of individual animals and plotted on a graph against the number of days after grouping. BWC(%) = [(Weight on day n) - (Weight on day 0)] / (Weight on day 0) × 100

[0332] The efficacy of combination therapy with CBDCA / pemetrexed and TAS6417 was investigated compared to TAS6417 monotherapy. H1975ins SVD cells were transplanted into the flanks of mice. The efficacy of combination therapy with CBDCA / pemetrexed and TAS6417 was observed in this xenograft model (Figures 12-13). TAS6417 in combination with CBDCA / pemetrexed resulted in a significant reduction in tumor growth compared to TAS6417 monotherapy (Aspin-Welch trial, p<0.05). This combination setting showed similar weight changes as TAS6417 monotherapy (Figure 14).

[0333] Table 11 below presents results from preclinical animal studies of various treatment regimens with compound (1)(TAS6417) and / or CBDCA / pemetrexed at various maximum doses of compound (1)(TAS6417). Plots of tumor volume presented in Table 11 below, as well as additional time points between day 1 and day 8, are shown in Figures 12-13.

[0334] As can be seen, CBDCA / pemetrexed did not inhibit the increase in tumor volume. However, administration of compound (1)(TAS6417) along with or in combination with CBDCA / pemetrexed resulted in dramatically smaller tumor volume after 8 days. Furthermore, when compound (1)(TAS6417) was administered in combination with CBDCA / pemetrexed at a dose of 100 mg / kg, tumor volume was statistically significantly reduced (indicated by square brackets and asterisks in Figure 13). These data demonstrate the remarkable effect of administering both together.

[0335] Figure 14 shows a plot of mean body weight change over the entire treatment period for preclinical animal studies. Reasonable stability of body weight over the entire treatment period indicates that none of the regimens resulted in increased or unacceptable levels of toxicity. [Table 11]

[0336] Example 8: Evaluation of the efficacy of TAS6417 in a xenotransplant model with EGFR exon 20 insertion mutations (insSVD) after relapse following amivantamab 10 mg / kg / day treatment.

[0337] Methods: NCI-H1975 EGFR D770_N771insSVD (H1975insSVD) was transplanted into the flanks of male BALB / cA Jcl-nu mice at a rate of 5 × 10⁶ cells / mouse. Amivantamab was administered intraperitoneally at 10 mg / kg twice weekly. TAS6417 was administered orally at 200 mg / kg daily.

[0338] The vehicle and compound TAS6417 were mixed in 0.1 mol / L hydrochloric acid to prepare a suspension. Amivantamab was diluted in physiological saline to prepare a suspension.

[0339] The efficacy of TAS6417 was investigated in a model prior to amivantamab treatment. H1975ins SVD cells were transplanted into the flanks of mice. Amivantamab was administered intraperitoneally at a dose of 10 mg / kg twice weekly starting when the tumor volume reached approximately 200 mm3. The tumors temporarily regressed but regrowed to approximately 500 mm3. The amivantamab-recurrent tumors were randomly stratified into two groups of 5 animals each to ensure a uniform mean tumor volume. TAS6417 was orally administered to one mouse group at a dose of 200 mg / kg daily, while the other group continued to receive amivantamab as a control. TAS6417 resulted in a significant reduction in tumor growth compared to amivantamab (Aspin-Welch p-value < 0.05) (Figure 15).

[0340] Example 9: Phase 2b trial NCT05967689 (REZILIENT2) is an international, open-label, multi-cohort, phase 2b trial designed to evaluate the efficacy and safety of diparereltinib (compound (1), TAS6417) in adult patients with pathologically confirmed, locally advanced or metastatic NSCLC containing EGFR ex20ins and other uncommon single or compound.

[0341] EGFR mutations, including those in patients with brain metastases and leptomeningeal disease. Eligible patients will be assigned to one of four cohorts based on their prior treatment and EGFR mutation type.

[0342] Cohort A: Patients with EGFR ex20ins mutations whose disease has progressed during or after first-line platinum-based chemotherapy and prior therapy targeting ex20ins mutations (administered together or separately) for progressive disease. Patients with brain metastases must be neurologically stable.

[0343] Cohort B: Patients with EGFR ex20ins mutations who have not received prior treatment for progressive disease.

[0344] Cohort C includes patients with ex20ins, other uncommon single or compound EGFR mutations, and active brain metastases (including leptomeningeal disease (LMD)), regardless of prior treatment history for progressive disease.

[0345] Cohort D: Patients with other, uncommon, non-ex20ins, single or compound EGFR mutations that have progressed during or after standard systemic therapy.

[0346] This study has the following endpoints.

[0347] Primary: Objective response rate (ORR) as assessed by the principal investigator according to the Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.

[0348] Secondary metrics: Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), intracranial efficacy (ORR, DOR, DCR) as assessed by the RANO-BM response assessment for neuro-oncological brain metastases (Cohort C), safety and tolerability, and pharmacokinetics (PK).

[0349] Exploratory objectives: Population PK parameters, their association with safety and efficacy, and EGFR mutations / biomarkers from tumor samples and circulating tumor DNA (ctDNA).

[0350] Example 10: A study characterizing the antitumor activity of EGFR ex20ins TKIs in patients with a history of amivantamab treatment.

[0351] As of January 2024, 31 patients were enrolled. The patient data was as follows: median age: 62.5 years (39-77 years), median number of previous therapy lines: 3 (1-6), previous PD1 / L1: 16 (51.6%), history of brain metastases: 15 (48.4%).

[0352] Treatment-related adverse events occurring in ≥10% of patients included rash (38.7%), anemia (25.8%), paronychia (22.6%), dry skin (19.4%), nausea (19.4%), stomatitis (12.9%), itching (12.9%), and folliculitis (12.9%).

[0353] Treatment-related adverse events of grade ≥3 were observed in six patients, including one patient with four events (increased amylase, lymphopenia, hypoxia, and pneumonia), one patient with two events (anemia and rash), and four patients each with one event (folliculitis, ILD, hypertension, or rash).

[0354] Treatment-related adverse events leading to dose reduction and discontinuation occurred in 2 patients (6.5%) and 2 patients (6.5%), respectively. In the disease-dependent occlusion (DCO) group, 18 patients were evaluable for response (at least two intra-treatment evaluations or progression / death), of which 7 (38.9%) achieved partial response (PR), 9 (50.0%) achieved stable disease (SD), and 1 (5.6%) achieved an unconfirmed partial response (uPR, awaiting confirmation). The disease control rate (CR+PR / uPR+SD) was 94.4%. Median duration of response and progression-free survival were not yet estimable.

[0355] In patients with advanced EGFR ex20ins-mutated NSCLC who had received prior treatment with amivantamab, diparereltinib demonstrated similar efficacy to patients who had progressed after platinum-based chemotherapy and had a manageable safety profile.

[0356] Example 11: Safety and antitumor activity of diparereltinib in NSCLC patients with EGFR exon 20 insertion (ex20ins) mutations who have received prior treatment with amivantamab.

[0357] Diparereltinib (CLN-081, TAS6417) is a novel EGFR TKI that demonstrated a confirmed objective response rate (ORR) of 41% and manageable safety in a phase 1 / 2a trial in patients with ex20ins NSCLC following prior platinum-containing chemotherapy (JCO 2023). Here, we present data from the phase 2b REZILIENT1 trial in patients with diparereltinib module C who had EGFR ex20ins mutant NSCLC that had progressed after prior amivantamab.

[0358] Methods: Patients whose disease had progressed after at least one prior treatment, including amivantamab, were enrolled to receive diparereltinib orally at a dose of 100 mg twice daily. Tumor response was assessed by the investigator according to RECIST v1.1. Stable, asymptomatic, or treated brain metastases were tolerated.

[0359] Results: As of the data cutoff (DCO) on March 29, 2024, 45 patients were enrolled, with a median age of 62 years (33-85 years), a median number of previous therapy lines of 3 (1-6), 43 patients (96%) who had previously received platinum-based chemotherapy, 20 patients (44%) who had previously received anti-PD1 / L1, 22 patients (49%) who had previously received EGFR TKI, and 22 patients (49%) with a history of brain metastases.

[0360] Figure 16 is a summary of the entire patient statistics module C ami. The entire module C Ami includes patients who progressed with amivantamab, with or without prior mobosertinib and / or other exon 20ins drugs (excluding patients who took only mobosertinib and / or other exon 20ins drugs but not amivantamab). Figure 17 shows a summary of the best overall tumor response based on investigator assessment according to RECIST v1.1. This includes all treated patients with measurable disease at baseline who received at least one dose of diparereltinib and had at least two treatment tumor evaluations, death, or discontinuation due to disease progression (either clinically or according to RECIST v1.1 based on investigator assessment). NE = Not evaluable, NA = Not applicable. Figure 18 is a waterfall plot of the best change from baseline in target lesions. The efficacy population includes all treated patients with measurable disease at baseline who have received at least one dose of diparereltinib and have experienced one of the following: 1) at least two treatment tumor evaluations, 2) death, or 3) discontinuation due to disease progression (either clinically or according to RECIST v1.1 based on investigator assessment). A positive change in tumor size indicates tumor growth, and a negative change in tumor size indicates tumor reduction. If the dimension was recorded as "TOO SMAL TO MEASURE," a default value of 5 mm was assigned. If the dimension was recorded as "INDTERMINATE," a value from the previous evaluation was assigned. Ami includes only patients who have previously taken amivantamab alone, while Ami+ex20ins drugs include patients who have previously taken amivantamab and mobosertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs).

[0361] Figure 19 is a swim plot for the study treatment duration. The study treatment duration is treatment end date - first dose date + 1. For subjects still in progress, the study duration is data cutoff date - first dose date + 1. Ami includes only patients previously receiving amivantamab alone, while Ami + ex20ins drugs includes patients previously receiving amivantamab and mobosertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs). Figure 20 is a Kaplan-Meier plot of progression-free survival based on RECIST v1.1. Ami includes only patients who previously took amivantamab alone, Ami+ex20ins drugs include patients who previously took amivantamab and mobosertinib or other EGFR exon 20 insertion (ex20ins) targeted tyrosine kinase inhibitors (TKIs), and Ami as a whole includes both patient populations (excluding patients who took mobosertinib and / or other ex20ins drugs alone but not amivantamab).

[0362] Treatment-related adverse events (TRAEs) occurring in ≥10% of patients included rash (38%), paronychia (36%), anemia (24%), dry skin (20%), acneiform dermatitis (16%), nausea (16%), and stomatitis (11%). Grade 3 TRAEs were reported in 14 patients (31%): those occurring in ≥2 patients included anemia (4), rash (3), and pneumonia / ILD (3). There were no grade 4 or 5 TRAEs. TRAEs leading to dose reduction and discontinuation occurred in 3 patients (7%) each. In DCO, 30 patients were evaluable for response (at least two intratreatment evaluations or cases with PD / death), of which 1 patient (3%) achieved CR, 11 patients (37%) achieved partial response (PR), and 15 patients (50%) achieved stable disease (SD). The ORR was 40%, and the disease control rate (CR+PR+SD) was 90%. The median duration of response was not yet estimable, and the median PFS was 9.7 months. Figure 21 is a summary of treatment-related adverse events of any grade observed in ≥10% of patients. Figure 22 is a summary of grade 3 treatment-related adverse events in ≥2 patients.

[0363] Example 12: Phase 3 trial NCT05973773 (REZILIENT3) is an international, randomized, controlled, open-label, phase 3 trial to compare the efficacy and safety of diparereltinib (compound (1), TAS6417) plus standard first-line platinum-based chemotherapy and chemotherapy alone in patients with locally advanced or metastatic non-squamous NSCLC with EGFR ex20ins mutations.

[0364] This trial was designed in two parts: a safety introductory phase (Part A) and a randomized phase 3 phase (Part B). Part A was designed to confirm the recommended dose of diparereltinib in combination with standard chemotherapy (pemetrexed + carboplatin or cisplatin) to be tested in Part B. Part B will compare the efficacy and safety of diparereltinib plus chemotherapy with chemotherapy alone.

[0365] Part A Treatment regimen: Dipareretinib + pemetrexed + carboplatin or cisplatin. For patients with EGFR ex20ins or other common single or compound EGFR mutations.

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[0366] Part B The study population must meet all of the following criteria: 1) previously untreated, locally advanced or metastatic non-squamous NSCLC; 2) EGFR exon 20ins mutation by local testing; 3) ≥1 measurable lesion by RECIST v1.1; 4) ECOG PS of 0 or 1; 5) observed stable brain metastases; and 6) archived tumor tissue available for submission.

[0367] Previous EGFR TKI monotherapy (not targeting ex20ins mutations) lasted <8 weeks, with documented lack of response and cured associated toxicity, and was possible with a half-life of >2 weeks / 4 before randomization; alternatively, for early-stage NSCLC, approved adjuvant / neoadjuvant therapy discontinued >6 months prior to the first dose of the study treatment is possible. Patients with previously treated brain metastases and stable central nervous system disease (defined as neurologically stable and without corticosteroid use for ≥2 weeks prior to enrollment) are eligible. Asymptomatic brain metastases ≤2 cm in size may be eligible to be included if, in the investigator's view, no immediate definitive treatment has been indicated. Patients with insufficient tissue may be eligible after consultation with the sponsor.

[0368] This study has the following endpoints.

[0369] Primary endpoint: PFS determined by blinded independent central review (BICR).

[0370] Secondary endpoints: PFS, ORR, DCR, and DOR as assessed by the principal investigator according to RECIST v1.1; ORR, DOR, and DCR according to BICR according to RECIST v1.1; intracranial ORR, DCR, and DOR; adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0; OS; safety; PK; and patient-reported outcomes (PRO).

[0371] Clearly, in light of the above teachings, many modifications and variations of the present invention are possible. Therefore, it should be understood that, within the scope of the appended claims, the present invention can be carried out in ways other than those specifically described herein.

Claims

1. A method for treating a subject having cancer that has at least one abnormality in EGFR, The treatment comprises administering to the subject an effective amount of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof, A method wherein the subject has previously been treated with systemic therapy consisting of at least one selected from the group comprising chemotherapy agents and molecularly targeted therapies.

2. The method according to claim 1, wherein the cancer is at least one selected from the group consisting of locally advanced cancers and cancers that have metastasized to the brain of the subject.

3. The method according to claim 1, wherein the cancer is locally progressive.

4. The method according to any one of claims 1 to 3, wherein the cancer is unresectable.

5. The method according to any one of claims 1 to 3, wherein at least one abnormality in the EGFR is an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.

6. The method according to claim 5, wherein at least one abnormality in the EGFR is an EGFR mutation in exon 20.

7. The method according to any one of claims 1 to 3, wherein at least one abnormality in the EGFR is an EGFR exon 20 insertion mutation.

8. The aforementioned EGFR exon 20 insertion mutations are D770_N771insX, V769_D770insX, H773_V774insX, P772_H773insX, N771_P772insX, A763_Y764insX, V774_C775insX, D761_E762insX, A763_Y764insTLA, Y764_V765insHH, A767_S768insASV, S768dupSVD, A767_S768insX, S768_V769insX, Y764_V765insX, V765_M766insX, A763 _Y764insFQEA, A767_S768insTLA, S768_V769insVAS, S768_V769insAWT, V 769_D770insGV, V769_D770insCV, V769_D770insDNV, V769_D770insGSV, V 769_D770insGVV, V769_D770insMASVD, V769_D770insASV, V769_D770insG E, V769_D770delInsDGEL, D770_N771insSVD, D770_N771insNPG, D770_N77 1insKH, D770_N771insGNPH, D770_N771insAPW, D770_N771insD, D770_N77 1insDG, D770delinsGY, D770_N771insGL, D770_N771insN, D770_N771insN PH, D770_N771insSVP, D770_N771insSVQ, D770_N771insMATP, D770_N771i nsG, D770_N771insY, D770_N771insGF, D770_N771insGT, delD770insGY, N 771_P772insH, N771_P772insN, delN771insGY, delN771insGF, N771delin sGY, N771_P772insRH, P772_H773insPR, P772_H773insYNP, P772_H773ins DPH, P772_H773insDNP, P772_H773insQV, P772_H773insTPH, P772_H773in sN, P772_H773insV, P772_H773insNP, P772_H773insNPH, H773_V774insH,The method according to claim 7, wherein at least one selected from the group consisting of H773_V774insNPH, H773_V774insPH, H773_V774insGNPH, H773_V774insG, H773_V774insGH, H773_V774insAH, H773_V774delInsLM, H773_V774delInsTY, and V774_C775insHV.

9. The method according to any one of claims 1 to 3, wherein approximately 10 to approximately 500 mg of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.

10. The method according to any one of claims 1 to 3, wherein approximately 30 to approximately 300 mg per day of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject.

11. The method according to any one of claims 1 to 3, wherein (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (BID).

12. The method according to any one of claims 1 to 3, wherein (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject daily for a therapeutic cycle lasting 21 days.

13. The method according to any one of claims 1 to 3, wherein 100 mg of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (BID) for a therapeutic cycle lasting 21 days.

14. The method according to any one of claims 1 to 3, further comprising administering an effective amount of an additional therapeutic agent to the subject.

15. The method according to claim 14, wherein the additional therapeutic agent is at least one selected from the group consisting of chemotherapeutic agents, tyrosine kinase inhibitors, and immunotherapeutic agents.

16. The method according to any one of claims 1 to 3, wherein the systemic treatment is systemic treatment with a molecularly targeted therapy selected from the group consisting of EGFR-targeted therapeutics other than compound (1) and non-EGFR-targeted therapeutics.

17. The method according to claim 16, wherein the EGFR-targeted therapeutic agent other than compound (1) is at least one selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, poziotinib, mobosertinib, razertinib, sunbozertinib, DZD9008, BDTX-189, necitumumab, pembrolizumab, brigatinib, icotinib, neratinib, olmutinib, rosiletinib, vandetanib, lapatinib, durigotuzumab, panitumumab, zaltumumab, cetuximab, depatuxizumab, depatuxizumab mafodotin, imugatuzumab, matsuzumab, and nimotuzumab.

18. The method according to claim 17, wherein the EGFR-targeted therapeutic agent other than compound (1) is osimertinib.

19. The method according to claim 17, wherein the EGFR-targeting therapeutic agent other than compound (1) is mobocertinib.

20. The method according to claim 17, wherein the EGFR-targeting therapeutic agent other than compound (1) is afatinib.

21. The method according to claim 17, wherein the EGFR-targeted therapeutic agent other than compound (1) is gefitinib.

22. The method according to claim 17, wherein the EGFR-targeted therapeutic agent other than compound (1) is poziotinib.

23. The method according to claim 16, wherein the EGFR-targeted therapeutic agent other than compound (1) is sunvozertinib.

24. The method according to claim 16, wherein the non-EGFR-targeted therapeutic agent is at least one selected from the group consisting of crizotinib, ceritinib, alectinib, ensartinib, entrectinib, repotrectinib, belizatinib, alcotinib, folitinib, CEP-37440, TQ-B3139, PLB1003, zotizarquib, contertinib, nivolumab, pembrolizumab, semiprimab, atezolizumab, durvalumab, bevacizumab, ipilimumab, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, and vinorelbine.

25. The method according to claim 24, wherein the non-EGFR-targeted therapeutic agent is nivolumab.

26. The method according to claim 24, wherein the non-EGFR-targeted therapeutic agent is pembrolizumab.

27. The method according to claim 24, wherein the non-EGFR-targeted therapeutic agent is semiprimab.

28. The method according to claim 24, wherein the non-EGFR-targeted therapeutic agent is atezolizumab.

29. The method according to claim 24, wherein the non-EGFR-targeted therapeutic agent is durvalumab.

30. The method according to any one of claims 1 to 3, wherein the subject did not respond to the systemic treatment, or the subject had disease progression after the systemic treatment.

31. The method according to any one of claims 1 to 3, wherein the systemic treatment is systemic treatment with a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dicycloplatin, heptaplatin, lovaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

32. The method according to claim 31, wherein the chemotherapeutic agent is cisplatin.

33. The method according to claim 31, wherein the chemotherapeutic agent is carboplatin.

34. The method according to any one of claims 1 to 3, wherein the subject has previously received at least two systemic treatments for the cancer.

35. The method according to any one of claims 1 to 3, wherein the subject has previously received at least three systemic treatments for the cancer.

36. A method for treating a subject having cancer that has at least one abnormality in EGFR, The aforementioned target, An effective amount of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof, A method comprising administering an effective amount of a platinum-based anticancer drug.

37. The method according to claim 36, wherein the cancer is a solid tumor.

38. The method according to claim 36, wherein the cancer is lung cancer.

39. The method according to claim 36, wherein the cancer is non-small cell lung cancer.

40. The method according to claim 39, wherein the non-small cell lung cancer is non-squamous non-small cell lung cancer.

41. The method according to claim 36, wherein the cancer is at least one selected from the group consisting of locally advanced cancers and cancers that have metastasized to the brain of the subject.

42. The method according to claim 36, wherein the cancer is locally progressive.

43. The method according to claim 36, wherein the cancer is unresectable.

44. The method according to claim 36, wherein the cancer has metastasized to the brain of the subject.

45. The method according to claim 36, wherein the cancer has EGFR amplification / overexpression.

46. The method according to claim 36, wherein the cancer has an EGFR mutation in at least one exon selected from the group consisting of exon 18, exon 19, exon 20, and exon 21.

47. The method according to claim 36, wherein the cancer has an EGFR mutation in exon 20.

48. The method according to claim 36, wherein the cancer has an EGFR exon 20 insertion mutation.

49. The method according to claim 36, wherein the subject is determined to have the abnormality in EGFR prior to administration.

50. The method according to claim 36, wherein the subject has not previously received systemic treatment for the cancer.

51. The method according to claim 36, wherein (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject.

52. The method according to claim 36, wherein (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (BID).

53. The method according to claim 36, wherein (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject daily for a therapeutic cycle lasting 21 days.

54. The method according to claim 36, wherein the platinum anticancer agent is administered intravenously to the subject.

55. The method according to claim 36, wherein the platinum anticancer drug is administered only on the first day of a 21-day treatment cycle.

56. The method according to claim 1, further comprising administering an effective amount of pemetrexed to the subject.

57. The method according to claim 56, wherein the pemetrexed is administered only on the first day of a 21-day treatment cycle.

58. The method according to claim 56, wherein the pemetrexed is administered intravenously to the subject.

59. The method according to claim 36, wherein the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl) acrylamide or a pharmaceutically acceptable salt thereof, and the platinum anticancer agent are administered over 1 to 10 treatment cycles, each treatment cycle lasting 21 days.

60. The method according to claim 36, wherein the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl) acrylamide or a pharmaceutically acceptable salt thereof, and the platinum anticancer agent are administered over four treatment cycles, each treatment cycle lasting 21 days.

61. The method according to claim 56, wherein the pemetrexed is administered over four treatment cycles, each treatment cycle lasting 21 days.

62. The method according to claim 36, wherein approximately 10 to approximately 500 mg of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl) acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.

63. The method according to claim 36, wherein approximately 30 to approximately 150 mg of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject per day.

64. The method according to any one of claims 1 to 3, wherein 100 mg of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (BID) for a therapeutic cycle lasting 21 days.

65. The method according to claim 36, wherein the platinum anticancer agent is at least one selected from the group consisting of cisplatin and carboplatin.

66. The method according to claim 36, wherein the platinum anticancer agent is cisplatin, and approximately 50 to approximately 100 mg / m2 of cisplatin is administered to the subject only on the first day of a 21-day treatment cycle.

67. The method according to claim 36, wherein the platinum anticancer agent is carboplatin, and carboplatin at an AUC of approximately 2.5 mg / mL / min to approximately 7.5 mg / mL / min is administered to the subject only on the first day of a 21-day treatment cycle.

68. The method according to claim 56, wherein approximately 250 to approximately 750 mg / m2 of pemetrexed is administered to the subject only on the first day of a 21-day treatment cycle.

69. The method according to claim 36, wherein the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl) acrylamide or a pharmaceutically acceptable salt thereof is administered orally to the subject in at least one form selected from the group consisting of tablets and capsules.

70. The method according to claim 69, wherein the tablet or capsule comprises a pharmaceutically acceptable carrier.

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