Combination therapy for cancer using quinoline-substituted compound

Abstract

The present invention addresses the problem of providing a novel combination therapy having a potent antitumor effect and few side effects. The present invention provides an antitumor agent containing zipalertinib or a salt thereof as an active ingredient and used so as to be administered to a cancer patient in combination with an additional antitumor agent, wherein the additional antitumor agent is at least one selected from the group consisting of molecular targeting agents, immune checkpoint inhibitors, and antibody-drug conjugates.

Description

Cancer combination therapy using quinoline-substituted compounds

[0001] The present invention relates to an antitumor agent used in combination with a quinoline-substituted compound or a salt thereof and a molecularly targeted drug, an immune checkpoint inhibitor, or an antibody-drug conjugate; an antitumor therapy in which a quinoline-substituted compound or a salt thereof and a molecularly targeted drug, an immune checkpoint inhibitor, or an antibody-drug conjugate are administered simultaneously or sequentially in combination; and an enhancer of the antitumor effect of a molecularly targeted drug, an immune checkpoint inhibitor, or an antibody-drug conjugate.

[0002] EGFR (Epidermal Growth Factor Receptor) is a receptor tyrosine kinase that, in normal tissues, binds to its ligand, epidermal growth factor (EGF), and exerts physiological functions, contributing to proliferation and inhibition of apoptosis in epithelial tissue (Non-Patent Literature 1).

[0003] EGFR is also an oncogene, and amplification of the EGFR gene, high expression of the protein, and mutations are known to occur in various types of cancer, such as head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, and brain tumors (Non-patent Literature 2).

[0004] Therefore, inhibitors that can control EGFR kinase activity are expected to exert antitumor effects by inhibiting EGFR and downstream signaling in cancer cells with EGFR gene amplification, overexpression, and / or mutations, and are therefore considered useful for the treatment, survival, and improvement of quality of life of cancer patients.

[0005] Currently, EGFR inhibitors are being researched and developed as antitumor agents and are being used to treat EGFR mutation-positive tumors. Clinical development is also underway in combination with other antitumor agents (Non-patent documents 3, 4).

[0006] Diparereltinib or its salts, which are quinoline-substituted compounds, are known as EGFR inhibitors (Patent Document 1), and clinical trials (jRCT: 2061230058) concerning their combination administration with pemetrexed and platinum-based drugs (carboplatin or cisplatin) have been reported to date (Non-Patent Documents 5, 6).

[0007] International Publication WO2015 / 025936, International Publication WO2025 / 006697

[0008] Nature Rev. Cancer, vol. 6, pp803-811 (2006) J. Clin. Oncol. , vol. 19, 32s-40s (2001) Am J Cancer Res 2016;6(8):1609-1623Oncotarget, Vol. 8, (No. 3), pp: 3980-4000 (2017) Journal of Clinical Oncology Vol. 42, (No. 16) Meeting Abstract: 2024 ASCO Annual Meeting I (2024) https: / / jrct. niph.go.jp / en-latest-detail / jRCT2061230058

[0009] While the pharmaceutical technology to which this invention belongs has made the aforementioned advances, there is still a strong desire for improved therapies to prevent tumor progression or treat cancer. Under these circumstances, the problem that this invention aims to solve is to provide a new combination therapy that has high antitumor efficacy and few side effects.

[0010] In view of the current situation, the inventors have found that the above problems can be solved by combining diparereltinib or a salt thereof, which has EGFR inhibitory activity, with a molecularly targeted drug, an immune checkpoint inhibitor, or an antibody-drug conjugate. Based on this new finding, the inventors have completed the present invention after extensive trial and error regarding the dosage and administration of diparereltinib or a salt thereof, the type of molecularly targeted drug, immune checkpoint inhibitor, or antibody-drug conjugate, and the dosage and administration methods.

[0011] Accordingly, the present invention provides the following [1] to

[84] : [1] An antitumor agent comprising diparereltinib or a salt thereof as an active ingredient, to be used in combination with other antitumor agents for use in cancer patients, wherein the other antitumor agent is at least one selected from the group consisting of molecular targeted drugs, immune checkpoint inhibitors and antibody-drug conjugates. [2] The antitumor agent according to [1], wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists and antibody-drug conjugates. [3] The antitumor agent according to [1], wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates. [4] The antitumor agent according to [1], wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin. [5] The antitumor agent according to [4], characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gumarontinib once daily. [6] The antitumor agent according to [4], characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily and 300 mg / day or 250 mg / day of gumarontinib once daily.[7] The antitumor agent according to [5] or [6], characterized in that it is administered to patients having MET overexpression or MET amplification. [8] The antitumor agent according to [7], characterized in that, if the patient has MET overexpression, IHC3+ is observed in 50% or more of the tumor cells taken from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS. [9] The antitumor agent according to [4], characterized in that 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for five consecutive days, followed by 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day or 40 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

[10] The antitumor agent according to [4], characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then resting for two days.

[11] (a) Diparereltinib or a salt thereof administered twice daily at a dose of 200 mg / day or 100 mg / day, and quemrecrustat administered at doses of 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose, or 25 mg / dose once every two weeks, or (b) Diparereltinib or a salt thereof administered twice daily at a dose of 200 mg / day or 100 mg / day, and quemrecrustat administered at doses of 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose, or 100 mg / dose once every three weeks, the antitumor agent according to [4].

[12] The antitumor agent according to [4], characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

[13] (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle lasting 28 days. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week. In subsequent cycles, 700 mg of amivantamab is administered every two weeks. (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The antitumor agent according to [4], characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1050 mg is administered once a week each time, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks each time, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1400 mg is administered once a week each time, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks each time.

[14] (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab once every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab once every two weeks from the second cycle onward, or (c) The antitumor agent according to [4], characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with one cycle consisting of 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amibantamab administered once every two weeks from the second cycle onward. The antitumor agent according to

[15] ,

[13] , or

[14] , characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

[16] An antitumor agent according to any one of items [1] to

[15] , wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

[17] An antitumor agent according to any one of items [1] to

[16] , wherein the cancer patient is a patient with lung cancer.

[18] An antitumor agent according to any one of items [1] to

[17] , wherein the cancer patient is a cancer patient with an EGFR mutation.

[19] An antitumor agent according to

[18] , wherein the EGFR mutation is an EGFR exon 19 deletion mutation or an exon 21 L858R mutation.

[20] An antitumor agent according to any one of items [1] to

[19] , wherein the cancer patient is a cancer patient resistant to EGFR inhibitors.

[21] An antitumor agent according to

[20] , wherein the EGFR inhibitor resistance is osimertinib resistance.

[22] A method for treating a tumor, comprising administering to a cancer patient in need of the same an effective amount of diparereltinib or a salt thereof as an active ingredient and an effective amount of another antitumor agent, which is at least one selected from the group consisting of molecularly targeted drugs, immune checkpoint inhibitors and antibody-drug conjugates.

[23] The method according to

[22] , wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists and antibody-drug conjugates.

[24] The method according to

[22] , wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates.

[25] The method according to

[22] , wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

[26] The method according to

[25] , characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gumarontinib once daily.

[27] The method according to

[25] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily and 300 mg / day or 250 mg / day of gumarontinib once daily.

[28] The method according to

[26] or

[27] , characterized in that the patient has MET overexpression or MET amplification.

[29] The method according to

[28] , characterized in that if the patient has MET overexpression, IHC3+ is observed in 50% or more of the tumor cells taken from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS.

[30] The method according to

[25] , characterized in that 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for five consecutive days, followed by 2 days of drug-free administration of 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day or 40 mg / day of pimitespive once daily for five consecutive days.

[31] The method according to

[25] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

[32] (a) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily for daily administration, and administering 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose or 25 mg / dose of quemrecrustat once every two weeks, or (b) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily for daily administration, and administering 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose or 100 mg / dose of quemrecrustat once every three weeks, the method according to

[25] .

[33] The method according to

[25] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

[34] (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle being 28 days, and in the first week of the first cycle, 700 mg is administered in two divided doses, and in the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week, and in the second cycle and beyond, 700 mg of amivantamab is administered once every two weeks, (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The method according to

[25] , characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1050 mg is administered once a week, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1400 mg is administered once a week, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks.

[35] (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab once every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab once every two weeks from the second cycle onward, or (c) The method according to

[25] , characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with one cycle consisting of 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amibantamab administered once every two weeks from the second cycle onward. The method according to

[36] ,

[34] , or

[35] , characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

[37] The method according to any one of

[22] to

[36] , wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

[38] The method according to any one of

[22] to

[37] , wherein the cancer patient is a patient with lung cancer.

[39] The method according to any one of

[22] to

[38] , wherein the cancer patient is a cancer patient with an EGFR mutation.

[40] The method according to

[39] , wherein the EGFR mutation is an EGFR exon 19 deletion mutation or an exon 21 L858R mutation.

[41] The method according to any one of

[22] to

[40] , wherein the cancer patient is a cancer patient resistant to EGFR inhibitors.

[42] The method according to

[41] , wherein the EGFR inhibitor resistance is osimertinib resistance.

[43] Diparereltinib or a salt thereof, to be used in combination with other antitumor agents for use in cancer patients, wherein the other antitumor agent is at least one selected from the group consisting of molecularly targeted drugs, immune checkpoint inhibitors and antibody-drug conjugates.

[44] The compound or salt thereof according to

[43] , wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists and antibody-drug conjugates.

[45] The compound or salt thereof according to

[43] , wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates.

[46] The compound or salt thereof described in

[43] , wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

[47] The compound or salt thereof according to

[46] , characterized by administering 200 mg / day or 100 mg / day of dipareretinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gumarontinib once daily.

[48] The compound or salt thereof according to

[46] , characterized by administering 200 mg / day of dipareretinib or a salt thereof twice daily, and 300 mg / day or 250 mg / day of gumarontinib once daily.

[49] The compound or salt thereof according to

[47] or

[48] , characterized in that the patient has MET overexpression or MET amplification.

[50] The compound or salt thereof according to

[49] , characterized in that if the patient has MET overexpression, IHC3+ is observed in 50% or more of the tumor cells taken from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS.

[51] The compound or salt thereof according to

[46] , characterized in that 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for five consecutive days, followed by 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day or 40 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

[52] The compound or salt thereof according to

[46] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

[53] (a) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily for consecutive days, and administering 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose or 25 mg / dose of quemrecrustat once every two weeks, or (b) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily for consecutive days, and administering 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose or 100 mg / dose of quemrecrustat once every three weeks, the compound or salt thereof according to

[46] .

[54] The compound or salt thereof according to

[46] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

[55] (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle lasting 28 days. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week. In subsequent cycles, 700 mg of amivantamab is administered every two weeks. (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The compound or salt thereof according to

[46] , characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third and fourth weeks of the first cycle, 1050 mg is administered once a week each time, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks each time, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice a day for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third and fourth weeks of the first cycle, 1400 mg is administered once a week each time, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks each time.

[56] (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab once every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab once every two weeks from the second cycle onward, or (c) The compound or salt thereof according to

[46] , characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with one cycle consisting of 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amibantamab administered once every two weeks thereafter. The antitumor agent according to

[57] ,

[55] , or

[56] , characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

[58] The compound or a salt thereof according to any one of

[43] to

[57] , wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

[59] The compound or a salt thereof according to any one of

[43] to

[58] , wherein the cancer patient is a patient with lung cancer.

[60] The compound or a salt thereof according to any one of

[43] to

[59] , wherein the cancer patient is a cancer patient with an EGFR mutation.

[61] The compound or a salt thereof according to

[60] , wherein the EGFR mutation is an EGFR exon 19 deletion mutation or an exon 21 L858R mutation.

[62] The compound or a salt thereof according to any one of

[43] to

[61] , wherein the cancer patient is a cancer patient resistant to EGFR inhibitors.

[63] The compound or salt thereof according to

[62] , wherein the EGFR inhibitor resistance is osimertinib resistance.

[64] A pharmaceutical composition for treating cancer, comprising dipareretinib or a salt thereof as an active ingredient, to be used in combination with other antitumor agents to cancer patients, wherein the other antitumor agent is at least one selected from the group consisting of molecular targeted drugs, immune checkpoint inhibitors and antibody-drug conjugates.

[65] The composition according to

[64] , wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists and antibody-drug conjugates.

[66] The composition according to

[64] , wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates.

[67] The composition according to

[64] , wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

[68] The composition according to

[67] , characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gumarontinib once daily.

[69] The composition according to

[67] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily and 300 mg / day or 250 mg / day of gumarontinib once daily.

[70] The composition according to

[68] or

[69] , characterized in that it is administered to a patient having MET overexpression or MET amplification.

[71] The composition according to

[70] , characterized in that if the patient has MET overexpression, IHC3+ is observed in 50% or more of the tumor cells taken from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS.

[72] The composition according to

[67] , characterized in that 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for five consecutive days, followed by 2 days of drug-free administration of 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day or 40 mg / day of pimitespive once daily for five consecutive days.

[73] The composition according to

[67] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by administration of 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

[74] (a) Diparereltinib or a salt thereof administered twice daily at a dose of 200 mg / day or 100 mg / day, and quemrecrustat administered at doses of 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose, or 25 mg / dose once every two weeks, or (b) Diparereltinib or a salt thereof administered twice daily at a dose of 200 mg / day or 100 mg / day, and quemrecrustat administered at doses of 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose, or 100 mg / dose once every three weeks, as described in

[67] .

[75] The composition according to

[67] , characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

[76] (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle being 28 days, and in the first week of the first cycle, 700 mg is administered in two divided doses, and in the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week, and in the second cycle and beyond, 700 mg of amivantamab is administered once every two weeks, (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The composition according to

[67] , characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1050 mg is administered once a week each time, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks each time, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice a day for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1400 mg is administered once a week each time, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks each time.

[77] (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab once every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab once every two weeks from the second cycle onward, or (c) The composition according to

[67] , characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with one cycle consisting of 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amibantamab administered once every two weeks from the second cycle onward. The composition according to

[78] ,

[76] , or

[77] , characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

[79] The composition according to any one of

[64] to

[78] , wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

[80] The composition according to any one of

[64] to

[79] , wherein the cancer patient is a patient with lung cancer.

[81] The composition according to any one of

[64] to

[80] , wherein the cancer patient is a cancer patient with an EGFR mutation.

[82] The composition according to

[81] , wherein the EGFR mutation is an EGFR exon 19 deletion mutation or an exon 21 L858R mutation.

[83] The composition according to any one of

[64] to

[82] , wherein the cancer patient is a cancer patient resistant to EGFR inhibitors.

[84] The composition according to

[83] , wherein the EGFR inhibitor resistance is osimertinib resistance.

[0012] The present invention provides a novel method for treating tumors using diparereltinib or a salt thereof with a molecularly targeted drug, an immune checkpoint inhibitor, or an antibody-drug conjugate. The antitumor agent of the present invention makes it possible to treat cancer with excellent antitumor effects while suppressing the occurrence of side effects.

[0013] This paper shows the antitumor effects of TAS6417 (dipareretinib) and bevacizumab, either alone or in combination, on II-18 xenograft model mice carrying EGFR L858R. It also shows the percentage change in body weight of II-18 xenograft model mice carrying EGFR L858R when TAS6417 and bevacizumab are used alone or in combination. Furthermore, it shows the antitumor effects of TAS6417 and bevacizumab, either alone or in combination, on H1975insSVD xenograft model mice carrying EGFR exon 20 insertion mutations. This shows the antitumor effect, as measured by Kaplan-Meier curves, of H1975insSVD xenograft model mice with EGFR exon 20 insertion mutations when TAS6417 and bevacizumab or TAS6417 and DC101 (mouse anti-VEGFR antibody) are used alone or in combination. This shows the percentage change in body weight of H1975insSVD xenograft model mice with EGFR exon 20 insertion mutations when TAS6417 and bevacizumab are used alone or in combination. This shows the percentage change in body weight of H1975insSVD xenograft model mice with EGFR exon 20 insertion mutations when TAS6417 and DC101 (mouse anti-VEGFR antibody) are used alone or in combination. This document shows the antitumor effect of HCC827OR8 xenograft model mice with EGFR exon 19 deletion and MET amplification when TAS6417 and capmatinib or TAS6417 and amibantamab are used alone or in combination. This document also shows the percentage change in body weight of HCC827OR8 xenograft model mice with EGFR exon 19 deletion and MET amplification when TAS6417 and capmatinib or TAS6417 and amibantamab are used alone or in combination. This shows the antitumor effects of H1975insSVD xenograft model mice with EGFR exon 20 insertion mutations when TAS6417 and amivantamab are used alone or in combination.This shows the percentage change in body weight of H1975insSVD xenograft model mice with EGFR exon 20 insertion mutations when TAS6417 and amibantamab are used alone or in combination. This shows the antitumor effect of II-18 xenograft model mice with EGFR L858R when TAS6417 and amibantamab or TAS6417 and sacituzumab govitecan are used alone or in combination. This shows the percentage change in body weight of II-18 xenograft model mice with EGFR L858R when TAS6417 and amibantamab are used alone or in combination. This shows the percentage change in body weight of II-18 xenograft model mice with EGFR L858R when TAS6417 and amibantamab are used alone or in combination. This document shows the antitumor effects of NCI-H1975 xenograft model mice with EGFR L858R / T790M when TAS6417 and TAS-116 (pimitespive) are used alone or in combination. This document also shows the percentage change in body weight of NCI-H1975 xenograft model mice with EGFR L858R / T790M when TAS6417 and TAS-116 are used alone or in combination. Furthermore, it shows the antitumor effects of HCC827GR6 xenograft model mice with EGFR exon 19 deletion and MET amplification when TAS6417 and TAS-116 are used alone or in combination. This shows the percentage change in body weight in HCC827GR6 xenograft model mice with EGFR exon 19 deletion and MET amplification when TAS6417 and TAS-116 are used alone or in combination. This shows the cell viability using HCC827OR8 with EGFR exon 19 deletion and MET amplification when TAS6417 is used alone or in combination with gumarontinib. This shows the cell viability in the 4T1-OVA_hEGFR Ex20insSVD cell line when futivatinib is used alone or in combination with TAS6417. This shows the antitumor effect in II-18 xenograft model mice with EGFR L858R when TAS6417 and datopotamab deruxtecan are used alone or in combination. This study demonstrates the antitumor effects of using TAS6417 and trastuzumab deruxtecan alone or in combination in II-18 xenograft model mice possessing EGFR L858R.This document shows the antitumor effects of II-18 xenograft model mice with EGFR L858R when TAS6417 and enfortumab vedotin are used alone or in combination. It also shows the percentage change in body weight of II-18 xenograft model mice with EGFR L858R when TAS6417 and datopotamab deruxtecan, trastuzumab deruxtecan, and enfortumab vedotin are used alone or in combination. The document also shows the antitumor effects of the control group's 4T1-OVA_hEGFR_Ex20insASV-SG allograft model mice. Finally, it shows the antitumor effects of 4T1-OVA_hEGFR_Ex20insASV-SG allograft model mice when TAS6417 is used alone. This shows the antitumor effect of the 4T1-OVA_hEGFR_Ex20insASV-SG allograft model mouse when using an anti-PD-1 antibody alone. This shows the antitumor effect of the 4T1-OVA_hEGFR_Ex20insASV-SG allograft model mouse when using TAS6417 in combination with an anti-PD-1 antibody.

[0014] Typically, in embodiments, this specification discloses combinations of diparereltinib or a salt thereof with at least one antitumor compound (another antitumor agent) selected from the group consisting of molecularly targeted drugs, immune checkpoint inhibitors, or antibody-drug conjugates. When both are used in combination, the antitumor effect is enhanced compared to using each alone, and furthermore, the enhancement of toxicity is suppressed and the occurrence of side effects is reduced. Therefore, this combination makes it possible to treat tumors with excellent antitumor effects while suppressing the occurrence of side effects.

[0015] In this specification, diparereltinib is a quinoline-substituted compound having EGFR inhibitory activity, represented by the following formula (I).

[0016] The quinoline-substituted compound of the present invention ((S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide) may also be called Zipalertinib, TAS6417, or CLN-081.

[0017] In this specification, all daily doses of diparereltinib or its salts are expressed in free form equivalents unless otherwise specified.

[0018] Diparereltinib can be manufactured, for example, by the manufacturing method described in publication WO2015 / 025936A1 or by the methods shown in the examples. However, the manufacturing method of diparereltinib is not limited to these reaction examples.

[0019] If diparereltinib or other antitumor agents have isomers such as optical isomers, stereoisomers, or tautomers, then unless otherwise specified, all isomers and mixtures thereof are included under the name diparereltinib. For example, if diparereltinib has optical isomers, then unless otherwise specified, the racemic mixture and the optical isomers separated from the racemic mixture are also included under the name diparereltinib.

[0020] In the case of diparerertinib, "salt" refers to a pharmaceutically acceptable salt, which may include base-added salts or acid-added salts. Similarly, in the case of other antitumor agents, "salt" refers to a pharmaceutically acceptable salt, which may include base-added salts or acid-added salts.

[0021] Examples of the base addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; and organic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, and N,N'-dibenzylethylenediamine salt.

[0022] Examples of the acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; organic salts such as acetate, formate, maleate, fumarate, tartrate, citrate, ascorbate, and trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.

[0023] From the viewpoint of enhancing the antitumor effect (preferably additive, more preferably synergistic) when used in combination with diparereltinib or its salt, in this specification, "other antitumor agents" are one or more selected from molecularly targeted drugs, immune checkpoint inhibitors, and antibody-drug conjugates.

[0024] Diparereltinib or its salts may be used in combination with other antitumor agents, in addition to molecularly targeted drugs, immune checkpoint inhibitors, and antibody-drug conjugates, as long as the effects of the present invention are achieved.

[0025] Other antitumor agents used in combination can be manufactured or obtained using publicly known and conventional manufacturing methods. Alternatively, commercially available antitumor agents can also be used.

[0026] In this specification, "antagonist" or "inhibitor" refers to compounds and / or drugs that inhibit a receptor or another protein by partially or completely blocking, reducing, preventing, delaying, inactivating, reducing sensitivity, or downregulating the activity of a gene, protein, ligand, receptor, biological pathway, or cell (e.g., receptor activity or protein activity). This also includes compounds that inhibit the biological activity of a target protein by interacting with other elements of a signaling pathway where the target protein is an element of that pathway. Inhibitors also include multi-kinase inhibitors. Antagonists include small molecules and large molecules (such as antibodies). In this specification, "multi-kinase inhibitor" refers to a drug that can reduce or inhibit the action of two or more protein kinases. Multi-kinase inhibitors are not particularly limited, but can reduce or inhibit the action of serine kinase, tyrosine kinase, threonine kinase, and / or other types of kinases.

[0027] As used herein, the term "antibody" generally includes immunoglobulin (Ig) molecules composed of four polypeptide chains, namely two heavy (H) chains and two light (L) chains, single-domain antibodies, and antigen-binding fragments thereof. "Antibody" is used in its broadest sense and is not particularly limited as long as it exhibits antigen-binding activity, and examples include monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antigen-binding fragments thereof. Also, "bispecific antibody" refers to an antibody in which the antigen-binding protein has two different antigen-binding specificities. In the present invention, monoclonal antibodies or multispecific antibodies are preferred.

[0028] Antibodies are not particularly limited, and examples include human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric human antibodies, etc. It includes all known types of antibodies and their functional fragments. In the present invention, human antibodies or humanized antibodies are preferred.

[0029] As used herein, the term "molecular target drug" refers to a drug that acts on a specific molecule of cancer cells and exhibits an anti-cancer effect. The molecular target drugs are not particularly limited, and examples include VEGF signal transduction pathway antagonists, HGF / c-MET signal transduction pathway antagonists, ErbB / HER signal transduction pathway antagonists, FGF signal transduction pathway antagonists, adenosine signal transduction pathway antagonists, ubiquitin proteasome signal transduction pathway antagonists, RAS / MAPK signal transduction pathway antagonists, etc. Preferably, it is a VEGF signal transduction pathway antagonist, HGF / c-MET signal transduction pathway antagonist, ErbB / HER signal transduction pathway antagonist, FGF signal transduction pathway antagonist, adenosine signal transduction pathway antagonist, or ubiquitin proteasome signal transduction pathway antagonist.

[0030] In this specification, "immune checkpoint inhibitor" refers to a drug that activates T cells and attacks cancer cells by completely or partially reducing or blocking the activity of one or more immune checkpoint proteins involved in T cell inhibition, thereby inhibiting the immunosuppressive effects of cancer cells and antigen-presenting cells. Examples of immune checkpoint inhibitors are not particularly limited, but include PD-1 / PD-L1 signaling pathway antagonists, ICOS signaling pathway agonists, CTLA-4 signaling pathway antagonists, CD28 signaling pathway agonists, BTLA signaling pathway antagonists, 4-1BB signaling pathway agonists, CD155 / TIGIT signaling pathway antagonists, CD47 / SIRPα signaling pathway antagonists, and the like. In the present invention, the immune checkpoint inhibitor is preferably a PD-1 / PD-L1 signaling pathway antagonist.

[0031] In this specification, “signaling pathway” refers to a pathway through which stimuli or inhibitory signals are transmitted to and within cells to trigger intracellular responses. Regulators of signaling pathways include compounds that modulate the activity of one or more cellular proteins mapped to the same specific signaling pathway. Regulators can increase or decrease the activity of signaling molecules.

[0032] In this specification, the "VEGF signaling pathway" refers to the signaling pathway mediated by the vascular endothelial growth factor (VEGF) receptor family (VEGFR1, VEGFR2, VEGFR3). Examples of VEGF signaling pathway antagonists include VEGF / VEGFR inhibitors. A VEGF / VEGFR inhibitor refers to a drug that targets and inhibits, inactivates, or reduces the expression or activity level of VEGF or VEGFR1-3.

[0033] Although not particularly limited, examples of the VEGF / VEGFR inhibitor include fruquintinib, axitinib, nintedanib, riboceranib, cabozantinib, cediranib, acrizanib, tivozanib, surufatinib, telatinib mesylate, bevacizumab, pazopanib, ramucirumab, regorafenib, TAS-115 and the like. The VEGF / VEGFR inhibitor is preferably bevacizumab or ramucirumab.

[0034] As used herein, the "HGF / c-Met signaling pathway" refers to a signaling pathway induced by the interaction between hepatocyte growth factor (HGF) and its receptor c-Met (or Met). Examples of the HGF / c-Met signaling pathway antagonist include MET inhibitors. The MET inhibitor refers to a drug that can target, inhibit, inactivate, or reduce the expression level or activity level of MET (c-Met), which is a receptor type with HGF as a ligand.

[0035] Although not particularly limited, examples of the MET inhibitor include capmatinib, cabozantinib, crizotinib, tepotinib, savolitinib, gumaronitinib, pamufetinib, amivantamab, TAS-115 and the like. The MET inhibitor is preferably capmatinib, gumaronitinib or amivantamab.

[0036] In this specification, the "ErbB / HER signaling pathway" refers to signaling pathways mediated by the ErbB receptor (EGF receptor) family (EGFR (HER1 or ErbB1), HER2 (ErbB2), HER3, HER4). Examples of ErbB / HER signaling pathway antagonists include EGFR inhibitors, HER2 inhibitors, and HER3 inhibitors. An EGFR inhibitor refers to a drug that targets and inhibits, inactivates, or reduces the expression or activity level of the epidermal growth factor receptor (EGFR), and a HER2 inhibitor refers to a drug that targets and inhibits, inactivates, or reduces the expression or activity level of the human epidermal growth factor receptor type 2 (HER2).

[0037] Examples of EGFR inhibitors, though not limited to them, include afatinib, gefitinib, erlotinib, vandetanib, amivantamab, poziotinib, osimertinib, cetuximab, panitumumab, and TAS2940. Examples of HER2 inhibitors, though not particularly limited, include lapatinib, tucatinib, afatinib, TAS0728, trastuzumab, pertuzumab, margetuximab, poziotinib, and TAS2940. Amivantamab is preferred as the EGFR inhibitor.

[0038] In this specification, the "FGF signaling pathway" refers to the signaling pathway mediated by the fibroblast growth factor (FGF) receptor family (FGFR1, FGFR2, FGFR3, FGFR4). Examples of FGF signaling pathway antagonists include FGFR inhibitors. An FGFR inhibitor is a drug that targets and inhibits, inactivates, or reduces the expression or activity level of FGF or FGFR1-4.

[0039] Examples of FGFR inhibitors, though not particularly limited, include erdafitinib, MHPL-453, futibatinib, infigratinib, tasulgratinib succinate, derazantinib, and CBT-004. Futibatinib is preferred as the FGFR inhibitor.

[0040] In this specification, the term "adenosine signaling pathway" refers to signaling pathways mediated by adenosine receptors (A2, A2AA2B, A3). Adenosine is a nucleoside with immunosuppressive properties, present in high concentrations in the tumor microenvironment, and limiting immune cell infiltration, cytotoxicity, and cytokine production. Examples of adenosine signaling pathway antagonists include adenosine A2A receptor antagonists, adenosine A2A receptor agonists, and CD73 inhibitors. CD73 inhibitors are preferred. CD73 inhibitors refer to drugs that target and inhibit, inactivate, or reduce the expression or activity level of CD73, which produces adenosine that suppresses cancer immunity.

[0041] Examples of CD73 inhibitors, though not limited to them, include quemliclustat (AB680), ABSK-051, ATG-037, AB-308, PSB-12379, PSB-12441, PSB-12425, CB-708, oleculumab, mupadolimab, ORIC-533, uliledlimab, dalutrafusp alpha, AK-119, AK-123, AK-137, HB-0045, IPH-5301, NZV-930, PM-101, PT-199, BR-101, IBI-325, JAB-BX102, and Sym-024. Preferably, the CD73 inhibitor is quemrecrustat.

[0042] In this specification, the "ubiquitin-proteasome signaling pathway" refers to a system pathway in which ubiquitin binds to a target protein, and the proteasome degrades the unwanted protein. Examples of ubiquitin-proteasome signaling pathway antagonists include proteasome inhibitors and HSP90 inhibitors. An HSP90 inhibitor refers to a drug that targets, reduces, inhibits, inactivates, or lowers the expression or activity level of HSP90.

[0043] HSP90 inhibitors include, but are not limited to, tanespimycin, luminespib, and alvespimycin hydrochloride. Examples include hydrochloride, ganetespib, BIIB021, onalespib, pimitespib, geldanamycin, NVP-BEP800, SNX-2112, PF-4929113 (SNX-5422), KW-2478, XL888, VER155008, VER-50589, CH5138303, VER-49009, NMS-E973, PU-H71, HSP990, and KNK437. Pimitespib is preferred as the HSP90 inhibitor.

[0044] In this specification, the "RAS / MAPK signaling pathway" refers to a signaling pathway mediated by RAS. When the RAS protein is activated, a series of kinases such as RAF, MEK, and ERK are sequentially activated, thereby transmitting a signal. RAS / MAPK signaling pathway antagonists are not particularly limited, but include MEK inhibitors (e.g., MEK1 inhibitors, MEK2 inhibitors, inhibitors of both MEK1 and MEK2, etc.), RAF inhibitors (ARAF inhibitors, BRAF inhibitors, CRAF inhibitors, pan-RAF inhibitors, etc.), and RAS inhibitors (KRAS inhibitors, etc.).

[0045] Examples of MEK inhibitors, though not particularly limited, include trametinib, cobimetinib, binimetinib, and serumetinib. Examples of RAF inhibitors, though not particularly limited, include vemurafenib, dabrafenib, and encorafenib. Examples of RAS inhibitors, though not particularly limited, include fulzerasib, garsorasib, adagrasib, sotrasib, salirasib, lonafarnib, and MK-1084.

[0046] The PD-1 / PD-L1 signaling pathway typically plays a role in regulating immune responses and maintaining tissue homeostasis. PD-1 / PD-L1 signaling pathway antagonists are not limited to PD-1 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors.

[0047] "PD-1 inhibitor" refers to a drug that reduces the amount or activity of PD-1. For example, a PD-1 inhibitor may be a drug that binds to the PD-1 protein and inhibits its interaction with PD-L1. Examples of PD-1 inhibitors include antibodies that bind to PD-1 or their antigen-binding fragments, peptide-based inhibitors, small molecules, etc. In this specification, PD-1 inhibitors are preferably anti-PD-1 antibodies. "PD-L1 inhibitor" refers to a drug that reduces the amount or activity of PD-L1. For example, a PD-L1 inhibitor may be a drug that binds to the PD-L1 protein and inhibits its interaction with PD-1. Examples of PD-L1 inhibitors include antibodies that bind to PD-L1 or their antigen-binding fragments, peptide-based inhibitors, small molecules, or ADCs, etc.

[0048] In this specification, the PD-1 / PD-L1 signaling pathway antagonist is preferably a PD-1 inhibitor or a PD-L1 inhibitor, and more preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0049] PD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, zimberelimab, cemiprimab, spartalizumab, budigalimab, camrelizumab, and cetrelimab. Examples include trelimab, dostarlimab, ezabenlimab, pimivalimab, pucotenlimab, sasanlimab, cintilimab, tislerizumab, and tripalimab. Examples of PD-L1 inhibitors, though not particularly limited, include atezolizumab, durvalumab, avelumab, rodapolimab, cosibelimab, and socazolimab. Preferably, the PD-L1 inhibitor is nivolumab, pembrolizumab, or zimbererimab, and more preferably pembrolizumab or zimbererimab.

[0050] In this specification, the "CD155 / TIGIT signaling pathway" refers to the immunosuppressive signaling pathway mediated by TIGIT expressed on T cells and its ligand, CD155. CD155 / TIGIT signaling pathway antagonists are not particularly limited, but examples include CD155 inhibitors and TIGIT inhibitors.

[0051] Examples of CD155 inhibitors, though not particularly limited, include TSRF-786C and NTX-1088. Examples of TIGIT inhibitors, though not particularly limited, include domvanalimab, AB308, vibostolimab, osperimerimab, tiragolumab, AGEN-1777, HB-0036, HLX-301, ONO-4686, M-6223, PM-1022, etigilimab, ZG-005, AZD-2936, Belrestotug, and JS-006.

[0052] In this specification, the "CD47 / SIRPα signaling pathway" refers to a pathway by which SIRPα binds to CD47, thereby inhibiting phagocytosis. Examples of CD47 / SIRPα signaling pathway antagonists include CD47 inhibitors.

[0053] Examples of CD47 inhibitors, though not limited to them, include magrolimab, Evorpacept, IMM-01, Lemzoparlimab, ligufalimab, letaprimab, AUR-103, AO-176, IMM2520, PF-07257876, and HX-009.

[0054] In this specification, "ADC (Antibody-Drug Conjugate)" is also called "antibody-drug conjugate" or "antibody-drug complex." An ADC is a technology that utilizes the antigen-specific binding ability of antibodies. It involves conjugating a drug with cytotoxic activity to an antibody that can bind to an antigen expressed on the surface of cancer cells and thereby internalize the antigen into the cell. Such drugs may be cancer treatment agents, cytotoxic agents, etc. In a typical embodiment, an ADC includes an antibody, a drug such as a cytotoxic agent or therapeutic agent, and a linker that conjugates the drug to the antibody. A "cytotoxic agent" refers to a drug that exerts a cytotoxic effect on cells. Examples of cytotoxic agents are not particularly limited, but include monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), SN-38, emtansine, exatecan, deruxtecan, eribulin, calicheamicin, etc.

[0055] In a preferred embodiment, the ADC contains a monoclonal antibody capable of binding to surface-specific antigens of cancer cells. These antigens are not particularly limited, but include several proteins on the surface of immune system B cells and T cells, such as CD20, CD22, human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), TROP-2, and prostate-specific membrane antigen (PSMA). The antibodies included in the ADC are those that specifically bind to these antigens. Therefore, the ADC may contain monoclonal antibodies capable of specifically binding to surface-specific antigens of cancer cells. These antibodies can be linked to highly toxic drugs by a cleavable linker unit. In a typical embodiment, the drug is designed to induce apoptosis in cancer cells by inducing irreversible DNA damage or interfering with cell division.

[0056] Furthermore, while not particularly limited, the drugs that can be included in ADC in the present invention include mitotic inhibitors, antitumor antibiotics, immunomodulators, gene therapy vectors, alkylating agents, anti-angiogenic drugs, antimetabolites, boron-containing agents, chemotherapeutic agents, hormones, anti-hormone agents, corticosteroids, photosensitive therapeutic agents, oligonucleotides, radionuclides, topoisomerase inhibitors, tyrosine kinase inhibitors, and radiosensitizers. These drugs can be used individually or in combination of two or more.

[0057] In the present invention, the antibodies included in ADC are not particularly limited, but include anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-CD3 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD56 antibody, anti-CD98 antibody, anti-DR5 antibody, anti-EGFR antibody, anti-EPHA2 antibody, anti-FFFR2 antibody, anti-FFFR4 antibody, anti-c-MET antibody, anti-FOLR1 antibody, anti-VEGF antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD70 antibody, anti-nectin-4 antibody, anti-PSMA antibody, anti-CEA antibody, anti-Mesothelin antibody, anti-CEACAM5 antibody, anti-AXL antibody, and the like. The antibodies included in ADC are preferably anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, anti-B7-H3 antibody, anti-nectin-4 antibody, anti-EGFR antibody, anti-VEGF antibody, anti-c-MET antibody, anti-CEACAM5 antibody, and anti-AXL antibody, and more preferably anti-HER2 antibody, anti-HER3 antibody, anti-TROP2 antibody, and anti-nectin-4 antibody. These antibodies can be used individually or in combination of two or more.

[0058] In the present invention, the ADC is not particularly limited, but includes anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, anti-TROP2 antibody drug conjugates, anti-B7-H3 antibody drug conjugates, anti-CD3 antibody drug conjugates, anti-CD30 antibody drug conjugates, anti-CD33 antibody drug conjugates, anti-CD37 antibody drug conjugates, anti-CD56 antibody drug conjugates, anti-CD98 antibody drug conjugates, anti-DR5 antibody drug conjugates, anti-EGFR antibody drug conjugates, anti-EPHA2 antibody drug conjugates, and anti-FG Examples include FR2 antibody-drug conjugates, anti-FGFR4 antibody-drug conjugates, anti-c-MET antibody-drug conjugates, anti-FOLR1 antibody-drug conjugates, anti-VEGF antibody-drug conjugates, anti-CD20 antibody-drug conjugates, anti-CD22 antibody-drug conjugates, anti-CD70 antibody-drug conjugates, anti-nectin-4 antibody-drug conjugates, anti-PSMA antibody-drug conjugates, anti-CEA antibody-drug conjugates, anti-Mesothelin antibody-drug conjugates, anti-CEACAM5 antibody-drug conjugates, and anti-AXL antibody-drug conjugates. Preferably, ADCs include anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, anti-TROP2 antibody drug conjugates, anti-B7-H3 antibody drug conjugates, anti-nectin-4 antibody drug conjugates, anti-EGFR antibody drug conjugates, anti-VEGF antibody drug conjugates, anti-c-MET antibody drug conjugates, anti-CEACAM5 antibody drug conjugates, anti-AXL antibody drug conjugates, and more preferably, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, anti-TROP2 antibody drug conjugates, anti-nectin-4 antibody drug conjugates, and so on. These ADCs can be used individually or in combination of two or more.

[0059] In some embodiments, the ADC is not particularly limited, but may include sacituzumab govitecan, datopotamab deruxtecan (Dato-DXd, DATROWAY®), trastuzumab deruxtecan (ENHERTU®), trastuzumab emtansine, patritumab deruxtecan, and sacituzumab tirumotecan, SHR-A1921, LCB-84, IMMU-132, IBI-130, PF-06664178, Enfortumab Vedotin (PADCEV®), SC-101, ST-219, JS-114, NTX1105, BT-8009, SHR-A1811, TAA013, RC-48, BAT8001, ARX788, A166, BAT8003, DAC-002, DS-1062, SKB264, RC-108, TR1801-ADC, Brentuximab Vedotin Examples include Vedotin, gemtuzumab ozogamicin, belantamab mafodotin, ADCT-402, PTK7-ADC, and TRS005. Preferably, the ADCs are sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

[0060] In this specification, the ADC is preferably an anti-HER2 antibody-drug conjugate, an anti-HER3 antibody-drug conjugate, an anti-TROP2 antibody-drug conjugate, or an anti-nectin-4 antibody-drug conjugate, and more preferably trastuzumab deruxtecan (anti-HER2 antibody), patritumab deruxtecan (anti-HER3 antibody), datopotamab deruxtecan (anti-TROP2 antibody), sacituzumab govitecan (anti-TROP2 antibody), or enfortumab vedotin (anti-nectin-4 antibody).

[0061] In the present invention, from the viewpoint of enhancing the antitumor effect (preferably additive, more preferably synergistic) when used in combination with diparereltinib or a salt thereof as another antitumor agent, it is preferably one or more selected from molecular targeted drugs, immune checkpoint inhibitors and antibody-drug conjugates, more preferably one or more selected from VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists and antibody-drug conjugates, and more preferably More preferably, it is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates, and more preferably, it is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amivantamab, futivatinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin. In the present invention, the "other antitumor agents" described above can be used individually or in combination of two or more.

[0062] The tumors targeted in this invention are not particularly limited as long as they exhibit the antitumor effect of the antitumor agent, but are preferably tumors in which diparerertinib or a salt thereof exerts an antitumor effect, and more preferably malignant tumors involving EGFR. "Malignant tumors involving EGFR" refers to malignant tumors in which the incidence is reduced, symptoms are relieved, alleviated, and / or cured by deletion, suppression, and / or inhibition of EGFR function. Such malignant tumors are preferably malignant tumors with EGFR overexpression, EGFR gene amplification, or EGFR mutation positivity. More preferably, they are malignant tumors with EGFR mutation positivity. EGFR mutations include point mutations, insertion mutations, and / or deletion mutations.

[0063] The detection method for EGFR proteins is not limited, but commonly used methods include ELISA, Western blotting, or immunohistochemistry using antibodies that specifically bind to EGFR proteins. Antibodies that specifically bind to EGFR proteins can be commercially available or prepared using commonly used methods.

[0064] Furthermore, commonly used detection methods for the EGFR gene include, for example, Northern blotting, Southern blotting, RT-PCR, real-time PCR, digital PCR, DNA microarray, in-situ hybridization, and sequencing analysis. Another method for detecting the EGFR gene is to use commercially available EGFR gene mutation detection kits, such as the cobas EGFR mutation detection kit (Roche Diagnostics).

[0065] In one embodiment of the present invention, an antitumor agent used for the treatment of malignant tumors involving EGFR, other antitumor agents used in combination with diparereltinib or a salt thereof include at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, HER2 inhibitors, EGFR inhibitors, FGFR inhibitors, RAS inhibitors, ErbB inhibitors, HSP90 inhibitors, CD73 inhibitors, CD47 inhibitors, anti-TROP2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, anti-nectin-4 antibody drug conjugates, TIGIT inhibitors, and PD-1 inhibitors.

[0066] In some embodiments, diparereltinib or a salt thereof exhibits inhibitory activity against mutant EGFRs. In this specification, "mutant EGFR" refers to an EGFR having one or more activating mutations or resistance-acquiring mutations, such as insertion mutations, point mutations, and / or deletion mutations, in the exon 18, exon 19, exon 20, exon 21, etc., of human wild-type EGFR. In the present invention, "insertion mutation" refers to a mutation involving the insertion of one or more (preferably about 1 to 30, 1 to 20, 1 to 10, 1 to 7, or 1 to 4) amino acid residues into the amino acid sequence, and may include in-frame insertions as nucleic acids. In the present invention, "point mutation" refers to a mutation resulting in the substitution, insertion, or deletion of one or more (preferably about 1 to 10, 1 to 5, or 1, 2, or 3) amino acid residues, and may also include in-frame insertions and / or deletion mutations as nucleic acids. In the present invention, "deletion mutation" means a mutation involving the deletion of one or more amino acid residues (preferably about 1 to 50, 1 to 40, 1 to 30, 1 to 15, or 1 to 10), and may include in-frame insertions as nucleic acids. Furthermore, the term "deletion mutation" also includes mutations in which one or more arbitrary amino acids are inserted in addition to the amino acid deletion.

[0067] In this specification, "exon 18" refers to the region from 688 to 728 in the amino acid sequence of the human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1).

[0068] In the present invention, "exon 18 mutation" refers to amino acid insertion mutations, point mutations, and / or deletion mutations in the exon 18 region of human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1). Examples of exon 18 point mutations include E709X or G719X, which are point mutations in which the 709th glutamic acid or 719th glycine in the exon 18 region is replaced with any amino acid. Examples of E709X include E709K, which is a point mutation in which the 709th glutamic acid in the exon 18 region is replaced with lysine, and E709A, which is a point mutation in which it is replaced with alanine. Examples of G719X include G719A, which is a point mutation in which the 719th glycine in the exon 18 region is replaced with alanine, G719S, which is a point mutation in which it is replaced with serine, and G719C, which is a point mutation in which it is replaced with cysteine. Furthermore, exon 18 deletion mutations include not only mutations resulting from the deletion of some amino acids in the exon 18 region, but also mutations in which one or more arbitrary amino acids are inserted in addition to the deleted amino acids. An example of an exon 18 deletion mutation is the mutation in which glutamic acid at position 709 and threonine at position 710 in the exon 18 region are deleted, and aspartic acid is inserted (Del E709-T710insD).

[0069] In this specification, "exon 19" refers to the region from amino acid 729 to 761 in the amino acid sequence of the human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1).

[0070] In this specification, "exon 19 mutation" refers to insertion mutations, point mutations, and / or deletion mutations of one or more amino acids in the exon 19 region of the human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1). Deletion mutations in the exon 19 region include not only mutations resulting from the deletion of some amino acids in the exon 19 region, but also mutations in which one or more arbitrary amino acids are inserted in addition to the amino acid deletion. Examples of exon 19 deletion mutations include a mutation in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750 (also referred to as d746-750)), a mutation in which seven amino acids from leucine at position 747 to proline at position 753 in the exon 19 region are deleted followed by the insertion of serine (Del L747-P753insS), a mutation in which five amino acids from leucine at position 747 to threonine at position 751 in the exon 19 region are deleted (Del L747-T751), and a mutation in which four amino acids from leucine at position 747 to alanine at position 750 in the exon 19 region are deleted followed by the insertion of proline (Del L747-A750insP). In a preferred embodiment of the present invention, the exon 19 deletion mutation is a mutation (Del E746-A750) in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted.

[0071] In this specification, "exon 20" refers to the region from amino acid 762 to 823 in the amino acid sequence of the human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1).

[0072] In this specification, "exon 20 mutation" refers to amino acid insertion mutations, point mutations, and / or deletion mutations in the exon 20 region of the human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1). Examples of exon 20 mutations include A763insFQEA, A767insASV, S768dupSVD, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, T790M, and the like.

[0073] In this specification, "exon 21" refers to the region from 824 to 875 in the amino acid sequence of the human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1).

[0074] In this specification, "exon 21 mutation" refers to insertion mutations, point mutations, and / or deletion mutations in the amino acids of the exon 21 region of the human wild-type EGFR protein (a protein consisting of the amino acid sequence shown in SEQ ID NO: 1). Examples of exon 21 point mutations include point mutations in which one amino acid in the exon 21 region is substituted, preferably L858X or L861X, which are point mutations in which leucine at position 858 or 861 in the exon 21 region is substituted with any amino acid. An example of L858X is L858R, which is a point mutation in which leucine at position 858 in the exon 21 region is substituted with arginine. An example of L861X is L861Q, which is a point mutation in which leucine at position 861 in the exon 21 region is substituted with glutamine.

[0075] In this specification, "MET gene abnormality" refers to a structural or functional abnormality of the MET gene or MET protein in tumor cells. Specifically, this includes MET gene amplification, where the copy number of the MET gene increases abnormally; MET exon 14 skipping mutations, where exon 14 is deleted due to splicing abnormalities of the MET gene; and MET overexpression, where the expression level of the MET protein is significantly higher than in normal tissue. These abnormalities are known to be involved in the molecular mechanisms of tumor progression and treatment resistance, and serve as important biomarkers in selecting patients for treatment.

[0076] In this specification, "MET gene amplification" refers to a condition in which the copy number of the MET gene in tumor cells is abnormally increased compared to normal cells. This amplification is evaluated by methods such as fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS), but is not limited to these. Methods for evaluating MET gene amplification serve as important indicators in selecting patients for treatment, as they indicate abnormal activation of the gene. In the FISH method, the presence or absence of amplification is determined by calculating the MET / CEP7 ratio in tumor cells using probes for the MET gene region and the centromere region of chromosome 7 (CEP7). The copy number (GCN) of the MET gene can also be evaluated using the FISH method. In this specification, examples of MET gene amplification include a MET / CEP7 ratio of 1.8 or higher, 2 or higher, 2.2 or higher, 3.0 or higher, or 5.0 or higher, or a GCN of 3 or higher, 4 or higher, 5 or higher, 6 or higher, 7 or higher, 8 or higher, 9 or higher, 10 or higher, 11 or higher, or 12 or higher. In the present invention, when measured by the FISH method, the MET gene amplification value is preferably a MET / CEP7 ratio of 2 or higher, or a GCN of 4 or higher (for example, a MET / CEP7 ratio of 4 or higher, or a GCN of 10 or higher). In the NGS method, the presence or absence of amplification is evaluated by quantitatively analyzing the copy number of the MET gene, i.e., GCN (Gene Copy Number), from tumor tissue or circulating tumor DNA in the blood. In this specification, examples of MET gene amplification include GCN values ​​of 3 or higher, 4 or higher, 5 or higher, 6 or higher, 7 or higher, 8 or higher, 9 or higher, 10 or higher, 11 or higher, and 12 or higher. In the present invention, when measured by the NGS method, the GCN is preferably 4 or higher, and more preferably 10 or higher. In the present invention, when the MET / CEP7 ratio is 2 or higher or the GCN is 4 or higher, it indicates an activation of a MET gene amplification abnormality, which is a preferred embodiment in the present invention.

[0077] In the present invention, "MET overexpression" refers to a state in which the amount of MET protein in tumor cells is abnormally increased. MET overexpression is evaluated by immunohistochemical testing (IHC), but is not limited to this. In IHC evaluation, a score (0, 1+, 2+, 3+) is assigned based on the intensity of membrane staining. Preferably, MET overexpression is a state in which an IHC score of 2+ (moderate membrane staining) or 3+ (strong, complete membrane staining) is observed. Specific embodiments include states in which an IHC score of 2+ or 3+ is observed in 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of tumor cells. MET overexpression is preferable when an IHC score of 2+ or 3+ is observed in 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of tumor cells. In the present invention, a state in which an IHC score of 3+ is observed in 50% or more of tumor cells is considered to be a state of MET overexpression, and is a more preferred embodiment in the present invention.

[0078] In this specification, “cancer” and “tumor” refer to a physiological condition in mammals characterized by uncontrolled cell proliferation. “Cancer” and “tumor” are synonymous and used interchangeably in this specification. Cancer includes solid tumors and hematological cancers. Cancer includes diseases of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. Cancer also includes primary cancers and metastatic cancers. However, cancer includes, but is not limited to, carcinomas, lymphomas, leukemias, blastomas, sarcomas, and borderline malignancies (carcinoids).

[0079] The tumors covered by the present invention are not particularly limited, but specifically include head and neck cancers, brain tumors, digestive tract cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancers (gallbladder and bile duct cancers, etc.), pancreatic cancer, small intestine cancer, colorectal cancers (colon and rectal cancers, colon cancers, rectal cancers, etc.)), lung cancers (non-small cell lung cancer, small cell lung cancer, etc.), breast cancer, ovarian cancer, uterine cancers (cervical cancer, endometrial cancer, etc.), kidney cancer, bladder cancer, prostate cancer, skin cancers (malignant melanoma, epidermal carcinoma, etc.), and hematological cancers (multiple myeloma, acute myeloid leukemia, etc.). Of these, from the viewpoint of enhancing the antitumor effect (preferably additive, more preferably synergistic) when other antitumor agents are used in combination with diparereltinib or its salts, the preferred antitumor agents are head and neck cancer, brain tumors, gastrointestinal cancers, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer, more preferably head and neck cancer, brain tumors, gastrointestinal cancers, lung cancer, or breast cancer, and particularly preferably lung cancer. Here, cancer includes not only the primary tumor but also cancers that have metastasized to other organs (e.g., liver, brain, etc.). Furthermore, the antitumor agent of the present invention may be used in adjuvant chemotherapy performed after surgical removal of a tumor to prevent recurrence, or it may be used in preoperative adjuvant chemotherapy performed before surgical removal of a tumor.

[0080] In one embodiment of the present invention, the tumor is localized or metastatic lung cancer.

[0081] In this specification, "resistance" refers to a condition in which, after administration of a drug or compound, no therapeutic effect is expected, or the therapeutic effect is reduced, and disease progression is confirmed in at least one clinical evaluation (e.g., imaging diagnosis based on RECIST criteria). This also includes intolerance to the drug or compound, recurrence after administration, or a condition in which no therapeutic effect is expected despite no prior treatment history with the drug or compound.

[0082] In one embodiment of the present invention, the tumor is a tumor that has developed resistance to treatment with an EGFR inhibitor. The EGFR inhibitor to which the tumor has resistance is not particularly limited, but includes afatinib, gefitinib, erlotinib, osimertinib, and the like. Preferably, the tumor is an osimertinib-resistant tumor. Here, "osimertinib resistance" includes a state in which disease progression is confirmed after administration of osimertinib, or a state in which resistance mechanisms such as resistance-related mutations (e.g., C797S, G796S) or MET amplification are present. This may be either osimertinib monotherapy or osimertinib in combination with another agent. More preferably, the tumor is locally advanced or metastatic non-small cell lung cancer (NSCLC) with a history of osimertinib treatment.

[0083] In one embodiment of the present invention, the tumor is a malignant tumor having EGFR overexpression, EGFR gene amplification, or EGFR mutation. The EGFR mutation includes activating mutations in exons 18-21. In a further embodiment, the activating mutation in EGFR includes at least one selected from the group consisting of exon 19 deletion; exon 20 insertion; and exon 21 insertion and / or point mutation. In a further embodiment, the activating mutation in EGFR includes either or both of an exon 19 deletion mutation and an exon 21 L858R mutation. In yet another embodiment, the mutation in EGFR includes so-called Uncommon mutations (e.g., E709X, G719X, S768I, P848L, L861Q, exon 19 insertion mutation, etc.).

[0084] In one embodiment of the present invention, the tumor is a tumor having at least one selected from the group consisting of a deletion mutation in exon 19; an insertion mutation in exon 20; and an L858R mutation in exon 21. In another embodiment of the present invention, the tumor is a tumor having an Uncommon mutation.

[0085] In one embodiment of the present invention, the tumor is preferably a tumor having either an exon 19 deletion mutation or an exon 21 L858R mutation, or both. More preferably, the tumor is one in which EGFR exon 19 deletion mutation or exon 21 L858R mutation positivity has been confirmed at the time of diagnosis of locally advanced or metastatic disease or thereafter.

[0086] In this specification, "combination therapy" of two or more compounds / drugs refers to two or more compounds / drugs administered as part of the same overall treatment plan. The dosages of the individual compounds in the two or more compounds / drugs may differ, and the individual compounds / drugs may be administered simultaneously or separately. Therefore, the combination compounds / drugs may be administered sequentially (e.g., before or after) or simultaneously as the same formulation or as different formulations. The same single formulation may be administered simultaneously, while non-single formulations may be administered simultaneously or separately as different formulations. The dosages of the individual compounds / drugs in combination therapy may also differ depending on the route of administration.

[0087] The combination of the present invention (diparerertinib or a salt thereof combined with other antitumor agents) exhibits a more effective therapeutic effect compared to the therapeutic effects of the individual compounds / agents when administered separately.

[0088] The bonding between two or more compounds / drugs in a combination can be either physical or non-physical.

[0089] The compounds / drugs that are physically bound and combined are not particularly limited, but include compositions containing two or more compounds / drugs in a mixture (e.g., within the same unit dose) (e.g., single formulations), compositions containing materials that chemically / physicochemically link two or more compounds / drugs (e.g., by crosslinking, molecular aggregation or bonding with a common solvent portion), compositions containing materials that chemically / physicochemically package two or more compounds / drugs together (e.g., arranged on or inside lipid vesicles, particles (e.g., microparticles / nanoparticles) and emulsion droplets), and pharmaceutical kits, pharmaceutical packs or patient packs in which two or more compounds / drugs are packaged together or coexist (e.g., as part of a formulation encapsulated in a series of unit doses).

[0090] The compounds / drugs that are non-physically linked and combined are not particularly limited, but include, with instructions for the accidental association of at least one compound / drug to form a physical link between two or more compounds / drugs, a material containing at least one of two or more compounds / drugs (e.g., a non-monochemical formulation), a material containing at least one of two or more compounds / drugs (e.g., a non-monochemical formulation), a material containing at least one other of two or more compounds / drugs, a material containing at least one other of two or more compounds / drugs, a material containing at least one other of two or more compounds / drugs in amounts or forms specifically applied in combination with one or more of two or more compounds / drugs.

[0091] In this specification, “effective dose” or “effective amount” of diparerertinib or its salts and other antitumor agents means the amount of diparerertinib or its salts and other antitumor agents (therapeutic effective dose) that causes a target biological or medical response, such as a decrease or inhibition of enzyme or protein activity, or an improvement in symptoms, relief of a condition, or slowing or delaying the progression of a disease.

[0092] In this specification, "synergistic" means that the therapeutic effect produced by a combination of drugs is greater than the sum of the effects of the individual drugs. In this specification, "additive" means that the therapeutic effect produced by a combination of drugs is greater than the therapeutic effect of any of the drugs individually.

[0093] In this specification, “subjects” include mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, hedgehogs, kangaroos, moles, wild boars, bears, tigers, and lions. Examples of non-mammals include, but are not limited to, birds, fish, and reptiles. In the present invention, diparerertinib or its salts and other antitumor agents are preferably used for the treatment of cancer in mammals, particularly humans. These may be humans diagnosed as requiring treatment for any of the symptoms, conditions, or diseases disclosed herein.

[0094] In this specification, “treatment” is used in the context of treating a medical condition, i.e., a pathological condition, disorder, or disease. Generally, treatment and therapy, whether for humans or animals (e.g., in the field of veterinary medicine), include achieving a desired therapeutic effect, such as inhibiting the progression of a medical condition, which includes slowing the rate of progression, temporarily halting the rate of progression, alleviating the medical condition, reducing or alleviating at least one symptom related to or caused by the symptom being treated, and curing the medical condition.

[0095] In this specification, "antitumor effect" is not particularly limited, but examples include a reduction in tumor volume, stagnation of tumor growth, and extension of survival time, and these can be evaluated.

[0096] When diparerertinib or its salts and other antitumor agents are used as pharmaceuticals, a pharmaceutically acceptable carrier may be added as needed, and various dosage forms may be adopted depending on the purpose of prevention or treatment. The dosage forms are not particularly limited, but specific examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, powders, etc.), injections, suppositories, patches, ointments, etc. The preferred dosage form for diparerertinib or its salts is oral preparation. Diparerertinib or its salts and other antitumor agents may be administered in the same dosage form or in different dosage forms. Each of these dosage forms can be manufactured by pharmaceutical methods known and commonly used by those skilled in the art.

[0097] There are no particular limitations on pharmaceutically acceptable carriers, but examples include excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.

[0098] The administration schedule for diparereltinib or its salts and other antitumor agents should be appropriately selected within the range in which each active ingredient exerts its antitumor effect, and each active ingredient may be administered simultaneously or separately with intervals in between. If administered separately, either one may be administered first.

[0099] Dipareretinib or its salts and other antitumor agents may be formulated by dividing each active ingredient into multiple dosage forms, or by combining them into a single dosage form, based on the administration form and schedule of each active ingredient. Furthermore, each formulation may be manufactured and sold together in a single package suitable for concomitant administration, or each formulation may be manufactured and sold in separate packages.

[0100] The administration schedule for diparerertinib or its salts (e.g., dosage and administration interval) may be appropriately selected at the discretion of the physician, depending on the type and stage of cancer, the location of the disease, the patient's height, weight, sex, or medical history.

[0101] In the present invention, the number of times dipareretinib or its salt is administered can be every other day, once a day, twice a day, or three times a day. The dosage of dipareretinib or its salt is not particularly limited, but can be 50 mg to 300 mg, 50 mg to 200 mg, 50 mg to 150 mg, 50 mg to 130 mg, 50 mg to 100 mg, 65 mg to 300 mg, 65 mg to 200 mg, 65 mg to 150 mg, 65 mg to 130 mg, or 65 mg to 100 mg per day. In certain embodiments, it is desirable that the daily dose be 50 mg, 65 mg, 100 mg, 130 mg, 150 mg, 195 mg, 200 mg, 250 mg, 260 mg, or 300 mg. Specific embodiments include a configuration in which diparerertinib or its salt is administered twice daily, with a dosage of 200 mg / day, 130 mg / day, or 100 mg / day. Another specific embodiment includes a configuration in which diparerertinib or its salt is administered once daily, with a dosage of 100 mg / day, 65 mg / day, or 50 mg / day. Preferred specific embodiments include a configuration in which diparerertinib or its salt is administered twice daily, with a dosage of 200 mg / day. Another preferred specific embodiment includes a configuration in which diparerertinib or its salt is administered twice daily, with a dosage of 130 mg / day. Another preferred specific embodiment includes a configuration in which diparerertinib or its salt is administered twice daily, with a dosage of 100 mg / day. Depending on the severity of the patient's adverse reactions, diparereltinib or its salts may be administered once daily, the dose reduced to 65 mg / day or 50 mg / day, or the drug may be temporarily suspended or discontinued. Administration may be resumed once the adverse reactions subside.

[0102] The administration schedule for other antitumor agents (e.g., dosage and administration interval) may also be appropriately selected at the physician's discretion based on the type and stage of cancer, the location of the disease, the patient's height, weight, sex, or medical history.

[0103] In the present invention, the number of doses of bevacizumab or its salts may be, for example, once daily, or, if administered per cycle, once, twice, three times, four times or more times per cycle, with one cycle lasting 14 to 28 days. The dosage is not particularly limited, but may be 2.5 mg to 12.5 mg / kg (body weight), 5 mg to 20 mg / kg (body weight), 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), 7.5 mg to 20 mg / kg (body weight), 7.5 mg to 15 mg / kg (body weight), etc. A preferred administration schedule is once every two weeks, with a dosage of 5 mg / kg (body weight) per dose. Another preferred administration schedule is once every two weeks, with a dosage of 10 mg / kg (body weight) per dose. In yet another specific embodiment, a preferred administration schedule is once every three weeks, with a dose of 7.5 mg / kg (body weight) per dose. In yet another specific embodiment, a preferred administration schedule is once every three weeks, with a dose of 15 mg / kg (body weight) per dose. Depending on the occurrence and severity of the patient's side effects, the administration interval may be extended as appropriate, and the dose may be reduced, temporarily suspended, or discontinued. Administration may be resumed if the side effects subside.

[0104] In the present invention, the frequency of administration of ramucirumab or its salts may include, for example, administration once daily, once every two days, once every three days, once every five days, once a week, once every two weeks, or once every three weeks, with an administration cycle of 14 to 28 days. The dosage is not particularly limited, but examples include 2 mg to 14 mg / kg (body weight), 2 mg to 11 mg / kg (body weight), 5 mg to 11 mg / kg (body weight), 5 mg to 8 mg / kg (body weight), 6 mg to 14 mg / kg (body weight), 6 mg to 10 mg / kg (body weight), etc. As a specific embodiment, a preferred administration schedule is administration once every two weeks with a dosage of 8 mg / kg (body weight). Another specific embodiment is a preferred administration schedule is administration once every three weeks with a dosage of 10 mg / kg (body weight). Depending on the occurrence of side effects in the patient and the severity of their condition, the administration interval can be appropriately extended, and the dosage can be reduced, the drug can be temporarily stopped, or the drug can be discontinued. Administration may be resumed once the side effects have subsided.

[0105] In the present invention, the number of administrations of capmatinib can be, for example, every other day, once a day, twice a day, or three times a day. The dosage is not particularly limited, but can be 400 mg to 1000 mg, 600 mg to 1000 mg, or 600 mg to 800 mg per day. In a specific embodiment, a preferred administration schedule is twice a day with a dosage of 800 mg / day. In another specific embodiment, a preferred administration schedule is twice a day with a dosage of 600 mg / day. In yet another specific embodiment, a preferred administration schedule is twice a day with a dosage of 400 mg / day. Depending on the severity of the patient's adverse reactions, the dosage can be reduced to 600 mg / day, 400 mg / day, etc., or the drug can be temporarily stopped or discontinued. Administration may be resumed once the adverse reactions have subsided.

[0106] In the present invention, the number of times gmarontinib is administered can be, for example, every other day, once a day, twice a day, or three times a day. The dosage is not particularly limited, but can be 150 mg to 350 mg, 200 mg to 350 mg, 200 mg to 300 mg, 250 mg to 300 mg per day. In a particular embodiment, it is desirable that the daily dosage be 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg. In a specific embodiment, a preferred administration schedule is once a day with a dosage of 300 mg / day. In another specific embodiment, a preferred administration schedule is once a day with a dosage of 250 mg / day. In yet another specific embodiment, a preferred administration schedule is once a day with a dosage of 200 mg / day. In yet another specific embodiment, a preferred administration schedule is once a day with a dosage of 150 mg / day. Depending on the severity of the patient's side effects, the dosage may be reduced to 250 mg / day, 200 mg / day, 150 mg / day, etc., or the drug may be temporarily suspended or discontinued. Administration may be resumed once the side effects have subsided.

[0107] In the present invention, the number of administrations of amivantamab can be, for example, once, twice, three times, four times or more per cycle, with each cycle lasting 14 to 28 days. While there are no particular limitations on the dosage, examples include 140 mg to 2450 mg, 140 mg to 2100 mg, 140 mg to 1750 mg, 140 mg to 1400 mg, 140 mg to 1050 mg, 140 mg to 700 mg, 140 mg to 560 mg, 350 mg to 2450 mg, 350 mg to 2100 mg, 350 mg to 1750 mg, 350 mg to 1400 mg, 350 mg to 1050 mg, 350 mg to 700 mg, 350 mg to 560 mg, 700 mg to 2100 mg, 700 mg to 1750 mg, 700 mg to 1050 mg, 1400 mg to 1750 mg, and 1750 mg to 2100 mg per day. In certain embodiments, the daily dose is preferably one of 140 mg, 350 mg, 560 mg, 700 mg, 1050 mg, 1400 mg, 1750 mg, or 2100 mg. Possible administration schedules include administering twice a week in the first week, once a week from weeks 2 to 5, a rest period in week 6, and then administering once every two weeks from week 7 onwards, with a 14-day cycle. Another preferred administration schedule is one cycle of 21 days, with twice a week in the first week of the first cycle, once a week in weeks 2 and 3, and on the first day of each cycle from the second cycle onwards. Yet another preferred administration schedule is one cycle of 28 days, with twice a week in the first week of the first cycle, once a week in weeks 2, 3, and 4, and then once every two weeks from the second cycle onwards. In the present invention, a 28-day cycle administration schedule is particularly preferred.

[0108] A preferred administration schedule for amivantamab is to administer it twice a week in the first week, once a week in the second and third weeks, and once a week from the fourth week onward, with each cycle lasting 21 days. Specifically, one example of this schedule is to have a 21-day cycle, with a weekly dose of 1050 mg in the first cycle, administered in two divided doses over two days in the first week, once a week at a dose of 1050 mg / day in the second and third weeks, once a week at a dose of 1050 mg / day in the second cycle, and once a week at a dose of 1400 mg / day from the third cycle onward. The division ratio of the 1050 mg dose over two days in the first week is arbitrary, but a preferred ratio is 350 mg / day for the first dose and 700 mg / day for the second dose. Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 700 mg / day on the second day. Another specific example of a preferred administration schedule is a 21-day cycle, where the weekly dose for the first cycle is 1400 mg / week. In the first week of the first cycle, 1400 mg is administered in two divided doses. In the second and third weeks, it is administered once a week at a dose of 1400 mg / day. In the second cycle, it is administered once a week at a dose of 1400 mg / day. From the third cycle onward, it is administered once a week at a dose of 1750 mg / day. The division ratio of the 1400 mg dose in the first week into two doses is arbitrary, but it is preferable to administer 350 mg / day in the first dose and 1050 mg / day in the second dose. Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 1050 mg / day on the second day. Another specific example of a preferred administration schedule is a 21-day cycle, with the first cycle having a weekly dose of 1750 mg / week. The number of doses is as follows: in the first week of the first cycle, 1750 mg is administered in two divided doses; in the second and third weeks, it is administered once a week at a dose of 1750 mg / day; in the second cycle, it is administered once a week at a dose of 1750 mg / day; and from the third cycle onward, it is administered once a week at a dose of 2100 mg / day. The division ratio of the 1750 mg dose in the first week, when divided into two doses, is arbitrary, but a preferred ratio is 350 mg / day for the first dose and 1400 mg / day for the second dose.Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 1400 mg / day on the second day. Another preferred administration schedule is to administer twice a week in the first week, once a week from weeks 2 to 4, with a rest period in weeks 5 and 6, and then once every three weeks from week 7 onward, with a 21-day cycle. Specifically, a preferred administration schedule is to administer 1400 mg / week from weeks 1 to 4, with 1400 mg administered over two days in week 1, once a week from weeks 2 to 4 at a dose of 1400 mg / day, with a rest period in weeks 5 and 6, and then once every three weeks from week 7 onward, with a 21-day cycle at a dose of 1750 mg / day. The ratio of the 1400 mg dose in the first week, divided over two days, is arbitrary, but a preferred ratio is 350 mg / day for the first dose and 1050 mg / day for the second dose. Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 1050 mg / day on the second day. Another specific example of a preferred administration schedule is a dose of 1750 mg / week for weeks 1-4, with the following administration frequency: 1750 mg divided over two days in the first week, once a week for weeks 2-4 at a dose of 1750 mg / day, a rest period in weeks 5 and 6, and from week 7 onwards, once every three weeks with a dose of 2100 mg / day, with a cycle of 21 days. The ratio of the 1750 mg dose in the first week, divided over two days, is arbitrary, but a preferred ratio is 350 mg / day for the first dose and 1400 mg / day for the second dose. Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 1400 mg / day on the second day.

[0109] Another preferred dosage schedule involves administering the drug twice a week in the first week, once a week from weeks two to five, a rest period in week six, and then administering the drug every two weeks from week seven onward, with a 14-day cycle. Specifically, a preferred dosage schedule involves administering 1050 mg / week from weeks one to five, with the dosage divided into two doses over two days in week one, once a week from weeks two to five with a dosage of 1050 mg / day, a rest period in week six, and then administering the drug every two weeks from week seven onward, with a dosage of 1050 mg / day. The division ratio of the 1050 mg dose over two days in week one is arbitrary, but 350 mg / day for the first dose and 700 mg / day for the second dose is preferred. Furthermore, it is more preferable to administer 350 mg / day on day one of week one and 700 mg / day on day two.

[0110] Another specific example of a preferred administration schedule is a dose of 1400 mg / week for weeks 1-5, with the dose divided into two days for week 1, administered once a week for weeks 2-5 at a dose of 1400 mg / day, with a rest period in week 6, and then administered once every two weeks for 14 days from week 7 onwards at a dose of 1400 mg / day. The division ratio for the 1400 mg dose in week 1 is arbitrary, but 350 mg / day for the first dose and 1050 mg / day for the second dose is preferred. Furthermore, it is more preferable to administer 350 mg / day on day 1 of week 1 and 1050 mg / day on day 2.

[0111] Another specific example of an amivantamab administration schedule is a preferred schedule where one cycle is 28 days, and in the first cycle, the weekly dose is 700 mg / week. In the first week of the first cycle, 700 mg is administered in two divided doses. In weeks 2, 3, and 4, it is administered once a week at a dose of 700 mg / day, and from the second cycle onward, it is administered once every two weeks at a dose of 700 mg / day. This administration schedule is preferably used when the patient's weight is less than 80 kg, but it may also be used when the patient's weight is 80 kg or more. The division ratio of the 700 mg dose in the first week into two doses is arbitrary, but 140 mg / day for the first dose and 560 mg / day for the second dose is preferred. Furthermore, it is more preferable to administer 140 mg / day on the first day of the first week and 560 mg / day on the second day.

[0112] Another specific example of a preferred administration schedule is a 28-day cycle, where the weekly dose for the first cycle is 1050 mg / week. In the first week of the first cycle, 1050 mg is administered in two divided doses. In the second, third, and fourth weeks, the dose is administered once a week at a rate of 1050 mg / day. From the second cycle onward, the dose is administered once every two weeks at a rate of 1050 mg / day. This administration schedule may be used whether the patient's weight is less than 80 kg or 80 kg or more. The division ratio of the 1050 mg dose in the first week into two doses is arbitrary, but a preferred ratio is 350 mg / day for the first dose and 700 mg / day for the second dose. Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 700 mg / day on the second day. Another specific example of a preferred administration schedule is a 28-day cycle, where the weekly dose for the first cycle is 1400 mg / week. In the first week of the first cycle, 1400 mg is administered in two divided doses. In the second, third, and fourth weeks, the dose is administered once a week at a rate of 1400 mg / day. From the second cycle onward, the dose is administered once every two weeks at a rate of 1400 mg / day. This administration schedule is preferred when the patient weighs 80 kg or more, but it may also be used when the patient weighs less than 80 kg. The division ratio of the 1400 mg dose in the first week into two doses is arbitrary, but 350 mg / day for the first dose and 1050 mg / day for the second dose is preferred. Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 1050 mg / day on the second day.

[0113] Another specific example of a preferred administration schedule is a 28-day cycle, with a weekly dose of 1750 mg / week for the first cycle. The administration frequency is as follows: 1750 mg is administered over two days during the first week of the first cycle; once a week for weeks 2, 3, and 4, at a dose of 1750 mg / day; and once every two weeks for subsequent cycles, at a dose of 1750 mg / day. While the division ratio for the 1750 mg dose over two days in the first week is arbitrary, a preferred ratio is 350 mg / day for the first dose and 1400 mg / day for the second dose. Furthermore, it is more preferable to administer 350 mg / day on the first day of the first week and 1400 mg / day on the second day.

[0114] The dosage and frequency of administration are not limited to these. The dosage of the drug composition according to the present invention can be adjusted according to the patient's body weight. Depending on the degree of adverse reactions experienced by the patient, the administration interval can be appropriately extended, and the dosage can be reduced, paused, or discontinued to 1750 mg / day, 1400 mg / day, 1050 mg / day, 700 mg / day, 350 mg / day, etc. Administration may be resumed once the adverse reactions have subsided.

[0115] In the present invention, the number of administrations of futivatinib can be, for example, every other day, once a day, twice a day, or three times a day. The dosage is not particularly limited, but can be 8 mg to 24 mg, 12 mg to 24 mg, 12 mg to 20 mg, or 16 mg to 20 mg per day. In certain embodiments, it is desirable that the daily dosage be 4 mg, 8 mg, 12 mg, or 16 mg. In specific embodiments, a preferred number of administrations is once a day, with a dosage of 20 mg / day. In another specific embodiment, a preferred administration schedule is once a day, with a dosage of 16 mg / day. In yet another specific embodiment, a preferred administration schedule is once a day, with a dosage of 12 mg / day. Depending on the severity of the patient's adverse reactions, the dosage can be reduced to 16 mg / day, 12 mg / day, etc., or the drug can be temporarily stopped or discontinued. Administration may be resumed once the adverse reactions have subsided.

[0116] In the present invention, the number of administrations of pimitespive or its salt can be, for example, five consecutive days of administration followed by two days of rest, four consecutive days of administration followed by three days of rest, every other day, once a day, twice a day, or three times a day. The dosage is not particularly limited, but can be 40 mg to 200 mg, 80 mg to 200 mg, 80 mg to 160 mg, 120 mg to 160 mg per day, etc. In certain embodiments, it is desirable that the daily dosage be 40 mg, 80 mg, 120 mg, or 160 mg. As a specific embodiment, a preferred administration schedule is once a day, with a dosage of 160 mg / day administered daily for five consecutive days, followed by two days of rest. Another specific embodiment is a preferred administration schedule, with once a day, with a dosage of 120 mg / day administered daily for five consecutive days, followed by two days of rest. Furthermore, another specific example of a preferred administration schedule is once-daily administration at a dose of 80 mg / day for five consecutive days, followed by a two-day rest period. Depending on the severity of the patient's side effects, the dose may be reduced to 120 mg / day, 80 mg / day, or 40 mg / day, or the drug may be temporarily stopped or discontinued. Administration may be resumed once the side effects have subsided.

[0117] In the present invention, the number of doses of quemrecrustat or its salt can be, for example, once a day, or, if administered per cycle, once, twice, three times, four or more times per cycle, with one cycle lasting 14 to 56 days. The dosage is not particularly limited, but examples include 25 mg to 300 mg, 25 mg to 200 mg, 25 mg to 125 mg, 25 mg to 100 mg, 50 mg to 300 mg, 50 mg to 200 mg, 50 mg to 125 mg, 50 mg to 100 mg, 75 mg to 300 mg, 75 mg to 200 mg, 75 mg to 100 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 200 mg, 150 mg to 350 mg, 150 mg to 300 mg, 150 mg to 200 mg, 200 mg to 300 mg, etc. In certain embodiments, the dose per administration is preferably one of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg. Specific examples include an administration schedule of 21-day cycles, with a dose of 150 mg once every three weeks. Another specific example is an administration schedule of 28-day cycles, with a dose of 100 mg once every two weeks. Yet another specific example is an administration schedule of 21-day cycles, with a dose of 300 mg once every three weeks. Yet another specific example is an administration schedule of 21-day cycles, with a dose of 200 mg once every three weeks.

[0118] The preferred administration schedule is a 21-day cycle with a dose of 300 mg once every three weeks, or a 21-day cycle with a dose of 200 mg once every three weeks. Depending on the severity of side effects in other patients, the administration interval may be extended, the dose reduced, or the drug may be temporarily stopped or discontinued. Administration may be resumed once the side effects have subsided.

[0119] In the present invention, the preferred number of doses of pembrolizumab is, for example, once daily, or, if administered in cycles, once, twice, three times, four or more times per cycle, with each cycle lasting 14 to 42 days. The dosage is not particularly limited, but examples include 100 mg to 300 mg, 100 mg to 200 mg, 200 mg to 500 mg, 300 mg to 500 mg, 300 mg to 400 mg per dose. In a specific embodiment, a preferred administration schedule is one cycle of 21 days, administered once every three weeks, with a dose of 200 mg / dose. In another specific embodiment, a preferred administration schedule is one cycle of 42 days, administered once every six weeks, with a dose of 400 mg / dose. Depending on the severity of the patient's side effects, the administration interval can be appropriately extended, and the dosage can be reduced, paused, or discontinued. Administration may be resumed once the side effects have subsided.

[0120] In the present invention, the preferred number of doses of zimberelimab is, for example, once daily, or, if administered per cycle, once, twice, three times, four times or more times per cycle, with each cycle lasting 14 to 28 days. The dosage is not particularly limited, but examples include 120 mg to 480 mg, 120 mg to 360 mg, 120 mg to 240 mg, 240 mg to 480 mg, 240 mg to 360 mg, 360 mg to 600 mg, 360 mg to 480 mg per dose. In a specific embodiment, a preferred administration schedule is one cycle of 14 days, administered once every two weeks, with a dosage of 240 mg per dose. In another specific embodiment, a preferred administration schedule is one cycle of 21 days, administered once every three weeks, with a dosage of 360 mg per dose. Furthermore, another specific example of a preferred administration schedule is a 28-day cycle, with administration once every four weeks at a dose of 480 mg per dose. Depending on the severity of the patient's side effects, the administration interval may be extended, the dose may be reduced, or the drug may be temporarily suspended or discontinued. Administration may be resumed once the side effects have subsided.

[0121] In the present invention, the preferred number of doses of sacituzumab govitecan is, for example, once daily, or, if administered in cycles, once, twice, three times, four times or more times per cycle, with each cycle lasting 14 to 28 days. The dosage is not particularly limited, but examples include 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), 7.5 mg to 10 mg / kg (body weight) per dose. As a specific embodiment, a preferred administration schedule is a 21-day cycle, with the drug administered once a week for the first two weeks at a dose of 10 mg / kg (body weight) per dose, followed by a rest period in the third week. Another preferred administration schedule is a 21-day cycle, with the drug administered once a week for the first two weeks at a dose of 7.5 mg / kg (body weight) per dose, followed by a rest period in the third week. In yet another embodiment, a preferred administration schedule is a 21-day cycle, with the drug administered once a week at a dose of 5 mg / kg (body weight) per dose for the first two weeks of each cycle, followed by a rest period in the third week. Depending on the severity of the patient's adverse reactions, the administration interval may be extended as appropriate, and the dose may be reduced to 7.5 mg / kg (body weight) per dose, 5 mg / kg (body weight) per dose, or the drug may be stopped or discontinued. Administration may be resumed once the adverse reactions have subsided.

[0122] In the present invention, the preferred number of doses of datopotamab deruxtecan is, for example, once daily, or, if administered in cycles, once, twice, three times, four or more times per cycle, with each cycle lasting 14 to 28 days. The dosage is not particularly limited, but examples include 4 mg to 8 mg / kg (body weight), 6 mg to 8 mg / kg (body weight) per dose. In specific embodiments, a preferred administration schedule is a 21-day cycle, administered once every three weeks at a dose of 8 mg / kg (body weight) per dose. In another specific embodiment, a preferred administration schedule is a 21-day cycle, administered once every three weeks at a dose of 6 mg / kg (body weight) per dose. In yet another embodiment, a preferred administration schedule is a 21-day cycle, administered once every three weeks at a dose of 4 mg / kg (body weight) per dose. The administration interval can be extended as appropriate, and the dosage can be reduced, paused, or discontinued. Administration may be resumed if side effects subside.

[0123] In the present invention, the preferred number of doses of trastuzumab deruxtecan is, for example, once daily, or, if administered in cycles, once, twice, three times, four or more times per cycle, with each cycle lasting 14 to 28 days. The dosage is not particularly limited, but examples include 3.2 mg to 7.4 mg / kg (body weight), 4.4 mg to 7.4 mg / kg (body weight), 4.4 mg to 6.4 mg / kg (body weight), 5.4 mg to 6.4 mg / kg (body weight) per dose. In a specific embodiment, a preferred administration schedule is a 21-day cycle, administered once every three weeks at a dose of 5.4 mg / kg (body weight) per dose. In another specific embodiment, a preferred administration schedule is a 21-day cycle, administered once every three weeks at a dose of 6.4 mg / kg (body weight) per dose. Furthermore, in another specific embodiment, a preferred administration schedule is a 21-day cycle, with a dose of 4.4 mg / kg (body weight) per dose administered once every three weeks. Depending on the severity of the patient's adverse reactions, the administration interval may be extended as appropriate, and the dose may be reduced to 5.4 mg / kg (body weight) per dose, 4.4 mg / kg (body weight) per dose, 3.2 mg / kg (body weight) per dose, or the drug may be temporarily suspended or discontinued. Administration may be resumed once the adverse reactions have subsided.

[0124] In the present invention, the preferred number of doses of patritumab deruxtecan is, for example, once daily, or, if administered in cycles, once, twice, three times, four times or more times per cycle, with each cycle lasting 14 to 28 days. The dosage is not particularly limited, but examples include 3.2 mg to 6.4 mg / kg (body weight), 3.2 mg to 5.6 mg / kg (body weight), 4.8 mg to 5.6 mg / kg (body weight) per dose. In a specific embodiment, a preferred administration schedule is a 21-day cycle, with administration once every three weeks at a dose of 5.6 mg / kg (body weight) per dose. In another specific embodiment, a preferred administration schedule is a 21-day cycle, with administration once every three weeks at a dose of 4.8 mg / kg (body weight) per dose. Depending on the severity of the patient's side effects, the dosing interval may be extended as appropriate, and the dosage may be reduced to 4.8 mg / kg (body weight) / dose, 3.2 mg / kg (body weight) / dose, or the drug may be temporarily suspended or discontinued. Administration may be resumed once the side effects have subsided.

[0125] In the present invention, the number of administrations of enfortumab vedotin is preferably, for example, once a day, or, if administered in cycles, once, twice, three times, four or more times per cycle, with each cycle lasting 14 to 28 days. The dosage is not particularly limited, but examples include 0.5 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.25 mg / kg (body weight), 1.0 mg to 1.25 mg / kg (body weight) per dose. As a specific embodiment, a preferred administration schedule is a 28-day cycle, with weekly administration for the first three weeks, a dosage of 1.25 mg / kg (body weight) per dose, and a rest period in the fourth week. As another specific embodiment, a preferred administration schedule is a 28-day cycle, with weekly administration for the first three weeks, a dosage of 1.0 mg / kg (body weight) per dose, and a rest period in the fourth week. Furthermore, in another specific embodiment, one cycle is defined as 21 days, with administration once a week for the first two weeks at a dose of 1.25 mg / kg (body weight) / dose, followed by a drug-free week in the third week. Depending on the severity of the patient's side effects, the administration interval may be extended as appropriate, and the dose may be reduced to 1.0 mg / kg (body weight) / dose, 0.75 mg / kg (body weight) / dose, 0.5 mg / kg (body weight) / dose, etc., or the drug may be stopped or discontinued. Administration may be resumed once the side effects have subsided.

[0126] In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 150 mg to 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 200 mg to 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 200 mg to 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 250 mg to 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 150 mg to 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 200 mg to 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 200 mg to 300 mg of gumarontinib per day. In another embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 250 mg to 300 mg of gumarontinib per day. In yet another embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 150 mg to 350 mg of gumarontinib per day.In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 200 mg to 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 200 mg to 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 250 mg to 300 mg of gumarontinib per day.

[0127] In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 200 mg of diparerertinib or its salt and 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 200 mg of diparerertinib or its salt and 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 200 mg of diparerertinib or its salt and 250 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 200 mg of diparerertinib or its salt and 200 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 200 mg of diparerertinib or its salt and 150 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 130 mg of diparerertinib or its salt and 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 130 mg of diparerertinib or its salt and 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 130 mg of diparerertinib or its salt and 250 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 130 mg of diparerertinib or its salt and 200 mg of gumarontinib per day. In another embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 130 mg of diparerertinib or its salt and 150 mg of gumarontinib per day.In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg of diparerertinib or its salt and 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg of diparerertinib or its salt and 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg of diparerertinib or its salt and 250 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg of diparerertinib or its salt and 200 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 100 mg of diparerertinib or its salt and 150 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 65 mg of diparerertinib or its salt and 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 65 mg of diparerertinib or its salt and 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 65 mg of diparerertinib or its salt and 250 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 65 mg of diparerertinib or its salt and 200 mg of gumarontinib per day. In another embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 65 mg of diparerertinib or its salt and 150 mg of gumarontinib per day.In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 65 mg of diparerertinib or its salt and 350 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg of diparerertinib or its salt and 300 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg of diparerertinib or its salt and 250 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg of diparerertinib or its salt and 200 mg of gumarontinib per day. In one embodiment, the dosage of diparerertinib or its salt and gumarontinib may be, for example, 50 mg of diparerertinib or its salt and 150 mg of gumarontinib per day.

[0128] In one embodiment, the administration schedule is 21 days long, and includes administering diparereltinib or a salt thereof twice daily at a dose of 200 mg / day, and administering gumarontinib once daily at a dose of 350 mg / day.

[0129] In one embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 200 mg / day, and gumarontinib is administered once daily at a dose of 300 mg / day. In another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 200 mg / day, and gumarontinib is administered once daily at a dose of 250 mg / day. In yet another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 200 mg / day, and gumarontinib is administered once daily at a dose of 200 mg / day. In one embodiment, an administration schedule is given in a 21-day cycle, in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and gumarontinib is administered once daily at a dose of 150 mg / day. In another embodiment, an administration schedule is given in a 21-day cycle, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day, and gumarontinib is administered once daily at a dose of 350 mg / day.

[0130] In one embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 130 mg / day, and gumarontinib is administered once daily at a dose of 300 mg / day. In another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 130 mg / day, and gumarontinib is administered once daily at a dose of 250 mg / day. In yet another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 130 mg / day, and gumarontinib is administered once daily at a dose of 200 mg / day. In one embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 130 mg / day, and gumarontinib is administered once daily at a dose of 150 mg / day. In another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 100 mg / day, and gumarontinib is administered once daily at a dose of 350 mg / day. In yet another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 100 mg / day, and gumarontinib is administered once daily at a dose of 300 mg / day. In one embodiment, an administration schedule is given in a 21-day cycle, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and gumarontinib is administered once daily at a dose of 250 mg / day. In another embodiment, an administration schedule is given in a 21-day cycle, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and gumarontinib is administered once daily at a dose of 200 mg / day.In one embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 100 mg / day, and gumarontinib is administered once daily at a dose of 150 mg / day. In another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 65 mg / day, and gumarontinib is administered once daily at a dose of 350 mg / day. In yet another embodiment, a 21-day cycle administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 65 mg / day, and gumarontinib is administered once daily at a dose of 300 mg / day. In one embodiment, a 21-day cycle administration schedule is provided, in which diparerltinib or its salt is administered twice daily at a dose of 65 mg / day, and gumarontinib is administered once daily at a dose of 250 mg / day. In another embodiment, a 21-day cycle administration schedule is provided, in which diparerltinib or its salt is administered twice daily at a dose of 65 mg / day, and gumarontinib is administered once daily at a dose of 200 mg / day. In yet another embodiment, a 21-day cycle administration schedule is provided, in which diparerltinib or its salt is administered twice daily at a dose of 65 mg / day, and gumarontinib is administered once daily at a dose of 150 mg / day. In one embodiment, an administration schedule is given in a 21-day cycle, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and gumarontinib is administered once daily at a dose of 350 mg / day. In another embodiment, an administration schedule is given in a 21-day cycle, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and gumarontinib is administered once daily at a dose of 300 mg / day.In one embodiment, a 21-day administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and gumarontinib is administered once daily at a dose of 250 mg / day. In another embodiment, a 21-day administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and gumarontinib is administered once daily at a dose of 200 mg / day. In yet another embodiment, a 21-day administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and gumarontinib is administered once daily at a dose of 150 mg / day.

[0131] In one embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 50 mg to 300 mg of diparerertinib or its salt and 40 mg to 200 mg of pimitespive per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 50 mg to 300 mg of diparerertinib or its salt and 80 mg to 200 mg of pimitespive per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 50 mg to 300 mg of diparerertinib or its salt and 80 mg to 160 mg of pimitespive per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 120 mg to 160 mg of pimitespive per day.

[0132] In one embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 50 mg to 200 mg of diparerertinib or its salt and 40 mg to 200 mg of pimitespive per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 50 mg to 200 mg of diparerertinib or its salt and 80 mg to 200 mg of pimitespive per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 50 mg to 200 mg of diparerertinib or its salt and 80 mg to 160 mg of pimitespive per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 120 mg to 160 mg of pimitespive per day.

[0133] In one embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 100 mg to 200 mg of diparerertinib or its salt and 40 mg to 200 mg of pimitespive per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 100 mg to 200 mg of diparerertinib or its salt and 80 mg to 200 mg of pimitespive per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespive is, for example, 100 mg to 200 mg of diparerertinib or its salt and 80 mg to 160 mg of pimitespive per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 120 mg to 160 mg of pimitespive per day.

[0134] In one embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 200 mg of diparerertinib or its salt and 200 mg of pimitespive per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 200 mg of diparerertinib or its salt and 160 mg of pimitespive per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 200 mg of diparerertinib or its salt and 120 mg of pimitespive per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 200 mg of diparerertinib or its salt and 80 mg of pimitespive per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 200 mg of diparerertinib or its salt and 40 mg of pimitespiv per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 130 mg of diparerertinib or its salt and 200 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 130 mg of diparerertinib or its salt and 160 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 130 mg of diparerertinib or its salt and 120 mg of pimitespiv per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespiv is, for example, 130 mg of diparerertinib or its salt and 80 mg of pimitespiv per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespiv is, for example, 130 mg of diparerertinib or its salt and 40 mg of pimitespiv per day.In one embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 100 mg of diparerertinib or its salt and 200 mg of pimitespiv per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 100 mg of diparerertinib or its salt and 160 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 100 mg of diparerertinib or its salt and 120 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 100 mg of diparerertinib or its salt and 80 mg of pimitespiv per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 100 mg of diparerertinib or its salt and 40 mg of pimitespiv per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 65 mg of diparerertinib or its salt and 200 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 65 mg of diparerertinib or its salt and 160 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 65 mg of diparerertinib or its salt and 120 mg of pimitespiv per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 65 mg of diparerertinib or its salt and 80 mg of pimitespive per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespive may be, for example, 65 mg of diparerertinib or its salt and 40 mg of pimitespive per day.In one embodiment, the dosage of diparerertinib or its salt and pimitespiv is, for example, 50 mg of diparerertinib or its salt and 200 mg of pimitespiv per day. In another embodiment, the dosage of diparerertinib or its salt and pimitespiv is, for example, 50 mg of diparerertinib or its salt and 160 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv is, for example, 50 mg of diparerertinib or its salt and 120 mg of pimitespiv per day. In yet another embodiment, the dosage of diparerertinib or its salt and pimitespiv is, for example, 50 mg of diparerertinib or its salt and 80 mg of pimitespiv per day. In one embodiment, the dosage of diparerertinib or its salt and pimitespiv may be, for example, 50 mg of diparerertinib or its salt per day and 40 mg of pimitespiv per day.

[0135] In one embodiment, the administration schedule is such that one cycle is 21 days, and diparereltinib or a salt thereof is administered twice daily at a dose of 200 mg / day for five consecutive days, followed by pimitespiv once daily at a dose of 200 mg / day for five consecutive days, and then a two-day rest period, which is repeated three times.

[0136] In one embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 160 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In another embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 120 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In one embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 80 mg / day for five consecutive days, followed by a two-day rest period, and this regimen is repeated three times. In another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 40 mg / day for five consecutive days, followed by a two-day rest period, and this regimen is repeated three times. In one embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 200 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In another embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 160 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In one embodiment, the administration schedule is such that one cycle is 21 days, and diparereltinib or a salt thereof is administered twice daily at a dose of 130 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 120 mg / day for five consecutive days, followed by a two-day rest period, and this schedule is repeated three times.In one embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 80 mg / day for five consecutive days, followed by a two-day rest period, and this regimen is repeated three times. In another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 40 mg / day for five consecutive days, followed by a two-day rest period, and this regimen is repeated three times. In one embodiment, an administration schedule is given in a cycle of 21 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 100 mg / day for consecutive days, pimitespive is administered once daily at a dose of 200 mg / day for five consecutive days, followed by a two-day rest period, and this is repeated three times. In another embodiment, an administration schedule is given in a cycle of 21 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 100 mg / day for consecutive days, pimitespive is administered once daily at a dose of 160 mg / day for five consecutive days, followed by a two-day rest period, and this is repeated three times. In one embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 120 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In another embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 80 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In one embodiment, the administration schedule is such that one cycle is 21 days, and diparereltinib or a salt thereof is administered twice daily at a dose of 100 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 40 mg / day for five consecutive days, followed by a two-day rest period, and this schedule is repeated three times.In one embodiment, an administration schedule is given in a cycle of 21 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 65 mg / day for consecutive days, pimitespive is administered once daily at a dose of 200 mg / day for consecutive days, followed by a 2-day rest period, and this schedule is repeated three times. In another embodiment, an administration schedule is given in a cycle of 21 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 65 mg / day for consecutive days, pimitespive is administered once daily at a dose of 160 mg / day for consecutive days, followed by a 2-day rest period, and this schedule is repeated three times. In one embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 65 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 120 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In another embodiment, a 21-day administration cycle is provided, in which diparereltinib or its salt is administered twice daily at a dose of 65 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 80 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In one embodiment, a 21-day cycle of administration is provided, in which diparereltinib or its salt is administered twice daily at a dose of 65 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 40 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In another embodiment, a 21-day cycle of administration is provided, in which diparereltinib or its salt is administered twice daily at a dose of 50 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 200 mg / day for five consecutive days, followed by a two-day rest period, and this cycle is repeated three times. In one embodiment, the administration schedule is such that one cycle is 21 days, and diparereltinib or a salt thereof is administered twice daily at a dose of 50 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 160 mg / day for five consecutive days, followed by a two-day rest period, and this schedule is repeated three times.In one embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 50 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 120 mg / day for five consecutive days, followed by a two-day rest period, and this regimen is repeated three times. In another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 50 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 80 mg / day for five consecutive days, followed by a two-day rest period, and this regimen is repeated three times. In one embodiment, the administration schedule is such that one cycle is 21 days, and diparereltinib or a salt thereof is administered twice daily at a dose of 50 mg / day for five consecutive days, pimitespive is administered once daily at a dose of 40 mg / day for five consecutive days, followed by a two-day rest period, and this schedule is repeated three times.

[0137] In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 25 mg to 125 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 50 mg to 125 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 50 mg to 100 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 75 mg to 100 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 100 mg to 350 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt and 150 mg to 350 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 150 mg to 300 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 200 mg to 300 mg of quemrecrustat per day.

[0138] In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 25 mg to 125 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 50 mg to 125 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 50 mg to 100 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 75 mg to 100 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 100 mg to 350 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 200 mg of diparerertinib or its salt and 150 mg to 350 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 150 mg to 300 mg of quemrecrustat per day.

[0139] In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 25 mg to 125 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 50 mg to 125 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 50 mg to 100 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 75 mg to 100 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 100 mg to 350 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg to 200 mg of diparerertinib or its salt and 150 mg to 350 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 150 mg to 300 mg of quemrecrustat per day.

[0140] In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 350 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 300 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 200 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 150 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 125 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 100 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 75 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 50 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 200 mg of diparerertinib or its salt and 25 mg of quemrecrustat per day.In one embodiment, the dosage of compound A or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 350 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 300 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 200 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 150 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 125 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 100 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 75 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt and 50 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 130 mg of diparerertinib or its salt per day and 25 mg of quemrecrustat per day.In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 350 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 300 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 200 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 150 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 125 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 100 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 75 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 50 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 100 mg of diparerertinib or its salt and 25 mg of quemrecrustat per day.In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 350 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 300 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 200 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 150 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 125 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 100 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 75 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 50 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 65 mg of diparerertinib or its salt and 25 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 350 mg of quemrecrustat per day.In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 300 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 200 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 150 mg of quemrecrustat per day. In yet another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 125 mg of quemrecrustat per day. In one embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 100 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 75 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 50 mg of quemrecrustat per day. In another embodiment, the dosage of diparerertinib or its salt and quemrecrustat may be, for example, 50 mg of diparerertinib or its salt and 25 mg of quemrecrustat per day.

[0141] In one embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered once every three weeks at a dose of 350 mg / dose. In another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered once every three weeks at a dose of 300 mg / dose. In yet another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered once every three weeks at a dose of 200 mg / dose. In one embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered once every three weeks at a dose of 150 mg / dose. In another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered once every three weeks at a dose of 100 mg / dose. In yet another embodiment, a 28-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered every two weeks at a dose of 125 mg / dose. In one embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered at a dose of 100 mg / dose every two weeks. In another embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered at a dose of 75 mg / dose every two weeks.In one embodiment, an administration schedule is given in a cycle of 28 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered at a dose of 50 mg / dose every two weeks. In another embodiment, an administration schedule is given in a cycle of 28 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 200 mg / day, and quemrecrustat is administered at a dose of 25 mg / dose every two weeks.

[0142] In one embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered once every three weeks at a dose of 350 mg / dose. In another embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered once every three weeks at a dose of 300 mg / dose. In yet another embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered once every three weeks at a dose of 200 mg / dose. In one embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered once every three weeks at a dose of 150 mg / dose. In another embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered once every three weeks at a dose of 100 mg / dose. In yet another embodiment, a 28-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered every two weeks at a dose of 125 mg / dose. In one embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered at a dose of 100 mg / dose every two weeks. In another embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered at a dose of 75 mg / dose every two weeks.In one embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered at a dose of 50 mg / dose every two weeks. In another embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 130 mg / day, and quemrecrustat is administered at a dose of 25 mg / dose every two weeks.

[0143] In one embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered once every three weeks at a dose of 350 mg / dose. In another embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered once every three weeks at a dose of 300 mg / dose. In yet another embodiment, a 21-day cycle administration schedule is provided, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered once every three weeks at a dose of 200 mg / dose. In one embodiment, an administration schedule is provided in a cycle of 21 days, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered once every three weeks at a dose of 150 mg / dose. In another embodiment, an administration schedule is provided in a cycle of 21 days, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered once every three weeks at a dose of 100 mg / dose. In yet another embodiment, an administration schedule is provided in a cycle of 28 days, in which diparereltinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered every two weeks at a dose of 125 mg / dose. In one embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered at a dose of 100 mg / dose every two weeks. In another embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered at a dose of 75 mg / dose every two weeks.In one embodiment, a 28-day cycle is defined as a regimen in which diparerertinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered at a dose of 50 mg / dose every two weeks. In another embodiment, a 28-day cycle is defined as a regimen in which diparerertinib or its salt is administered twice daily at a dose of 100 mg / day, and quemrecrustat is administered at a dose of 25 mg / dose every two weeks. In yet another embodiment, a 21-day cycle is defined as a regimen in which diparerertinib or its salt is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered at a dose of 350 mg / dose every three weeks. In one embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered once every three weeks at a dose of 300 mg / dose. In another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered once every three weeks at a dose of 200 mg / dose. In yet another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered once every three weeks at a dose of 150 mg / dose. In one embodiment, an administration schedule is given in a cycle of 21 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered once every three weeks at a dose of 100 mg / dose. In another embodiment, an administration schedule is given in a cycle of 28 days, in which diparereltinib or a salt thereof is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered repeatedly once every two weeks at a dose of 125 mg / dose.In one embodiment, a 28-day administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered at a dose of 100 mg / dose every two weeks. In another embodiment, a 28-day administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered at a dose of 75 mg / dose every two weeks. In yet another embodiment, a 28-day administration schedule is provided, in which diparerertinib or its salt is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered at a dose of 50 mg / dose every two weeks. In one embodiment, the administration schedule is such that one cycle is 28 days, and diparereltinib or a salt thereof is administered twice daily at a dose of 65 mg / day, and quemrecrustat is administered at a dose of 25 mg / dose every two weeks.

[0144] In one embodiment, an administration schedule is provided in a 21-day cycle, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered once every three weeks at a dose of 350 mg / dose. In another embodiment, an administration schedule is provided in a 21-day cycle, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered once every three weeks at a dose of 300 mg / dose. In yet another embodiment, an administration schedule is provided in a 21-day cycle, in which diparerertinib or its salt is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered once every three weeks at a dose of 200 mg / dose. In one embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered once every three weeks at a dose of 150 mg / dose. In another embodiment, a 21-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered once every three weeks at a dose of 100 mg / dose. In yet another embodiment, a 28-day cycle is defined as a regimen in which diparereltinib or its salt is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered every two weeks at a dose of 125 mg / dose. In one embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered at a dose of 100 mg / dose every two weeks. In another embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered at a dose of 75 mg / dose every two weeks.In one embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered at a dose of 50 mg / dose every two weeks. In another embodiment, an administration schedule is given in a 28-day cycle, in which diparereltinib or a salt thereof is administered twice daily at a dose of 50 mg / day, and quemrecrustat is administered at a dose of 25 mg / dose every two weeks.

[0145] In one embodiment, examples of the dosage of diparerertinib or its salt and bevacizumab or its salt include 50 mg to 300 mg of diparerertinib or its salt per day and 2.5 mg to 12.5 mg / kg (body weight), 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), 5 mg to 20 mg / kg (body weight), 7.5 mg to 20 mg / kg (body weight), or 7.5 mg to 15 mg / kg (body weight) of bevacizumab or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and bevacizumab or its salt may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 2.5 mg to 12.5 mg / kg (body weight), 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), 5 mg to 20 mg / kg (body weight), 7.5 mg to 20 mg / kg (body weight), or 7.5 mg to 15 mg / kg (body weight) of bevacizumab or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and bevacizumab or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 2.5 mg to 12.5 mg / kg (body weight), 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), 5 mg to 20 mg / kg (body weight), 7.5 mg to 20 mg / kg (body weight), or 7.5 mg to 15 mg / kg (body weight) of bevacizumab or its salt per day. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and bevacizumab or its salt include administering diparerertinib or its salt twice daily, with a dosage of 200 mg / day, 130 mg / day, or 100 mg / day, and bevacizumab or its salt at a dosage of 5 mg / kg (body weight) / dose with an interval of 2 weeks or more; 10 mg / kg (body weight) / dose with an interval of 2 weeks or more; 7.5 mg / kg (body weight) / dose with an interval of 3 weeks or more; or 15 mg / kg (body weight) / dose with an interval of 3 weeks or more.In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and bevacizumab or its salt include: diparerertinib or its salt administered once daily, with a dose of 65 mg / day or 50 mg / day, and bevacizumab or its salt administered at a dose of 5 mg / kg (body weight) per dose with an interval of 2 weeks or more; a dose of 10 mg / kg (body weight) per dose with an interval of 2 weeks or more; a dose of 7.5 mg / kg (body weight) per dose with an interval of 3 weeks or more; or a dose of 15 mg / kg (body weight) per dose with an interval of 3 weeks or more.

[0146] In one embodiment, the dosage of diparerertinib or its salt and ramucirumab or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 2 mg to 14 mg / kg (body weight), 2 mg to 11 mg / kg (body weight), 5 mg to 11 mg / kg (body weight), 5 mg to 8 mg / kg (body weight), 6 mg to 14 mg / kg (body weight), or 6 mg to 10 mg / kg (body weight) of ramucirumab or its salt per day. In one embodiment, the dosage of dipareretinib or its salt and ramucirumab or its salt may be, for example, 50 mg to 200 mg of dipareretinib or its salt per day and 2 mg to 14 mg / kg (body weight), 2 mg to 11 mg / kg (body weight), 5 mg to 11 mg / kg (body weight), 5 mg to 8 mg / kg (body weight), 6 mg to 14 mg / kg (body weight), or 6 mg to 10 mg / kg (body weight) of ramucirumab or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and ramucirumab or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 2 mg to 14 mg / kg (body weight), 2 mg to 11 mg / kg (body weight), 5 mg to 11 mg / kg (body weight), 5 mg to 8 mg / kg (body weight), 6 mg to 14 mg / kg (body weight), or 6 mg to 10 mg / kg (body weight) of ramucirumab or its salt per day. In one embodiment, the dosage, frequency, and method of administration of diparerertinib or its salt and ramucirumab or its salt include, for example, administering diparerertinib or its salt twice daily at a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and ramucirumab or its salt once every two weeks at a dose of 8 mg / kg (body weight) per dose, or administering it once every three weeks at a dose of 10 mg / kg (body weight) per dose. In another embodiment, the dosage, frequency, and method of administration of diparerertinib or its salt and ramucirumab or its salt include, for example, administering diparerertinib or its salt once daily at a dose of 65 mg / day or 50 mg / day, and ramucirumab or its salt once every two weeks at a dose of 8 mg / kg (body weight) per dose, or administering it once every three weeks at a dose of 10 mg / kg (body weight) per dose.

[0147] In one embodiment, the dosage of diparerertinib or its salt and capmatinib or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 400 mg to 1000 mg, 600 mg to 1000 mg, or 600 mg to 800 mg of capmatinib or its salt per day. In another embodiment, the dosage of diparerertinib or its salt and capmatinib or its salt may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 400 mg to 1000 mg, 600 mg to 1000 mg, or 600 mg to 800 mg of capmatinib or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and capmatinib or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 400 mg to 1000 mg, 600 mg to 1000 mg, or 600 mg to 800 mg of capmatinib or its salt per day. In one embodiment, the dosage, frequency of administration, and method of administration of diparerertinib or its salt and capmatinib or its salt may be, for example, administration of diparerertinib or its salt twice a day, with a dosage of 200 mg / day, 130 mg / day, or 100 mg / day, and administration of capmatinib or its salt twice a day, with a dosage of 800 mg / day, administration twice a day, with a dosage of 600 mg / day, or administration twice a day, with a dosage of 400 mg / day. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and capmatinib or its salt include administering diparerertinib or its salt once daily at a dose of 65 mg / day or 50 mg / day and capmatinib or its salt twice daily at a dose of 800 mg / day, twice daily at a dose of 600 mg / day, or twice daily at a dose of 400 mg / day.

[0148] In one embodiment, the dosage of diparerertinib or its salt and amivantamab or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 140 mg to 2450 mg, 140 mg to 2100 mg, 140 mg to 1750 mg, 140 mg to 1400 mg, 140 mg to 1050 mg, 140 mg to 700 mg of amivantamab or its salt per day. Examples of dosages include 40 mg to 560 mg, 350 mg to 2450 mg, 350 mg to 2100 mg, 350 mg to 1750 mg, 350 mg to 1400 mg, 350 mg to 1050 mg, 350 mg to 700 mg, 350 mg to 560 mg, 700 mg to 2100 mg, 700 mg to 1750 mg, 700 mg to 1050 mg, 1400 mg to 1750 mg, or 1750 mg to 2100 mg. In one embodiment, the dosage of diparerertinib or its salt and amivantamab or its salt is, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 140 mg to 2450 mg, 140 mg to 2100 mg, 140 mg to 1750 mg, 140 mg to 1400 mg, 140 mg to 1050 mg, 140 mg to 700 mg of amivantamab or its salt per day. Examples of dosages include 40 mg to 560 mg, 350 mg to 2450 mg, 350 mg to 2100 mg, 350 mg to 1750 mg, 350 mg to 1400 mg, 350 mg to 1050 mg, 350 mg to 700 mg, 350 mg to 560 mg, 700 mg to 2100 mg, 700 mg to 1750 mg, 700 mg to 1050 mg, 1400 mg to 1750 mg, or 1750 mg to 2100 mg. In one embodiment, the dosage of diparerertinib or its salt and amivantamab or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 140 mg to 2450 mg, 140 mg to 2100 mg, 140 mg to 1750 mg, 140 mg to 1400 mg, 140 mg to 1050 mg, 140 mg to 700 mg, 140 mg to 560 mg, 350 mg to 2450 mg, 350 mg to 2100 mg, 350 mg to 1750 mg, 350 mg to 1400 mg, 350 mg to 1050 mg, 350 mg to 700 mg, 350 mg to 560 mg, 700 mg to 2100 mg per day.Examples of dosages include 700 mg to 1750 mg, 700 mg to 1050 mg, 1400 mg to 1750 mg, or 1750 mg to 2100 mg. In one embodiment, the dosage, frequency of administration, and method of administration of diparerertinib or its salt and amibantamab or its salt may be, for example, diparerertinib or its salt administered twice daily, with a dosage of 200 mg / day, and amibantamab or its salt administered twice a week in the first week of the first cycle, once a week in the second and third weeks, and on the first day of each cycle from the second cycle onward; in the first cycle, with a dosage of 1400 mg / week, and in the first cycle, with a dosage of 1400 mg / week. The administration schedule is as follows: In the first week of the first cycle, 1400 mg is administered in two divided doses over two days; in the second and third weeks, it is administered once a week at a dose of 1400 mg / day; in the second cycle, it is administered once a week at a dose of 1400 mg / day; and from the third cycle onward, it is administered once a week at a dose of 1750 mg / day; one cycle is 21 days, and in the first cycle, the weekly dose is 1750 mg / week, with the number of doses being 1750 mg in two divided doses over two days in the first week of the first cycle, and once a week at a dose of 1750 mg / The administration schedule is as follows: for the second cycle, administration is once a week at a dose of 1750 mg / day; from the third cycle onward, administration is once a week at a dose of 2100 mg / day; for the first week, administration is twice a week; for weeks 2-4, administration is once a week; for weeks 5 and 6, there is a drug-free period; and from week 7 onward, administration is once every three weeks in a 21-day cycle; for weeks 1-4, the dose is 1400 mg / week, with the number of doses being 1400 mg divided over two days in the first week, once a week at a dose of 1400 mg / day in weeks 2-4, and from week 5 onward The drug is taken off during the 6th week, and from the 7th week onward, it is administered once every 3 weeks in a 21-day cycle, with a dosage of 1750 mg / day; the dosage for weeks 1-4 is 1750 mg / week, with the number of doses being 1750 mg divided over 2 days in the 1st week, once a week in weeks 2-4, with a dosage of 1750 mg / day, with no doses in weeks 5 and 6, and from the 7th week onward, it is administered once every 3 weeks in a 21-day cycle, with a dosage of 2100 mg / day; in the 1st week, it is administered twice a week, once a week in weeks 2-5, and no doses in week 6.From week 7 onwards, the administration schedule involves administering the drug once every two weeks in 14-day cycles; the dosage for weeks 1-5 is 1050 mg / week, with the administration frequency being 1050 mg divided over two days in week 1, once a week in weeks 2-5 with a dosage of 1050 mg / day, a rest period in week 6, and from week 7 onwards, the administration schedule involves administering the drug once every two weeks in 14-day cycles with a dosage of 1050 mg / day; or the dosage for weeks 1-5 is 1400 mg / week, with the administration frequency being 1400 mg divided over two days in week 1, once a week in weeks 2-5 with a dosage of 1400 mg / day, a rest period in week 6, and from week 7 onwards, the administration schedule involves administering the drug once every two weeks in 14-day cycles with a dosage of 1400 mg / day. In one embodiment, the dosage, frequency, and method of administration of diparerertinib or its salt and amivantamab or its salt are as follows: For example, diparerertinib or its salt is administered twice daily at a dose of 100 mg / day, and amivantamab or its salt is administered twice a week in the first week of the first cycle, once a week in the second and third weeks, and on the first day of each cycle from the second cycle onward; in one cycle of 21 days, the weekly dose for the first cycle is 1400 mg / week, with 1400 mg administered in two divided doses in the first week of the first cycle, once a week in the second and third weeks at a dose of 1400 mg / day, once a week in the second cycle at a dose of 1400 mg / day, and once a week from the third cycle onward at a dose of 1400 mg / day Dosage schedule of 1750 mg / day; one cycle is 21 days, and in the first cycle, the weekly dose is 1750 mg / week, with the number of doses being 1750 mg divided over two days in the first week of the first cycle, and once a week in the second and third weeks with a dose of 1750 mg / day, in the second cycle, once a week with a dose of 1750 mg / day, and from the third cycle onward, once a week with a dose of 2100 mg / day; dosage schedule of twice a week in the first week, once a week in weeks 2-4, with a drug-free period in weeks 5 and 6, and from week 7 onward, one cycle is 21 days and the drug is administered once every three weeks; the dose in weeks 1-4 is 1400 mg / week, with the number of doses being 1400 mg divided over two days in the first week, and once a week in weeks 2-4,The dosage is 1400 mg / day, with a rest period in weeks 5 and 6, and from week 7 onwards, it is administered once every 3 weeks in a 21-day cycle, with a dosage of 1750 mg / day; the dosage for weeks 1-4 is 1750 mg / week, with the number of doses being 1750 mg divided over 2 days in week 1, once a week in weeks 2-4 with a dosage of 1750 mg / day, with a rest period in weeks 5 and 6, and from week 7 onwards, it is administered once every 3 weeks in a 21-day cycle, with a dosage of 2100 mg / day; the dosage is twice a week in week 1, once a week in weeks 2-5, with a rest period in week 6, and from week 7 onwards, it is administered once every 2 weeks in a 14-day cycle; 1 The dosage for weeks 1-5 is 1050 mg / week, with the following administration schedule: 1050 mg administered in two divided doses over two days in week 1; once a week for weeks 2-5 at a dosage of 1050 mg / day; a rest period in week 6; and from week 7 onwards, administration every two weeks in a 14-day cycle at a dosage of 1050 mg / day; or the dosage for weeks 1-5 is 1400 mg / week, with the following administration schedule: 1400 mg administered in two divided doses over two days in week 1; once a week for weeks 2-5 at a dosage of 1400 mg / day; a rest period in week 6; and from week 7 onwards, administration every two weeks in a 14-day cycle at a dosage of 1400 mg / day.

[0149] In one embodiment, the dosage, frequency, and method of administration of diparerertinib or its salt and amivantamab or its salt may be, for example, diparerertinib or its salt administered twice daily, with a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and amivantamab or its salt administered twice a week in the first week of the first cycle, once a week in the second, third, and fourth weeks, and once every two weeks (every other week) from the second cycle onward. Schedule; One cycle is 28 days. In the first cycle, the weekly dose is 700 mg / week. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks, it is administered once a week at a dose of 700 mg / day. From the second cycle onward, it is administered once every two weeks at a dose of 700 mg / day. Administration schedule; One cycle is 28 days. In the first cycle, the weekly dose is 1050 mg / week. In terms of the number of administrations, one cycle The first week of the first cycle is administered with 1050 mg divided over two days, followed by one dose per week at a dose of 1050 mg / day in weeks 2, 3, and 4, and then one dose every two weeks at a dose of 1050 mg / day from the second cycle onward; one cycle is 28 days, and in the first cycle, the weekly dose is 1400 mg / week, with the number of doses being 1400 mg divided over two days in the first week of the first cycle, and one dose per week at a dose of 1400 mg in weeks 2, 3, and 4. The dosage is 1400 mg / day, administered once every two weeks from the second cycle onward; one cycle is 28 days, with the first cycle having a weekly dosage of 1750 mg / week, administered in two divided doses over two days during the first week of the first cycle, and once a week during weeks 2, 3, and 4 with a dosage of 1750 mg / day, administered once every two weeks from the second cycle onward with a dosage of 1750 mg / day.

[0150] In one embodiment, the dosage, frequency, and method of administration of diparerertinib or its salt and amivantamab or its salt may be, for example, once daily administration of diparerertinib or its salt, with a dosage of 65 mg / day or 50 mg / day of diparerertinib or its salt, with a cycle of 28 days, administered twice a week in the first week of the first cycle, once a week in the second, third, and fourth weeks, and once every two weeks (every other week) from the second cycle onward; 1 cycle The cycle is 28 days long. In the first cycle, the weekly dose is 700 mg / week. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks, it is administered once a week at a dose of 700 mg / day. From the second cycle onward, it is administered once every two weeks at a dose of 700 mg / day. The cycle is 28 days long. In the first cycle, the weekly dose is 1050 mg / week. In terms of the number of doses, in the first week of the first cycle, 10 The administration schedule is as follows: 50 mg is administered in two divided doses over two days, with the dose being 1050 mg / day once a week during weeks 2, 3, and 4, and then once every two weeks from the second cycle onward, with a dose of 1050 mg / day; one cycle is 28 days, and in the first cycle, the weekly dose is 1400 mg / week, with the number of doses being 1400 mg in two divided doses during the first week of the first cycle, and then once a week during weeks 2, 3, and 4, with a dose of 1400 mg / day. For the second and subsequent cycles, the dosage is once every two weeks at a dose of 1400 mg / day; one cycle is 28 days, and in the first cycle, the weekly dosage is 1750 mg / week, with the dosage being 1750 mg divided over two days in the first week of the first cycle, and once a week at a dose of 1750 mg / day in the second, third, and fourth weeks, and once every two weeks at a dose of 1750 mg / day from the second cycle onward.

[0151] Of the above administration schedules, a preferred schedule is one in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day or 130 mg / day, and amivantamab is administered twice a week in the first week of the first cycle, once a week from the second week onward, and every two weeks (every other week) from the second cycle onward. Furthermore, a more preferred administration schedule is one in which diparereltinib or its salt is administered twice daily at a dose of 200 mg / day, and amivantamab is administered twice a week in the first week of the first cycle, once a week from the second week onward, and every two weeks (every other week) from the second cycle onward.

[0152] In one embodiment, the dosage of diparerertinib or its salt and futivatinib or its salt is, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 8 mg to 24 mg, 12 mg to 24 mg, 12 mg to 20 mg, or 16 mg to 20 mg of futivatinib or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and futivatinib or its salt is, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 8 mg to 24 mg, 12 mg to 24 mg, 12 mg to 20 mg, or 16 mg to 20 mg of futivatinib or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and futivatinib or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 8 mg to 24 mg, 12 mg to 24 mg, 12 mg to 20 mg, or 16 mg to 20 mg of futivatinib or its salt per day. In one embodiment, the dosage, frequency of administration, and method of administration of diparerertinib or its salt and futivatinib or its salt may be, for example, a schedule in which diparerertinib or its salt is administered twice a day, with a dosage of 200 mg / day, a dosage of 130 mg / day, or a dosage of 100 mg / day and futivatinib or its salt is administered once a day, with a dosage of 20 mg / day; or a schedule in which it is administered once a day, with a dosage of 16 mg / day; or a schedule in which it is administered once a day, with a dosage of 12 mg / day. In one embodiment, examples of dosage, frequency of administration, and method of administration of diparerertinib or its salt and futivatinib or its salt include: a schedule of administering diparerertinib or its salt once daily at a dose of 65 mg / day or 50 mg / day and futivatinib or its salt once daily at a dose of 20 mg / day; or a schedule of administering it once daily at a dose of 16 mg / day; or a schedule of administering it once daily at a dose of 12 mg / day.

[0153] In one embodiment, the dosage of dipareretinib or its salt and pembrolizumab or its salt may be, for example, 50 mg to 300 mg of dipareretinib or its salt per day and 100 mg to 300 mg, 100 mg to 200 mg, 200 mg to 500 mg, 300 mg to 500 mg, or 300 mg to 400 mg of pembrolizumab or its salt per day. In one embodiment, the dosage of dipareretinib or its salt and pembrolizumab or its salt may be, for example, 50 mg to 200 mg of dipareretinib or its salt per day and 100 mg to 300 mg, 100 mg to 200 mg, 200 mg to 500 mg, 300 mg to 500 mg, or 300 mg to 400 mg of pembrolizumab or its salt per day. In one embodiment, the dosage of dipareretinib or its salt and pembrolizumab or its salt may be, for example, 100 mg to 200 mg of dipareretinib or its salt per day and 100 mg to 300 mg, 100 mg to 200 mg, 200 mg to 500 mg, 300 mg to 500 mg, or 300 mg to 400 mg of pembrolizumab or its salt per day. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and pembrolizumab or its salt include an administration schedule in which diparerertinib or its salt is administered twice daily at a dose of 200 mg / day and pembrolizumab or its salt is administered once every three weeks in a 21-day cycle at a dose of 200 mg / dose; and an administration schedule in which pembrolizumab or its salt is administered once every six weeks in a 42-day cycle at a dose of 400 mg / dose. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and pembrolizumab or its salt include an administration schedule in which diparerertinib or its salt is administered twice daily at a dose of 130 mg / day and pembrolizumab or its salt is administered once every three weeks in a 21-day cycle at a dose of 200 mg / dose; and an administration schedule in which pembrolizumab or its salt is administered once every six weeks in a 42-day cycle at a dose of 400 mg / dose.In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and pembrolizumab or its salt include an administration schedule in which diparerertinib or its salt is administered twice daily at a dose of 100 mg / day and pembrolizumab or its salt is administered once every three weeks in a 21-day cycle at a dose of 200 mg / dose; and an administration schedule in which pembrolizumab or its salt is administered once every six weeks in a 42-day cycle at a dose of 400 mg / dose. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and pembrolizumab or its salt include an administration schedule in which diparerertinib or its salt is administered once daily at a dose of 50 mg / day and pembrolizumab or its salt is administered once every three weeks in a cycle of 21 days at a dose of 200 mg / dose; and an administration schedule in which pembrolizumab or its salt is administered once every six weeks in a cycle of 42 days at a dose of 400 mg / dose. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and pembrolizumab or its salt include an administration schedule in which diparerertinib or its salt is administered once daily at a dose of 65 mg / day and pembrolizumab or its salt is administered once every three weeks in a 21-day cycle at a dose of 200 mg / dose; and an administration schedule in which pembrolizumab or its salt is administered once every six weeks in a 42-day cycle at a dose of 400 mg / dose.

[0154] In one embodiment, the dosage of dipareretinib or its salt and zimberelimab or its salt may be, for example, 50 mg to 300 mg of dipareretinib or its salt per day and 120 mg to 480 mg, 120 mg to 360 mg, 120 mg to 240 mg, 240 mg to 480 mg, 240 mg to 360 mg, 360 mg to 600 mg, or 360 mg to 480 mg of zimberelimab or its salt per day. In one embodiment, the dosage of dipareretinib or its salt and zimberelimab or its salt may be, for example, 50 mg to 200 mg of dipareretinib or its salt per day and 120 mg to 480 mg, 120 mg to 360 mg, 120 mg to 240 mg, 240 mg to 480 mg, 240 mg to 360 mg, 360 mg to 600 mg, or 360 mg to 480 mg of zimberelimab or its salt per day. In one embodiment, the dosage of dipareretinib or its salt and zimberelimab or its salt may be, for example, 100 mg to 200 mg of dipareretinib or its salt per day and 120 mg to 480 mg, 120 mg to 360 mg, 120 mg to 240 mg, 240 mg to 480 mg, 240 mg to 360 mg, 360 mg to 600 mg, or 360 mg to 480 mg of zimberelimab or its salt per day. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and zimbererimab or its salt include: diparerertinib or its salt administered twice daily at a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and zimbererimab or its salt administered once every two weeks in a 14-day cycle at a dose of 240 mg / dose; a 21-day cycle administered once every three weeks at a dose of 360 mg / dose; or a 28-day cycle administered once every four weeks at a dose of 480 mg / dose.In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and zimbererimab or its salt include: a schedule in which diparerertinib or its salt is administered once daily at a dose of 65 mg / day or 50 mg / day, and zimbererimab or its salt is administered once every two weeks in a 14-day cycle at a dose of 240 mg / dose; a schedule in which dimbererimab or its salt is administered once every three weeks in a 21-day cycle at a dose of 360 mg / dose; or a schedule in which dimbererimab is administered once every four weeks in a 28-day cycle at a dose of 480 mg / dose.

[0155] In one embodiment, the dosage of diparerertinib or its salt and sacituzumab govitecan or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), or 7.5 mg to 10 mg / kg (body weight) of sacituzumab govitecan or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and sacituzumab govitecan or its salt may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), or 7.5 mg to 10 mg / kg (body weight) of sacituzumab govitecan or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and sacituzumab govitecan or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 5 mg to 12.5 mg / kg (body weight), 5 mg to 10 mg / kg (body weight), or 7.5 mg to 10 mg / kg (body weight) of sacituzumab govitecan or its salt per day. In one embodiment, examples of dosage, frequency of administration, and method of administration of diparerertinib or its salt and sacituzumab govitecan or its salt include: diparerertinib or its salt administered twice daily, with a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and sacituzumab govitecan or its salt administered once a week for the first two weeks in a 21-day cycle, with a dose of 10 mg / kg (body weight) per dose and a rest period in the third week; a 21-day cycle administered once a week for the first two weeks, with a dose of 7.5 mg / kg (body weight) per dose and a rest period in the third week; or a 21-day cycle administered once a week for the first two weeks of each cycle, with a dose of 5 mg / kg (body weight) per dose and a rest period in the third week.In one embodiment, examples of dosage, frequency of administration, and method of administration of diparerertinib or its salt and sacituzumab govitecan or its salt include: a schedule in which diparerertinib or its salt is administered once daily, with a dose of 65 mg / day or 50 mg / day, and sacituzumab govitecan or its salt is administered once a week for the first two weeks in a 21-day cycle, with a dose of 10 mg / kg (body weight) per dose and a rest period in the third week; a schedule in which a 21-day cycle is administered once a week for the first two weeks, with a dose of 7.5 mg / kg (body weight) per dose and a rest period in the third week; or a schedule in which a 21-day cycle is administered once a week for the first two weeks of each cycle, with a dose of 5 mg / kg (body weight) per dose and a rest period in the third week.

[0156] In one embodiment, the dosage of diparerertinib or its salt and datopotamab deruxtecan or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 4 mg to 8 mg / kg (body weight) or 6 mg to 8 mg / kg (body weight) of datopotamab deruxtecan or its salt per day. In another embodiment, the dosage of diparerertinib or its salt and datopotamab deruxtecan or its salt may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 4 mg to 8 mg / kg (body weight) or 6 mg to 8 mg / kg (body weight) of datopotamab deruxtecan or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and datopotamab deruxtecan or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 4 mg to 8 mg / kg (body weight) or 6 mg to 8 mg / kg (body weight) of datopotamab deruxtecan or its salt per day. In one embodiment, examples of dosage, frequency of administration, and method of administration of diparerertinib or its salt and datopotamab deruxtecan or its salt include: a schedule in which diparerertinib or its salt is administered twice daily, with a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and datopotamab deruxtecan or its salt is administered once every three weeks in a 21-day cycle at a dose of 8 mg / kg (body weight) / dose; a schedule in which 6 mg / kg (body weight) is administered once every three weeks in a 21-day cycle; or a schedule in which 4 mg / kg (body weight) is administered once every three weeks in a 21-day cycle.In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and datopotamab deruxtecan or its salt include: a schedule in which diparerertinib or its salt is administered once daily, at a dose of 65 mg / day or 50 mg / day, and datopotamab deruxtecan or its salt is administered once every three weeks in a 21-day cycle at a dose of 8 mg / kg (body weight) / dose; a schedule in which datopotamab deruxtecan or its salt is administered once every three weeks in a 21-day cycle at a dose of 6 mg / kg (body weight) / dose; or a schedule in which 4 mg / kg (body weight) is administered once every three weeks in a 21-day cycle.

[0157] In one embodiment, the dosage of diparerertinib or its salt and trastuzumab deruxtecan or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 3.2 mg to 7.4 mg / kg (body weight), 4.4 mg to 7.4 mg / kg (body weight), 4.4 mg to 6.4 mg / kg (body weight), or 5.4 mg to 6.4 mg / kg (body weight) of trastuzumab deruxtecan or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and trastuzumab deruxtecan or its salt may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 3.2 mg to 7.4 mg / kg (body weight), 4.4 mg to 7.4 mg / kg (body weight), 4.4 mg to 6.4 mg / kg (body weight), or 5.4 mg to 6.4 mg / kg (body weight) of trastuzumab deruxtecan or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and trastuzumab deruxtecan or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 3.2 mg to 7.4 mg / kg (body weight), 4.4 mg to 7.4 mg / kg (body weight), 4.4 mg to 6.4 mg / kg (body weight), or 5.4 mg to 6.4 mg / kg (body weight) of trastuzumab deruxtecan or its salt per day. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and trastuzumab deruxtecan or its salt include: diparerertinib or its salt administered twice daily, with a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and trastuzumab deruxtecan or its salt administered once every three weeks in a 21-day cycle at a dose of 6.4 mg / kg (body weight) / dose; a schedule of administration of 5.4 mg / kg (body weight) / dose; a schedule of administration of 4.4 mg / kg (body weight) / dose once every three weeks in a 21-day cycle; or a schedule of administration of 3.2 mg / kg (body weight) / dose once every three weeks in a 21-day cycle.In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and trastuzumab deruxtecan or its salt include: diparerertinib or its salt administered once daily, with a dosage of 65 mg / day or 50 mg / day, and trastuzumab deruxtecan or its salt administered once every three weeks in a 21-day cycle at a dosage of 6.4 mg / kg (body weight) / dose; a schedule of administration of trastuzumab deruxtecan or its salt in a 21-day cycle at a dosage of 5.4 mg / kg (body weight) / dose; a schedule of administration of 4.4 mg / kg (body weight) / dose once every three weeks in a 21-day cycle; or a schedule of administration of 3.2 mg / kg (body weight) / dose once every three weeks in a 21-day cycle.

[0158] In one embodiment, the dosage of diparerertinib or its salt and patritumab deruxtecan or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 3.2 mg to 6.4 mg / kg (body weight), 3.2 mg to 5.6 mg / kg (body weight), or 4.8 mg to 5.6 mg / kg (body weight) of patritumab deruxtecan or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and patritumab deruxtecan or its salt may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 3.2 mg to 6.4 mg / kg (body weight), 3.2 mg to 5.6 mg / kg (body weight), or 4.8 mg to 5.6 mg / kg (body weight) of patritumab deruxtecan or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and patritumab deruxtecan or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 3.2 mg to 6.4 mg / kg (body weight), 3.2 mg to 5.6 mg / kg (body weight), or 4.8 mg to 5.6 mg / kg (body weight) of patritumab deruxtecan or its salt per day. In one embodiment, examples of the dosage, frequency of administration, and method of administration of diparerertinib or its salt and patritumab deruxtecan or its salt include a schedule in which diparerertinib or its salt is administered twice daily at a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and patritumab deruxtecan or its salt is administered once every three weeks in a 21-day cycle at a dose of 5.6 mg / kg (body weight) / dose; or a schedule in which patritumab deruxtecan or its salt is administered once every three weeks in a 21-day cycle at a dose of 4.8 mg / kg (body weight) / dose.In one embodiment, examples of the dosage, frequency, and method of administration of diparerertinib or its salt and patritumab deruxtecan or its salt include a schedule in which diparerertinib or its salt is administered once daily at a dose of 65 mg / day or 50 mg / day, and patritumab deruxtecan or its salt is administered once every three weeks in a 21-day cycle at a dose of 5.6 mg / kg (body weight) / dose; or a schedule in which patritumab deruxtecan or its salt is administered once every three weeks in a 21-day cycle at a dose of 4.8 mg / kg (body weight) / dose.

[0159] In one embodiment, the dosage of diparerertinib or its salt and enfortumab vedotin or its salt may be, for example, 50 mg to 300 mg of diparerertinib or its salt per day and 0.5 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.25 mg / kg (body weight), or 1.0 mg to 1.25 mg / kg (body weight) of enfortumab vedotin or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and enfortumab vedotin or its salt may be, for example, 50 mg to 200 mg of diparerertinib or its salt per day and 0.5 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.25 mg / kg (body weight), or 1.0 mg to 1.25 mg / kg (body weight) of enfortumab vedotin or its salt per day. In one embodiment, the dosage of diparerertinib or its salt and enfortumab vedotin or its salt may be, for example, 100 mg to 200 mg of diparerertinib or its salt per day and 0.5 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.5 mg / kg (body weight), 0.75 mg to 1.25 mg / kg (body weight), or 1.0 mg to 1.25 mg / kg (body weight) of enfortumab vedotin or its salt per day. In one embodiment, the dosage, frequency of administration, and method of administration of diparerertinib or its salt and enfortumab vedotin or its salt include, for example, a schedule in which diparerertinib or its salt is administered twice daily, with a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and enfortumab vedotin or its salt is administered once a week for the first three weeks in a 28-day cycle, with a dose of 1.25 mg / kg (body weight) / dose, followed by a rest period in the fourth week; a schedule in which a 28-day cycle is administered once a week for the first three weeks, with a dose of 1.0 mg / kg (body weight) / dose, followed by a rest period in the fourth week; or a schedule in which a 21-day cycle is administered once a week for the first two weeks, with a dose of 1.25 mg / kg (body weight) / dose, followed by a rest period in the third week.In one embodiment, the dosage, frequency of administration, and method of administration of diparerertinib or its salt and enfortumab vedotin or its salt include, for example, a schedule in which diparerertinib or its salt is administered once daily, with a dose of 65 mg / day or 50 mg / day, and enfortumab vedotin or its salt is administered once a week for the first three weeks in a 28-day cycle, with a dose of 1.25 mg / kg (body weight) / dose, followed by a rest period in the fourth week; a schedule in which diparerertinib or its salt is administered once a week for the first three weeks in a 28-day cycle, with a dose of 1.0 mg / kg (body weight) / dose, followed by a rest period in the fourth week; or a schedule in which diparerertinib or its salt is administered once a week for the first two weeks in a 21-day cycle, with a dose of 1.25 mg / kg (body weight) / dose, followed by a rest period in the third week.

[0160] In this invention, the daily dose of diparereltinib or its salts and other antitumor agents is, unless otherwise specified, the free-form equivalent dose, and may be the dose that provides the maximum therapeutic effect while being safe to use without causing serious side effects, as determined by clinical trials, etc. Specifically, this includes doses approved, recommended, and suggested by public institutions and organizations such as the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, the Food and Drug Administration (FDA) of the United States, and the European Medicines Agency (EMA), and which are described in package inserts, interview forms, treatment guidelines, etc., and doses approved by any of the public institutions of PMDA, FDA, or EMA are preferred.

[0161] In the present invention, either (i) or (ii) below is preferred: (i) the antitumor agent comprising diparerintinib or a salt thereof as an active ingredient, used in combination with gumarontinib for patients with lung cancer; (ii) the antitumor agent comprising gumarontinib as an active ingredient, used in combination with diparerintinib or a salt thereof for patients with lung cancer.

[0162] In these embodiments, among the lung cancer patients, non-small cell lung cancer patients are preferred. In another embodiment, among the lung cancer patients, those with MET gene abnormalities are preferred, and in yet another embodiment, among the lung cancer patients, those with MET amplification and / or MET overexpression are even more preferred.

[0163] In one embodiment, an antitumor agent is preferred in which diparereltinib or a salt thereof, either of the antitumor agents described in (i) or (ii), is administered twice daily at a dose of 200 mg / day, 130 mg / day, or 100 mg / day, and gumarontinib, either 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day, is administered once daily. In another embodiment, an antitumor agent is preferred in which diparereltinib or a salt thereof, either of the antitumor agents described in (i) or (ii), is administered once daily at a dose of 65 mg / day or 50 mg / day, and gumarontinib, either 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day, is administered once daily.

[0164] In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 200 mg / day of diparerertinib or a salt thereof twice daily and 300 mg / day of gumarontinib once daily. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 200 mg / day of diparerertinib or a salt thereof twice daily and 250 mg / day of gumarontinib once daily. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 130 mg / day of diparerertinib or a salt thereof twice daily and 300 mg / day of gumarontinib once daily. In one embodiment, an antitumor agent of either (i) or (ii) described above is more preferably an antitumor agent characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily and 250 mg / day of gumarontinib once daily.

[0165] In another embodiment, either (i) or (ii) below is preferred: (i) the antitumor agent comprising diparerertinib or a salt thereof as an active ingredient, used in combination with amivantamab for patients with lung cancer; (ii) the antitumor agent comprising amivantamab as an active ingredient, used in combination with diparerertinib or a salt thereof for patients with lung cancer. In these embodiments, among the lung cancer patients, non-small cell lung cancer patients are preferred.

[0166] In another embodiment, diparereltinib or a salt thereof, which is an antitumor agent according to either (i) or (ii) above, is administered twice daily at a dose of 200 mg / day, 130 mg / day, or 100 mg / day, for a cycle of 28 days, and the patient weighs less than 80 kg. In the first cycle, the weekly dose is 700 mg / week, with the first week of the first cycle being administered in two divided doses (140 mg / day on day 1 and 560 mg / day on day 2), and the second, third, and fourth weeks being administered once a week at a dose of 700 mg / day. An antitumor agent characterized by administering amibantamab once every two weeks from the second cycle onward, at a dose of 700 mg / day, or, more preferably, an antitumor agent characterized by, in the case of a patient weighing 80 kg or more, administering 1050 mg in two divided doses over two days in the first week of the first cycle (350 mg / day on the first day and 700 mg / day on the second day), administering once a week at a dose of 1050 mg / day in the second, third, and fourth weeks, and administering amibantamab once every two weeks from the second cycle onward, at a dose of 1050 mg / day.

[0167] In another embodiment, diparerertinib or a salt thereof, which is an antitumor agent according to either (i) or (ii) above, is administered twice daily at a dose of 200 mg / day, 130 mg / day, or 100 mg / day, for a cycle of 28 days, and the patient weighs less than 80 kg. In the first cycle, the weekly dose is 1050 mg / week, with the first week of the first cycle being administered in two divided doses (350 mg / day on day 1 and 700 mg / day on day 2), and the second, third, and fourth weeks being administered once a week at a dose of 1050 mg / day. Furthermore, an antitumor agent characterized by administering amibantamab once every two weeks from the second cycle onward, at a dose of 1050 mg / day, or, more preferably, an antitumor agent characterized by, in the case of a patient weighing 80 kg or more, administering 1400 mg in two divided doses over two days in the first week of the first cycle (350 mg / day on the first day and 1050 mg / day on the second day), administering once a week at a dose of 1400 mg / day in the second, third, and fourth weeks, and administering amibantamab once every two weeks from the second cycle onward, at a dose of 1400 mg / day.

[0168] In another embodiment, diparereltinib or a salt thereof, which is either the antitumor agent of (i) or (ii) described above, is administered once daily at a dose of 65 mg / day or 50 mg / day, for a cycle of 28 days, and the patient weighs less than 80 kg. In the first cycle, the weekly dose is 700 mg / week, with the first week of the first cycle being administered in two divided doses (140 mg / day on day 1 and 560 mg / day on day 2). In the second, third, and fourth weeks, the dose is administered once a week at a dose of 700 mg / day, and so on. An antitumor agent characterized by administering amibantamab once every two weeks from the second cycle onward, at a dose of 700 mg / day, or, more preferably, an antitumor agent characterized by, in the case of a patient weighing 80 kg or more, administering 1050 mg in two divided doses over two days in the first week of the first cycle (350 mg / day on the first day and 700 mg / day on the second day), administering once a week at a dose of 1050 mg / day in the second, third, and fourth weeks, and administering amibantamab once every two weeks from the second cycle onward, at a dose of 1050 mg / day.

[0169] In another embodiment, if the patient weighs less than 80 kg, and the antitumor agent is either (i) or (ii) above, diparereltinib or a salt thereof is administered once daily at a dose of 65 mg / day or 50 mg / day, for a cycle of 28 days, the weekly dose for the first cycle is 1050 mg / week, with the first week of the first cycle being administered in two divided doses (350 mg / day on day 1 and 700 mg / day on day 2), and the second, third, and fourth weeks being administered once a week at a dose of 1050 mg / day, and so on for the second cycle. An antitumor agent characterized by administering amibantamab once every two weeks from the second cycle onward, at a dose of 1050 mg / day, or, more preferably, an antitumor agent characterized by, in the case of a patient weighing 80 kg or more, administering 1400 mg in two divided doses over two days in the first week of the first cycle (350 mg / day on the first day and 1050 mg / day on the second day), administering once a week at a dose of 1400 mg / day in the second, third, and fourth weeks, and administering amibantamab once every two weeks from the second cycle onward, at a dose of 1400 mg / day.

[0170] In one embodiment, an antitumor agent of either (i) or (ii) described above is preferred, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days in a cycle, with 140 mg / day on day 1, 560 mg / day on day 2, and 700 mg / day on days 8, 15, and 22 of cycle 1 if the patient weighs less than 80 kg, and 700 mg / day of amibantamab on days 1 and 15 of cycle 2 and beyond. Alternatively, an antitumor agent is preferred, characterized by administering 350 mg / day on day 1, 700 mg / day on day 2, 1050 mg / day on days 8, 15, and 22 of cycle 1 if the patient weighs 80 kg or more, and 1050 mg / day of amibantamab on days 1 and 15 of cycle 2 and beyond.

[0171] In one embodiment, an antitumor agent of either (i) or (ii) described above is preferred, characterized in that 130 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days in a cycle, and if the patient weighs less than 80 kg, 140 mg / day is administered on day 1 of cycle 1, 560 mg / day on day 2, and 700 mg / day on days 8, 15, and 22, and 700 mg / day of amibantamab is administered on days 1 and 15 from cycle 2 onward. Alternatively, an antitumor agent is more preferably characterized in that if the patient weighs 80 kg or more, 350 mg / day is administered on day 1 of cycle 1, 700 mg / day on day 2, 1050 mg / day on days 8, 15, and 22, and 1050 mg / day of amibantamab is administered on days 1 and 15 from cycle 2 onward.

[0172] In one embodiment, an antitumor agent of either (i) or (ii) described above is preferred, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days per cycle, with 350 mg / day on day 1, 700 mg / day on day 2, and 1050 mg / day on days 8, 15, and 22 of cycle 1 if the patient weighs less than 80 kg, and 1050 mg / day of amibantamab on days 1 and 15 of cycle 2 and beyond. Alternatively, an antitumor agent is preferred, characterized by administering 350 mg / day on day 1, 1050 mg / day on day 2, 1400 mg / day on days 8, 15, and 22 of cycle 1 if the patient weighs 80 kg or more, and 1400 mg / day of amibantamab on days 1 and 15 of cycle 2 and beyond.

[0173] In one embodiment, an antitumor agent of either (i) or (ii) described above is preferred, characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily for 28 days in a cycle, with 350 mg / day on day 1, 700 mg / day on day 2, and 1050 mg / day on days 8, 15, and 22 of cycle 1 if the patient weighs less than 80 kg, and 1050 mg / day of amibantamab on days 1 and 15 of cycle 2 and beyond. Alternatively, an antitumor agent is preferred, characterized by administering 350 mg / day on day 1, 1050 mg / day on day 2, 1400 mg / day on days 8, 15, and 22 of cycle 1 if the patient weighs 80 kg or more, and 1400 mg / day of amibantamab on days 1 and 15 of cycle 2 and beyond.

[0174] In another embodiment, either (i) or (ii) below is preferred: (i) the antitumor agent comprising diparerertinib or a salt thereof as an active ingredient, used in combination with pimitespive for patients with lung cancer; (ii) the antitumor agent comprising pimitespive as an active ingredient, used in combination with diparerertinib or a salt thereof for patients with lung cancer. In these embodiments, among the lung cancer patients, non-small cell lung cancer patients are preferred.

[0175] In another embodiment, an antitumor agent according to either (i) or (ii) above, characterized by administering 200 mg / day, 130 mg / day, or 100 mg / day of diparereltinib or a salt thereof twice daily, and 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day, or 40 mg / day of pimitespive once daily, administered daily for 5 days, followed by a 2-day rest period. In another embodiment, an antitumor agent according to either (i) or (ii) above is preferred, characterized by administering 65 mg / day or 50 mg / day of diparereltinib or a salt thereof once daily, and 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day, or 40 mg / day of pimitespive once daily, administered daily for 5 days, followed by a 2-day rest period. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferable, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferable, characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferable, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 120 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 120 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferably one characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

[0176] In another embodiment, either (i) or (ii) below is preferred: (i) the antitumor agent comprising diparereltinib or a salt thereof as an active ingredient, used in combination with quemrecrustat for patients with lung cancer; or (ii) the antitumor agent comprising quemrecrustat as an active ingredient, used in combination with diparereltinib or a salt thereof for patients with lung cancer. In these embodiments, among the lung cancer patients, non-small cell lung cancer patients are preferred.

[0177] In another embodiment, an antitumor agent according to either (i) or (ii) above is preferred, characterized by administering 200 mg / day, 130 mg / day, or 100 mg / day of diparereltinib or a salt thereof twice daily, and 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose, or 25 mg / dose of quemrecrustat once every two weeks. In another embodiment, an antitumor agent according to either (i) or (ii) above is preferred, characterized by administering 65 mg / day or 50 mg / day of diparereltinib or a salt thereof once daily, and 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose, or 25 mg / dose of quemrecrustat once every two weeks. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily and 100 mg / dose of quemrecrustat once every two weeks. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily and 100 mg / dose of quemrecrustat once every two weeks.

[0178] In another embodiment, an antitumor agent according to either (i) or (ii) above is preferred, characterized by administering 200 mg / day, 130 mg / day, or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose, or 100 mg / dose of quemrecrustat once every three weeks. In another embodiment, an antitumor agent according to either (i) or (ii) above is preferred, characterized by administering 50 mg / day of diparereltinib or a salt thereof once daily, and 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose, or 100 mg / dose of quemrecrustat once every three weeks.

[0179] In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily and 300 mg / dose of quemrecrustat once every three weeks. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily and 300 mg / dose of quemrecrustat once every three weeks. In one embodiment, an antitumor agent according to either (i) or (ii) above is more preferred, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily and 200 mg / dose of quemrecrustat once every three weeks. In one embodiment, an antitumor agent of either (i) or (ii) described above is more preferably an antitumor agent characterized by administering 130 mg / day of diparereltinib or a salt thereof twice daily and 200 mg / dose of quemrecrustat once every three weeks.

[0180] In one embodiment of the present invention, when dipareretinib or a salt thereof is used in combination with gumarontinib, amivantamab, pimitespiv, or quemrecrustat, it is preferable to target patients with non-small cell lung cancer having an EGFR mutation. In a further embodiment of the present invention, it is preferable to target patients with osimertinib-resistant non-small cell lung cancer. In a further embodiment of the present invention, it is preferable to target patients with non-small cell lung cancer having an EGFR mutation and being osimertinib-resistant. In another further embodiment, it is preferable to target patients with osimertinib-resistant non-small cell lung cancer having at least one selected from the group consisting of an EGFR exon 19 deletion mutation, an exon 20 insertion mutation, and an exon 21 point mutation. In yet another embodiment, it is preferable to target patients with osimertinib-resistant non-small cell lung cancer having one or both of the EGFR exon 19 deletion mutation and / or exon 21 point mutation. Furthermore, in a further embodiment, it is preferable to target non-small cell lung cancer patients who have one or both of the EGFR exon 19 deletion mutation and / or the L858R mutation and are osimertinib resistant. In a further embodiment, it is preferable to target non-small cell lung cancer patients who have a history of osimertinib treatment. Furthermore, in a further embodiment, it is preferable to target non-small cell lung cancer patients who have at least one selected from the group consisting of the EGFR exon 19 deletion mutation, the exon 20 insertion mutation and / or the exon 21 point mutation and are osimertinib resistant. Furthermore, in a further embodiment, it is preferable to target non-small cell lung cancer patients who have one or both of the EGFR exon 19 deletion mutation and / or the L858R mutation and are osimertinib resistant.

[0181] One embodiment of the present invention provides an antitumor agent comprising dipareretinib or a salt thereof for the treatment of tumors, for use in combination with other antitumor agents. One embodiment of the present invention provides the use of a combination (combination drug, combination method, combination product, or therapeutic combination) of dipareretinib or a salt thereof and other antitumor agents for the treatment of tumors. One embodiment of the present invention provides an antitumor agent comprising dipareretinib or a salt thereof for tumor patients who have been administered other antitumor agents or tumor patients who will be administered (or are scheduled to be administered) other antitumor agents. One embodiment of the present invention provides an antitumor agent comprising other antitumor agents for the treatment of tumors, for use in combination with dipareretinib or a salt thereof. One embodiment of the present invention provides an antitumor agent comprising other antitumor agents for tumor patients who have been administered dipareretinib or a salt thereof or tumor patients who will be administered (or are scheduled to be administered) dipareretinib or a salt thereof. In one embodiment of the present invention, dipareretinib or a salt thereof is administered orally. One embodiment of the present invention provides the use of diparerertinib or a salt thereof for the manufacture of a pharmaceutical product used in combination with other antitumor agents in the treatment of tumors. Another embodiment of the present invention provides the use of other antitumor agents for the manufacture of a pharmaceutical product used in combination with diparerertinib or a salt thereof in the treatment of tumors. Another embodiment of the present invention provides the use of a combination of diparerertinib or a salt thereof and other antitumor agents for the manufacture of a pharmaceutical product used in the treatment of tumors. Another embodiment of the present invention provides an antitumor effect enhancer containing diparerertinib or a salt thereof for enhancing the antitumor effect of other antitumor agents. Another embodiment of the present invention provides an antitumor effect enhancer containing other antitumor agents for enhancing the antitumor effect of diparerertinib or a salt thereof. Another embodiment of the present invention provides diparerertinib or a salt thereof for use in the treatment of tumors in combination with other antitumor agents. Another embodiment of the present invention provides the use of diparerertinib or a salt thereof for use in the treatment of tumors in combination with other antitumor agents. Another embodiment of the present invention provides other antitumor agents for use in the treatment of tumors in combination with diparerertinib or a salt thereof.Furthermore, one embodiment of the present invention provides the use of other antitumor agents for use in combination with diparerertinib or a salt thereof for the treatment of tumors. One embodiment of the present invention provides diparerertinib or a salt thereof for treating tumor patients who have been administered other antitumor agents or tumor patients who will be administered (or are scheduled to be administered) other antitumor agents. Another embodiment of the present invention provides the use of diparerertinib or a salt thereof for treating tumor patients who have been administered other antitumor agents or tumor patients who will be administered (or are scheduled to be administered) other antitumor agents. One embodiment of the present invention provides other antitumor agents for treating tumor patients who have been administered diparerertinib or a salt thereof or tumor patients who will be administered (or are scheduled to be administered) diparerertinib or a salt thereof. Another embodiment of the present invention provides the use of other antitumor agents for treating tumor patients who have been administered diparerertinib or a salt thereof or tumor patients who will be administered (or are scheduled to be administered) diparerertinib or a salt thereof. Furthermore, in one embodiment of the present invention, an antitumor agent is provided comprising dipareretinib or a salt thereof and another antitumor agent as active ingredients. In one embodiment of the present invention, a combination (combination drug, combination method, combination product, or therapeutic combination) of dipareretinib or a salt thereof and another antitumor agent is provided, wherein the dipareretinib or a salt thereof and the other antitumor agent are administered simultaneously or separately (for example, sequentially or at intervals) in the treatment of a tumor. Furthermore, in one embodiment of the present invention, dipareretinib or a salt thereof is provided for enhancing the antitumor effect of another antitumor agent. In one embodiment of the present invention, the use of dipareretinib or a salt thereof is provided for enhancing the antitumor effect of another antitumor agent. Furthermore, in one embodiment of the present invention, another antitumor agent is provided for enhancing the antitumor effect of dipareretinib or a salt thereof. In one embodiment of the present invention, the use of another antitumor agent is provided for enhancing the antitumor effect of dipareretinib or a salt thereof. One embodiment of the present invention provides a method for treating a tumor, comprising the step of administering a therapeutically effective amount to a patient a combination of diparereltinib or a salt thereof and other antitumor agents.One embodiment of the present invention provides a method for treating a tumor, comprising the step of administering an effective amount of diparerertinib or a salt thereof and other antitumor agents to a patient who requires such an amount. Another embodiment of the present invention provides a method for treating a tumor, comprising administering an effective amount of a combination (combination drug, or combination product) of diparerertinib or a salt thereof and other antitumor agents to a patient who requires such a method. Another embodiment of the present invention provides a method for treating a tumor, comprising the step of administering a therapeutically effective amount of diparerertinib or a salt thereof to a tumor patient who has received other antitumor agents or who will receive (or is scheduled to receive) other antitumor agents. Another embodiment of the present invention provides a method for treating a tumor in combination with other antitumor agents, comprising administering an effective amount of diparerertinib or a salt thereof to a patient who requires such a method. Another embodiment of the present invention provides a pharmaceutical composition for the treatment of a tumor comprising diparerertinib or a salt thereof and other antitumor agents. One embodiment of the present invention provides a method for treating a tumor, comprising the step of administering a therapeutically effective amount of another antitumor agent to a tumor patient who has been administered dipareretinib or a salt thereof, or a tumor patient who will be administered (or is scheduled to be administered) dipareretinib or a salt thereof. Another embodiment of the present invention provides a method for enhancing the antitumor effect of dipareretinib or a salt thereof, comprising the step of administering a therapeutically effective amount of another antitumor agent to a tumor patient who has been administered dipareretinib or a salt thereof, or a tumor patient who will be administered (or is scheduled to be administered) dipareretinib or a salt thereof. Another embodiment of the present invention provides a method for enhancing the antitumor effect of another antitumor agent, comprising the step of administering a therapeutically effective amount of dipareretinib or a salt thereof to a tumor patient who has been administered another antitumor agent, or a tumor patient who will be administered (or is scheduled to be administered) dipareretinib or a salt thereof. The type, amount, and method of use of diparereltinib or its salts in these embodiments; the type, amount, and method of use of other antitumor agents (e.g., at least one selected from the group consisting of molecularly targeted drugs, immune checkpoint inhibitors, and antibody-drug conjugates); and other details such as other components are the same as described above (for example, the same as the section describing the requirements without specifying an embodiment, or the same as the conditions described and illustrated in the embodiments of antitumor agents).

[0182] Example 1. Evaluation of the combined effect of TAS6417 and bevacizumab in a II-18 xenograft model containing EGFR L858R.

[0183] Methods: Human non-small cell lung cancer cells II-18 (Institute of Development, Aging and Cancer, Tohoku University) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cultured II-18 cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 × 10⁶ cells. ６ The solution was prepared to a concentration of 0.1 mL of cells and then transplanted.

[0184] A digital caliper was used to measure the tumor diameter, and the long and short diameters of the tumor were measured. The TV (mm²) was then calculated using the following formula: TV (mm²) ３ ) = major diameter (mm) × minor diameter (mm) × minor diameter (mm) / 2 The average tumor volume (TV) after transplantation is approximately 200 mm ３ After allowing the tumors to grow to a certain size, six animals were assigned to each group using a stratified randomization method with TV as the indicator. The day on which the group assignment (n=6) was performed was designated as Day 0. The relative tumor volume change rate (T / C) was calculated from TV using the following formula: T / C (%) = (average TV of each drug administration group) / (average TV of the control group) × 100. An animal electronic balance was used to measure body weight. The percentage change in body weight on day n (BWCn) was calculated from the body weight on day n (BWn) using the following formula: Percentage change in body weight BWCn (%) = (BWn - BW1) / BW1 × 100. TAS6417 was administered orally once daily at a dose of 50 mg / kg or 200 mg / kg. Bevacizumab was administered intraperitoneally twice a week at a dose of 5 mg / kg or 20 mg / kg.

[0185] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Bevacizumab was diluted with physiological saline to prepare the administration solution.

[0186] The combined efficacy of TAS6417 and bevacizumab compared to TAS6417 monotherapy was investigated. In this xenograft model, the combined efficacy of TAS6417 and bevacizumab was observed (Table 1 and Figure 1A).

[0187]

[0188] The combination therapy of TAS6417 and bevacizumab significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups (Figure 1B). In the combination therapy group administered TAS6417 at 200 mg / kg, there appeared to be no apparent additive effect compared to TAS6417 monotherapy, but this is because TAS6417 monotherapy was already at a dose that produced a sufficient antitumor effect, and this does not negate the efficacy of the combination therapy of TAS6417 and bevacizumab.

[0189] Example 2. Evaluation of the combined efficacy of TAS6417 and bevacizumab in a xenograft model of NCI-H1975 EGFR D770_N771insSVD (H1975-EGFRinsSVD) with an EGFR exon 20 insertion mutation.

[0190] Methods: Human non-small cell lung cancer cells H1975-EGFRinsSVD (a human lung adenocarcinoma cell line established in-house, derived from NCI-H1975 cells obtained from the American Type Culture Collection and genetically modified to express the D770_N771insSVD mutant EGFR) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS) and 2 μg / mL puromycin. The cultured H1975-EGFRinsSVD cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 × 10⁶ layers. ６ The solution was prepared to a concentration of 0.1 mL of cells and then transplanted. The average tumor volume (TV) after transplantation was approximately 200 mm³. ３ After allowing the tumors to grow to a certain size, six animals were assigned to each group using a stratified randomization method with TV as the indicator. Tumor diameter and body weight measurements were performed in the same manner as in Example 1.

[0191] TAS6417 was administered orally once daily at a dose of 100 mg / kg or 200 mg / kg. Bevacizumab was administered intraperitoneally twice weekly at a dose of 20 mg / kg.

[0192] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Bevacizumab was diluted with physiological saline to prepare the administration solution.

[0193] The combined effect of TAS6417 and bevacizumab was investigated compared to TAS6417 monotherapy. In this xenograft model, a combined effect was observed (Table 2 and Figure 2A). The combination of TAS6417 and bevacizumab significantly suppressed tumor growth compared to TAS6417 monotherapy.

[0194]

[0195] To evaluate the efficacy of combination therapy with bevacizumab, the number of days until tumor volume increased to more than five times its initial size was analyzed using Kaplan-Meier curves (Table 3 and Figure 2B).

[0196]

[0197] Combination therapy with bevacizumab significantly extended the time to a fivefold increase in tumor volume (Log-Rank, p < 0.05). The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups (Figure 2C). In the combination therapy group administered TAS6417 at 200 mg / kg, there appeared to be no apparent additive effect compared to TAS6417 monotherapy, but this is because TAS6417 monotherapy was already at a dose that produced a sufficient antitumor effect, and this does not negate the efficacy of the combination therapy of TAS6417 and bevacizumab.

[0198] Example 3. Evaluation of the combined effect of TAS6417 and DC101 (mouse anti-VEGFR antibody) in an H1975-EGFRinsSVD xenograft model with EGFR exon 20 insertion mutations.

[0199] Methods: Human non-small cell lung cancer cells H1975-EGFRinsSVD (a human lung adenocarcinoma cell line established in-house, derived from NCI-H1975 cells obtained from the American Type Culture Collection and genetically modified to express the D770_N771insSVD mutant EGFR) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS) and 2 μg / mL puromycin. The cultured H1975-EGFRinsSVD cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 × 10⁶ cells. ６ The solution was prepared to a concentration of 0.1 mL of cells and then transplanted.

[0200] TAS6417 was administered orally once daily at a dose of 100 mg / kg or 200 mg / kg. DC101 was administered intraperitoneally twice a week at a dose of 20 mg / kg.

[0201] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. DC101 was diluted with physiological saline to prepare the administration solution.

[0202] To evaluate the combined effect with DC101, the number of days until tumor volume exceeded five times the initial volume was analyzed using Kaplan-Meier curves. The results are shown in Table 3 and Figure 2B. Combined use with DC101 significantly extended the time until tumor volume increased fivefold (Log-Rank, p < 0.05). The mean weight change rate in the combination therapy group did not show a significant increase or decrease compared to each monotherapy group (Figure 3).

[0203] Example 4. Evaluation of the combined effect of TAS6417 and capmatinib in an HCC827OR8 xenograft model with EGFR exon 19 deletion and MET amplification.

[0204] Methods: Human non-small cell lung cancer cells HCC827OR8 (a human lung adenocarcinoma cell line established using HCC827 cells obtained from the American Type Culture Collection) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS) and 100 nmol / L osimertinib. The cultured HCC827OR8 cells were placed in 10 × 10⁶ cells on the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male). ６ The solution was prepared to a concentration of 0.1 mL per cell and then transplanted. The average tumor volume (TV) after transplantation was approximately 200 mm³. ３ After allowing the tumors to grow to a certain size, six animals were assigned to each group using a stratified randomization method with TV as the indicator. Tumor diameter and body weight measurements were performed in the same manner as in Example 1.

[0205] TAS6417 was administered orally once daily at a dose of 25 mg / kg or 100 mg / kg. Capmatinib was administered orally once daily at a dose of 30 mg / kg.

[0206] Solvent and compound: TAS6417 was mixed with 0.1 mol / L hydrochloric acid to prepare the administration solution. Capmatinib was mixed with 0.25% w / v methylcellulose / 0.05% v / v Tween 80 solution to prepare the administration solution.

[0207] The combined efficacy of TAS6417 and capmatinib compared to TAS6417 monotherapy was investigated. HCC827OR8 cells were transplanted into the flanks of mice. In this xenograft model, the combined efficacy of TAS6417 and capmatinib was observed (Table 4 and Figure 4A).

[0208]

[0209] The combination therapy of TAS6417 and capmatinib significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups (Figure 4B).

[0210] Example 5. Evaluation of the combined effect of TAS6417 and amivantamab in the HCC827OR8 xenograft model with EGFR exon 19 deletion and MET amplification

[0211] Method: Human non-small cell lung cancer cell HCC827OR8 was cultured in RPMI 1640 medium (FUJIFILM Wako Pure Chemical Corporation) containing 10% fetal bovine serum (FBS) and 100 nmol / L osimertinib. The cultured HCC827OR8 cells were prepared to be 10×10 ６ cells / 0.1 mL and transplanted into the flanks of 6-week-old BALB / cAJcl-nu mice (Jackson Laboratory Japan KK) (male). After the tumors were grown until the average tumor volume (TV) reached about 200 mm ３ , animals were allocated into each group of 6 by a stratified random allocation method using TV as an index. Tumor diameter measurement and body weight measurement were the same as in Example 1.

[0212] TAS6417 was orally administered once a day for consecutive days at 25 mg / kg or 100 mg / kg. Amivantamab was intraperitoneally administered twice a week at 10 mg / kg.

[0213] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare a dosing solution. Amivantamab was diluted with physiological saline to prepare a dosing solution.

[0214] The combined effect of TAS6417 and amivantamab was examined when compared with TAS6417 alone. HCC827OR8 cells were transplanted into the flanks of mice. The results are shown in Table 4 and Figure 5A above. In this xenograft model, the combined effect of TAS6417 and amivantamab was observed. The combination of TAS6417 and amivantamab significantly inhibited tumor growth compared with TAS6417 alone. The average body weight change rate in the combined dosing group did not show significant increase or decrease compared with each single-agent group (Figure 5).

[0215] Example 6. Evaluation of the combined effect of TAS6417 and amivantamab in the H1975-EGFRinsSVD xenograft model with EGFR exon 20 insertion mutation

[0216] Methods: Human non-small cell lung cancer cells H1975-EGFRinsSVD were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS) and 2 μg / mL puromycin. 8 × 10⁶ H1975-EGFRinsSVD cells were placed in the flank of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan, Inc.) (male). ６ The solution was prepared to a concentration of 0.1 mL of cells and then transplanted. The average tumor volume (TV) after transplantation was approximately 200 mm³. ３ After allowing the tumors to grow to a certain size, six animals were assigned to each group using a stratified randomization method with TV as the indicator. Tumor diameter and body weight measurements were performed in the same manner as in Example 1.

[0217] TAS6417 was administered orally once daily at a dose of 100 mg / kg or 200 mg / kg. Amivantamab was administered intraperitoneally twice weekly at a dose of 10 mg / kg or 30 mg / kg.

[0218] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Amivantamab was diluted with physiological saline to prepare the administration solution.

[0219] The combined efficacy of TAS6417 and amivantamab compared to TAS6417 monotherapy was investigated. H1975insSVD cells were transplanted into the flanks of mice. In this xenograft model, the combined efficacy of TAS6417 and amivantamab was observed (Table 5, Figures 6A and 6B).

[0220]

[0221] The combination therapy of TAS6417 and amivantamab significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups (Figure 6C). In the combination therapy group administered TAS6417 at 200 mg / kg, there appeared to be no apparent additive effect compared to TAS6417 monotherapy, but this is because TAS6417 monotherapy was already at a dose that produced a sufficient antitumor effect, and this does not negate the efficacy of the combination therapy of TAS6417 and amivantamab.

[0222] Example 7. Evaluation of the combined effect of TAS6417 and amivantamab in a II-18 xenograft model with EGFR L858R.

[0223] Methods: Human non-small cell lung cancer cells II-18 (Institute of Development, Aging and Cancer, Tohoku University) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cultured II-18 cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 x 10⁶ layers. ６ The solution was prepared to a concentration of 0.1 mL per cell and then transplanted. The average tumor volume (TV) after transplantation was approximately 200 mm³. ３ After allowing the tumors to grow to a certain size, six animals were assigned to each group using a stratified randomization method with TV as the indicator. Tumor diameter and body weight measurements were performed in the same manner as in Example 1.

[0224] TAS6417 was administered orally once daily at a dose of 50 mg / kg or 100 mg / kg. Amivantamab was administered intraperitoneally twice weekly at a dose of 10 mg / kg.

[0225] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Amivantamab was diluted with physiological saline to prepare the administration solution.

[0226] The combined efficacy of TAS6417 and amibantamab compared to TAS6417 monotherapy was investigated. II-18 cells were transplanted into the flanks of mice. In this xenograft model, the combined efficacy of TAS6417 and amibantamab was observed (Table 6 and Figure 7A).

[0227]

[0228] The combination therapy of TAS6417 and amivantamab significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups (Figure 7B).

[0229] Example 8. Evaluation of the combined efficacy of TAS6417 and sacituzumab govitecan in a II-18 xenograft model possessing EGFR L858R.

[0230] Methods: Human non-small cell lung cancer cells II-18 (Institute of Development, Aging and Cancer, Tohoku University) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cultured II-18 cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 × 10⁶ cells. ６ The solution was prepared to a concentration of 0.1 mL of cells and then transplanted. The average tumor volume (TV) after transplantation was approximately 200 mm³. ３ After allowing the tumors to grow to a certain size, six animals were assigned to each group using a stratified randomization method with TV as the indicator. Tumor diameter and body weight measurements were performed in the same manner as in Example 1.

[0231] TAS6417 was administered orally at 50 mg / kg or 100 mg / kg daily. Sacituzumab govitecan was administered intravenously at 500 μg / body twice weekly.

[0232] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Sacituzumab govitecan was diluted with physiological saline to prepare the administration solution.

[0233] The combined effect of TAS6417 and sacituzumab govitecan compared to TAS6417 monotherapy was investigated. II-18 cells were transplanted into the flanks of mice. The results are shown in Table 6 and Figure 7A. In this xenograft model, the combined effect of TAS6417 and sacituzumab govitecan was observed. Tumor growth was significantly suppressed by the combination of TAS6417 and sacituzumab govitecan compared to TAS6417 monotherapy. The mean weight change rate in the combination therapy group did not show a significant increase or decrease compared to each monotherapy group (Figure 8).

[0234] Example 9. Evaluation of the combined effect of TAS6417 and TAS-116 (pimitespive) in an NCI-H1975 xenograft model possessing EGFR L858R / T790M.

[0235] Methods: Human non-small cell lung cancer cells, NCI-H1975 (American Type Culture Collection), were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cells were subculturified at a ratio of 1:4 to 1:10 every 2 to 5 days in a 37°C, 5% CO2 incubator. NCI-H1975 cells were subcutaneously introduced into the right posterior rib area of ​​6-week-old BALB / c-nu mice (Jackson Laboratory Japan, Inc.) (male) in 8 × 10⁶ cells. ６ The solution was prepared to a concentration of 0.1 mL of cells and then transplanted. Post-transplantation measurements were taken at 152–274 mm. ３ After allowing the tumors to grow to a certain tumor volume (TV), six animals were assigned to each group using a stratified randomization method based on TV. The day on which the group assignment (n=6) was performed was designated as Day 0. Tumor diameter and body weight measurements were performed in the same manner as in Example 1.

[0236] TAS6417 was administered orally once daily at a dose of 100 mg / kg or 200 mg / kg. TAS-116 was administered orally at a dose of 10 mg / kg or 14 mg / kg, with a regimen of 5 days of administration followed by 2 days of rest.

[0237] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. TAS-116 was suspended in a 0.5 w / v% hydroxypropyl methylcellulose solution to prepare the administration solution. The 0.5 w / v% hydroxypropyl methylcellulose solution was prepared by adding an appropriate amount of Japanese Pharmacopoeia Water for Injection to achieve a hypromellose concentration of 0.5 w / v%, then stirring with a stirrer to completely dissolve the solution.

[0238] The combined efficacy of TAS6417 and TAS-116 compared to TAS6417 monotherapy was investigated. NCI-H1975 cells were transplanted into the flanks of mice. In this xenograft model, a combined efficacy of TAS6417 100 mg / kg and TAS-116 was observed (Table 7 and Figure 9A).

[0239]

[0240] The combination therapy of TAS6417 100 mg / kg and TAS-116 significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase in toxicity compared to the TAS6417 100 mg / kg or TAS-116 monotherapy groups (Figure 9B). While the combination therapy group administered TAS6417 200 mg / kg did not show an additional benefit compared to TAS6417 monotherapy, this does not negate the potential benefits of these combinations, as monotherapy alone has a sufficient antitumor effect.

[0241] Example 10. Evaluation of the combined effect of TAS6417 and TAS-116 in an HCC827GR6 xenograft model with EGFR exon 19 deletion and MET amplification.

[0242] Methods: Human non-small cell lung cancer cells HCC827GR6 (EMD Millipore Corporation) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cells were subculturified at a ratio of 1:4 to 1:10 every 3 to 7 days in a 37°C, 5% CO2 incubator. 4 × 10⁶ HCC827GR6 cells were subcutaneously near the right posterior rib of 6-week-old BALB / c-nu mice (male) (Jackson Laboratory Japan Co., Ltd.). ６ Cell suspensions were prepared in 50% Matrigel (Corning) solution to a concentration of cells / 0.1 mL and transplanted. After transplantation, the tumors were allowed to grow until they reached a tumor volume (TV) of 161–261 mm³. Then, six animals were assigned to each group using a stratified randomization method based on TV. The day on which the group assignment (n=6) was performed was designated as Day 1. Tumor diameter measurement, body weight measurement, and preparation of TAS6417 solution or TAS-116 suspension were performed in the same manner as in Example 9.

[0243] The combined efficacy of TAS6417 and TAS-116 compared to TAS6417 monotherapy was investigated. HCC827GR6 cells were transplanted into the flanks of mice. In this xenograft model, the combined efficacy of TAS6417 and TAS-116 was observed (Table 8 and Figure 10A).

[0244]

[0245] The combination therapy of TAS6417 and TAS-116 significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase in toxicity compared to the TAS6417 or TAS-116 monotherapy groups (Figure 10B).

[0246] Example 11. Evaluation of the combined effect of TAS6417 and gumarontinib in vitro in HCC827OR8 having EGFR exon 19 deletion and MET amplification.

[0247] Methods: Human non-small cell lung cancer cells HCC827 and human non-small cell lung cancer cells HCC827OR8 (human lung adenocarcinoma cell lines established using HCC827 cells obtained from the American Type Culture Collection) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS), 10% FBS, and 100 nmol / L osimertinib, respectively.

[0248] Solvent and compound: TAS6417 and gumarontinib were prepared as 10 mM solutions using DMSO.

[0249] Cell viability assay: Cell viability was measured using CellTiter-Glo2.0 (Promega). After removing the culture medium from the culture flask, adherent cells were washed with PBS, detached by trypsin / EDTA treatment, and then pipetted with added culture medium. The cells were transferred to a centrifuge tube and recovered by centrifugation at 400xg, 3min, and 4°C. The cells were then suspended in RPMI-1640 medium containing 10% FBS and seeded in a 384-well plate. The seeding rate was 500 cells / 25 μL per well. After incubation overnight at 37°C and 5% CO2, TAS6417 adjusted to 0.1 mmol / L with DMSO and gumarontinib adjusted to 1 mmol / L were added using a Tecan D300e digital dispenser. TAS6417 was administered at nine concentrations, with a maximum concentration of 1000 nmol / L. Gumarontinib, used in combination, was administered at three final concentrations: 1 nmol / L, 10 nmol / L, and 100 nmol / L. A control group, receiving no drugs, was also included. After drug administration, cells were incubated at 37°C and 5% CO2 for a further three days. The experiment was conducted in four parallel wells (four wells per treatment group). Cell viability was calculated by adding 25 μL of CellTiter-Glo 2.0 solution to each well, incubating at room temperature for 30 minutes, and then measuring the chemiluminescence of each well using a plate reader. Cell viability (T / C%) at the time of drug administration was calculated as a ratio relative to the control group (set at 100%) using the following formula. The average value of the data from the four wells at each concentration was used for analysis.

[0250] Cell viability (T / C%) = (chemiluminescence of drug-treated group) / (chemiluminescence of control group) × 100

[0251] Results: TAS6417 monotherapy showed concentration-dependent inhibition of cell proliferation in the HCC827 cell line, but no inhibition of cell proliferation was observed in HCC827OR8 at any drug concentration. Concomitant use of gumarontinib (10 nmol / L and 100 nmol / L) restored the cell proliferation inhibitory effect of TAS6417 in HCC827OR8 to a level comparable to that of TAS6417 monotherapy in HCC827 (Figure 11).

[0252] Example 12: Evaluation of the combined efficacy of TAS6417 and futibatinib in vitro in 4T1-OVA_hEGFR Ex20ins SVD having an EGFR exon 20 insertion mutation.

[0253] Methods: Mouse mammary cancer cell lines 4T1-OVA (AcceGen) and 4T1-OVA_hEGFR Ex20insSVD (a mouse mammary cancer cell line established in-house, in which 4T1-OVA cells obtained from AcceGen were genetically modified to express the EGFR exon 20 insertion mutation (EGFR_D770_N771insSVD)) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS), 10% FBS, 10 μg / mL puromycin, and 100 μg / mL hydroxycin.

[0254] Solvent and compound: TAS6417 and futibatinib were prepared as 10 mM solutions using DMSO.

[0255] Cell viability assay: Cell viability was measured using CellTiter-Glo2.0 (Promega). After removing the culture medium from the culture flask, adherent cells were washed with PBS, detached by trypsin / EDTA treatment, and then pipetted with added culture medium. The cells were transferred to a centrifuge tube and recovered by centrifugation at 400xg, 3min, and 4°C. The cells were then suspended in RPMI-1640 medium containing 10% FBS and seeded in a 384-well plate. The seeding rate was 250 cells / 25 μL per well. After incubation overnight at 37°C and 5% CO2, TAS6417 adjusted to 2 mmol / L with DMSO and fucivatinib adjusted to 0.1 mmol / L were added using a Tecan D300e digital dispenser. Ten concentrations of fucivatinib were set, with a maximum concentration of 1000 nmol / L, and the final concentration of TAS6417, used in combination, was set to 10 nmol / L. A control group without any drugs was established as a reference. After adding the drugs to the cells, they were incubated at 37°C and 5% CO2 for a further 4 days. The experiment was performed in four sets (four wells per treatment group). Cell viability was calculated by adding 25 μL of CellTiter-Glo2.0 solution to each well, incubating at room temperature for 30 minutes, and then measuring the chemiluminescence of each well with a plate reader. The cell viability (T / C %) at the time of drug addition was calculated as a ratio with the control group set to 100% according to the following formula, and the average value of the data from four wells for each concentration was used for analysis. Cell viability (T / C %) = (chemiluminescence of drug-added group) / (chemiluminescence of control group) × 100

[0256] Results: Futibatinib monotherapy showed concentration-dependent inhibition of cell proliferation in the 4T1-OVA cell line, but its cytotoxic activity was attenuated in the 4T1-OVA_hEGFR Ex20ins SVD cell line. With concomitant use of TAS6417 10 nmol / L, the cell proliferation inhibitory effect of futibatinib in the 4T1-OVA_hEGFR Ex20ins SVD cell line was restored to a level comparable to that of TAS6417 monotherapy in the 4T1-OVA cell line (Figure 12).

[0257] Example 13. Evaluation of the combined effect of TAS6417 and datopotamab deruxtecan in a II-18 xenograft model containing EGFR L858R.

[0258] Methods: Human non-small cell lung cancer cells II-18 (Institute of Development, Aging and Cancer, Tohoku University) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cultured II-18 cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 × 10⁶ cells. ６ The solution was prepared to a concentration of 0.1 mL per cell and transplanted. An electronic caliper was used to measure the tumor diameter, measuring both the long and short diameters, and the TV was calculated using the following formula: TV (mm³) = Long diameter (mm) × Short diameter (mm) × Short diameter (mm) / 2 After allowing the tumors to grow until the average tumor volume (TV) after transplantation reached approximately 200-300 mm³, six animals were assigned to each group using a stratified random assignment method based on TV. The day on which the group assignment (n=6) was performed was designated as Day 0. An animal electronic balance was used to measure body weight. The percentage change in body weight on day n (BWCn) was calculated from the body weight on day n (BWn) using the following formula: Percentage change in body weight BWCn (%) = (BWn - BW1) / BW1 × 100

[0259] TAS6417 was administered orally once daily at a dose of 100 mg / kg. Datopotamab deruxtecan was administered intravenously once at a dose of 10 mg / kg.

[0260] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Datopotamab deruxtecan was diluted with 5% Otsuka sugar solution to prepare the administration solution.

[0261] The combined efficacy of TAS6417 and datopotamab deruxtecan compared to TAS6417 monotherapy was investigated. II-18 cells were transplanted into the flanks of mice. In this xenograft model, the combined efficacy of TAS6417 and datopotamab deruxtecan was observed (Figure 13, Table 9).

[0262]

[0263] The combination therapy of TAS6417 and datopotamab deruxtecan significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups (Figure 16).

[0264] Example 14. Evaluation of the combined effect of TAS6417 and trastuzumab deruxtecan in a II-18 xenograft model containing EGFR L858R.

[0265] Methods: Human non-small cell lung cancer cells II-18 (Institute of Development, Aging and Cancer, Tohoku University) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cultured II-18 cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 × 10⁶ cells. ６ The cells were prepared to a volume of 0.1 mL and transplanted. An electronic caliper was used to measure the tumor diameter, measuring the long and short diameters, and the TV was calculated using the following formula: TV (mm³) = Long diameter (mm) × Short diameter (mm) × Short diameter (mm) / 2 After allowing the tumors to grow until the average tumor volume (TV) after transplantation reached approximately 200-300 mm³, six animals were assigned to each group using a stratified random assignment method based on TV. The day on which the group assignment (n=6) was performed was designated as Day 0. An animal electronic balance was used to measure body weight. The percentage change in body weight on day n (BWCn) was calculated from the body weight on day n (BWn) using the following formula: Percentage change in body weight BWCn (%) = (BWn - BW1) / BW1 × 100

[0266] TAS6417 was administered orally once daily at a dose of 100 mg / kg. Trastuzumab deruxtecan was administered intravenously once at a dose of 3 mg / kg.

[0267] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Trastuzumab deruxtecan was diluted with 5% Otsuka sugar solution to prepare the administration solution.

[0268] The combined efficacy of TAS6417 and trastuzumab deruxtecan compared to TAS6417 monotherapy was investigated. II-18 cells were transplanted into the flanks of mice. In this xenograft model, the combined efficacy of TAS6417 and trastuzumab deruxtecan was observed (Figure 14, Table 9).

[0269] The combination therapy of TAS6417 and trastuzumab deruxtecan significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups (Figure 16).

[0270] Example 15. Evaluation of the combined effect of TAS6417 and enfortumab vedotin in a II-18 xenograft model containing EGFR L858R.

[0271] Methods: Human non-small cell lung cancer cells II-18 (Institute of Development, Aging and Cancer, Tohoku University) were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cultured II-18 cells were placed in the flanks of 6-week-old BALB / cA Jcl-nu mice (Jackson Laboratory Japan Co., Ltd.) (male) in 8 × 10⁶ cells. ６ The solution was prepared to a concentration of 0.1 mL per cell and transplanted. A caliper was used to measure the tumor diameter, measuring both the long and short diameters. The TV (TV) was calculated using the following formula: TV (mm³) = Long diameter (mm) × Short diameter (mm) × Short diameter (mm) / 2. The average tumor volume (TV) after transplantation was 200–300 mm³. ３ After allowing the tumors to grow to a certain extent, six animals were assigned to each group using a stratified randomization method with TV as the indicator. The day on which the group assignment (n=6) was performed was designated as Day 0. An animal electronic balance was used to measure body weight. The percentage change in body weight on day n (BWCn) was calculated from the body weight on day n (BWn) using the following formula: Percentage change in body weight BWCn (%) = (BWn - BW1) / BW1 × 100

[0272] TAS6417 was administered orally once daily at a dose of 100 mg / kg. Enfortumab vedotin was administered intravenously twice weekly at a dose of 1 mg / kg.

[0273] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. Enfortumab vedotin was diluted with physiological saline to prepare the administration solution.

[0274] The combined effect of TAS6417 and enfortumab vedotin compared to TAS6417 monotherapy was investigated. II-18 cells were transplanted into the flanks of mice. In this xenograft model, the combined effect of TAS6417 and enfortumab vedotin was observed (Figure 15, Table 9).

[0275] The combination therapy of TAS6417 and enfortumab vedotin significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to each monotherapy group. (Figure 16) Example 16. Evaluation of the combined effect of TAS6417 and anti-PD-1 antibody in an NIH / 3T3 EGFR H773_V774insNPH_SG5 allograft model having EGFR ex20ins.

[0276] Methods: Mouse embryonic fibroblast cell line NIH / 3T3 EGFR H773_V774insNPH_SG5 (a mouse embryonic fibroblast cell line established in-house, in which NIH / 3T3 cells obtained from the American Type Culture Collection were genetically modified to express the H773_V774insNPH mutant EGFR) was cultured in D-MEM (ATCC modification) medium (Thermo Fisher Scientific) containing 10% neonatal calf serum (NBCS) and 2 μg / mL puromycin. Cultured NIH / 3T3 EGFR H773_V774insNPH_SG5 cells were placed in the flanks of 6-week-old BALB / cJ mice (Jackson Laboratory Japan Co., Ltd.) (male) in 2 x 10⁶ cells. ６ The solution was prepared to a concentration of cells / 0.1 mL and transplanted. A caliper was used to measure the tumor's longest and shortest diameters, and TV was calculated using the following formula: TV (mm²) ３ ) = Long diameter (mm) × Short diameter (mm) × Short diameter (mm) / 2 Average tumor volume (TV) after transplantation is 150 mm ３After allowing the tumors to grow to a certain extent, 10 animals were assigned to each group using a stratified randomization method with TV as the indicator. The day on which the group assignment (n=10) was performed was designated as Day 0. An animal electronic balance was used to measure body weight. The percentage change in body weight on day n (BWCn) was calculated from the body weight on day n (BWn) using the following formula: Percentage change in body weight BWCn (%) = (BWn - BW1) / BW1 × 100

[0277] TAS6417 was administered orally once daily at a dose of 100 mg / kg or 200 mg / kg. Anti-PD-1 antibody was administered intraperitoneally twice a week at a dose of 3 mg / kg.

[0278] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. The anti-PD-1 antibody was diluted with physiological saline to prepare the administration solution.

[0279] The combined efficacy of TAS6417 and an anti-PD-1 antibody compared to TAS6417 monotherapy was investigated. NIH / 3T3 EGFR H773_V774insNPH_SG5 cells were transplanted into the flanks of mice. In this allogeneic transplantation model, the combined efficacy of TAS6417 and an anti-PD-1 antibody compared to anti-PD-1 antibody monotherapy was observed (Table 10).

[0280]

[0281] The combination therapy of TAS6417 and an anti-PD-1 antibody significantly suppressed tumor growth compared to anti-PD-1 antibody monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups.

[0282] Example 17. Evaluation of the combined effect of TAS6417 and an anti-PD-1 antibody in a 4T1-OVA_hEGFR_Ex20insASV-SG allograft model containing EGFR ex20ins.

[0283] Methods: The albumin (OVA)-derived antigen-transformed mouse mammary cancer cell line 4T1-OVA_hEGFR_Ex20insASV-SG (a mouse mammary cancer cell line established in-house, expressing the A767_V769insASV mutant EGFR through gene transfection of 4T1-OVA cells obtained from AcceGen) was cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS), 10 μg / mL puromycin, and 100 μg / mL hydroxycin. The cultured 4T1-OVA_hEGFR_Ex20insASV-SG cells were placed in the flanks of 6-week-old BALB / cJ mice (Jackson Laboratory Japan Co., Ltd.) (male) in 5 × 10⁶ cells. ５　 The solution was prepared to a concentration of 0.1 mL per cell and transplanted. A caliper was used to measure the tumor's longest and shortest diameters, and TV was calculated using the following formula: TV (mm²) ３ ) = major diameter (mm) × minor diameter (mm) × minor diameter (mm) / 2 Average tumor volume (TV) after transplantation is 200 mm ３ After allowing the tumors to grow to a certain extent, 10 animals were assigned to each group using a stratified randomization method with TV as the indicator. The day on which the group assignment (n=10) was performed was designated as Day 0. An animal electronic balance was used to measure body weight. The percentage change in body weight on day n (BWCn) was calculated from the body weight on day n (BWn) using the following formula: Percentage change in body weight BWCn (%) = (BWn - BW1) / BW1 × 100

[0284] TAS6417 was administered orally once daily at a dose of 200 mg / kg. Anti-PD-1 antibody was administered intraperitoneally twice a week at a dose of 0.1 mg / mouse.

[0285] Solvent and compound: TAS6417 was diluted with 0.1 mol / L hydrochloric acid to prepare the administration solution. The anti-PD-1 antibody, Anti-Mo CD279 (PD-1), was administered at a dose of 0.1 mL / mousse at a concentration of 1 mg / mL.

[0286] The combined effect of TAS6417 and an anti-PD-1 antibody was investigated compared to TAS6417 monotherapy. 4T1-OVA_hEGFR_Ex20insASV-SG cells were transplanted into the flanks of mice. In this allogeneic transplantation model, the combined effect of TAS6417 and an anti-PD-1 antibody was observed (Figures 17A-D, Table 11).

[0287]

[0288] The combination therapy of TAS6417 and an anti-PD-1 antibody significantly suppressed tumor growth compared to TAS6417 monotherapy. The mean weight change in the combination therapy group did not show a significant increase or decrease compared to the monotherapy groups.

[0289] Example 18. Platform trial (Clinical Trial 1 / 2) of diparereltinib in patients with EGFR gene mutation-positive non-small cell lung cancer.

[0290] This study is a Phase 1, non-randomized, open-label, multicenter, platform study evaluating the efficacy, safety, and tolerability of diparereltinib monotherapy and combination therapy in patients with EGFR gene mutation-positive non-small cell lung cancer (NSCLC). Objectives and endpoints:

[0291]

[0292]

[0293] Diagnostic and main inclusion criteria: Patients aged 18 years or older with EGFR gene mutation-positive non-small cell lung cancer. Prior treatment with osimertinib for locally advanced or metastatic non-small cell lung cancer. Dosage and administration method:

[0294] The starting doses for Part 1 of each cohort are as follows: Cohort C: Diparereltinib is administered orally at a dose of 100 mg twice daily (BID) (regardless of whether or not food is consumed). Gumarontinib is administered orally at a dose of 300 mg once daily on an empty stomach (avoiding administration 1 hour to 2 hours before a meal). Cohort D: Diparereltinib is administered orally at a dose of 100 mg twice daily (BID) (regardless of whether or not food is consumed). Pimitespiv is administered orally at a dose of 120 mg once daily on an empty stomach (avoiding administration 1 hour to 2 hours before a meal), with a schedule of 5 consecutive days of administration followed by a 2-day rest period. Cohort E: Diparereltinib is administered orally at a dose of 100 mg twice daily (BID) (regardless of whether or not food is consumed). Quemrecrustat is administered intravenously at a dose of 300 mg once every 3 weeks. Cohort F: Diparereltinib is administered orally at a dose of 100 mg twice daily (BID) (regardless of whether the patient has a meal). For patients weighing less than 80 kg, amivantamab is administered intravenously or subcutaneously in 28-day cycles: 350 mg on day 1, 700 mg on day 2, and 1,050 mg on days 8, 15, and 22 of the first cycle. From the second cycle onward, 1,050 mg is administered on days 1 and 15. For patients weighing 80 kg or more, 4-week cycles are administered: 350 mg on day 1, 1,050 mg on day 2, and 1,400 mg on days 8, 15, and 22 of the first cycle. From the second cycle onward, 1,400 mg is administered intravenously or subcutaneously on days 1 and 15. The Part 2 dose for each cohort will be determined based on the dose determined in Part 1.

[0295]

[0296]

[0297] Statistical methods: The population analyzed in this study is as follows (Table 17).

[0298] ATP (All treated population): Cases treated with the investigational drug DLT (Dose-limiting toxicity): Dose-limiting toxicity PPS (Per-protocol set): Population that fits the clinical trial protocol TRAE (Treatment-related adverse event): Adverse event related to the investigational treatment (investigational drug) IRR (Infusion-related reactions): Reactions associated with infusion

[0299] Analysis of primary endpoints: Part 1: For DLT-evaluable cases, the incidence of DLT is calculated for each dose level. All DLTs are listed by patient. Part 2: For the efficacy analysis population, the best overall response is compiled based on RECIST v1.1, and the objective response rate (ORR) and 95% confidence interval (CI) are estimated.

[0300] Table 18 shows the observation and examination schedules for cohorts C, D, and E.

[0301]

[0302] Table 19 shows the observation and examination schedule for Cohort F.

[0303] Criteria for patient selection and discontinuation:

[0304] Patients who meet all of the following criteria will be included in this study: 1) Written informed consent has been obtained for participation in this study. 2) The patient is 18 years of age or older at the time of obtaining consent. 3) Histologically or cytologically confirmed to be locally advanced or metastatic non-squamous NSCLC, and identified to have an epidermal growth factor receptor (EGFR) exon 19 deletion mutation or exon 21 L858R mutation at or after the diagnosis of locally advanced or metastatic cancer. 4) (Part 2 of Cohort C only) Confirmed MET overexpression (IHC3+ in ≥50% of tumor cells) or MET amplification (FISH / NGS: GCN ≥4 or MET / CEP7 ratio ≥2) after osimertinib refractory. 5) Submittable tumor tissue has been collected after progression under osimertinib treatment, and there is a minimum amount sufficient to evaluate the biomarker mutation status and, if possible, other biomarkers. Patients with insufficient tissue volume or no available tissue may be eligible in consultation with the sponsor (Cohort C only) 6) Have one of the following prior treatment histories: a. Progressed after osimertinib monotherapy or osimertinib with platinum-based chemotherapy as adjuvant therapy or first-line therapy as the most recent treatment. b. (Cohort C only) Progressed under second-line treatment with osimertinib monotherapy after first- or second-generation EGFR-TKI monotherapy or erlotinib with an angiogenesis inhibitor. c. (Cohort C only) Progressed under first-line treatment with osimertinib monotherapy and then received chemotherapy as second-line treatment. 7) Have at least one measurable lesion based on RECIST v1.1 (Part 2 only) 8) Meet one of the following criteria: a. No brain metastases b. Patients with brain metastases who have a history of curative local therapy and whose central nervous system disease is stable (defined as neurologically stable and not requiring increased doses of corticosteroids and / or anticonvulsants for at least 14 days prior to enrollment) are eligible. Curative local therapy for brain metastases must be completed at least 14 days prior to enrollment.Regarding corticosteroids, they may be administered at a dose of 10 mg / day or less in prednisolone equivalent at the time of enrollment as a treatment for intracranial lesions. c. Patients with brain metastases of 2 cm or less in size, no symptoms, and who are judged by the investigator to not require immediate curative treatment. 9) US East Coast Cancer Group (ECOG) Performance Status (PS) of 0 or 10) Able to take medication orally 11) Women of childbearing potential have had a negative pregnancy test (urine or serum) within 7 days prior to enrollment. (Women who are not of childbearing potential are defined as women who have undergone hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, or women who have not had menstruation for 12 months without other medical cause.) 12) Have sufficient organ function that meets the criteria. (Table 20) 13) Are willing to and able to comply with the visit schedule and study procedures specified in this study.

[0305]

[0306] Exclusion Criteria Patients who meet any of the following exclusion criteria will be excluded from this study: 1) Have received any of the following treatments within the specified period prior to enrollment in this study: a. Major surgery within 28 days prior to enrollment (excluding the placement of vascular access, and the surgical wound must be healed by the time of enrollment) b. Extensive radiotherapy within 28 days prior to enrollment or local radiotherapy within 14 days prior to enrollment c. Have received osimertinib within 15 days prior to enrollment d. Have received other anticancer drugs other than osimertinib or other investigational drugs within the past 28 days. However, if five times the half-life of the administered anticancer drug is shorter than 28 days and that period has elapsed, enrollment is possible e. Prescription drugs, over-the-counter drugs, nutritional supplements such as vitamins, or herbal medicines that strongly or moderately induce or inhibit CYP3A4 within 7 days prior to the first dose of the investigational drug. 2) (Part 1 of Cohort C only) After osimertinib refractory, no MET overexpression (less than 50% of tumor cells being IHC3+) and / or no MET amplification (FISH / NGS:GCN less than 4 and / or MET / CEP7 ratio less than 2) has been confirmed. 3) Platinum resistance to non-squamous NSCLC. Platinum resistance is defined as disease progression being confirmed during or within 60 days of the last dose of platinum-based chemotherapy. 4) Grade 2 or higher toxicity (excluding Grade 2 alopecia and skin pigmentation) from previous anticancer treatment has not recovered. Patients with other chronic but stable Grade 2 toxicity may be enrolled with the agreement of the investigator and the sponsor. 5) Positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody in baseline viral testing. Furthermore, patients who have been confirmed to be negative for HCV ribonucleic acid (RNA) are eligible even if they are positive for HCV antibodies. 6) Individuals with a confirmed diagnosis of human immunodeficiency virus (HIV) infection. 7) Individuals with or a history of interstitial lung disease / pneumonitis or drug-induced lung disease / pneumonitis (regardless of the grade of the event). 8) Individuals with persistent clinically significant pulmonary symptoms related to a past COVID-19 infection. 9) Individuals with a history of leptomeningeal disease and spinal compression. 10) Individuals with active hemorrhagic disease.11) Any clinically significant acute or chronic medical or mental condition, or any clinically significant abnormal clinical laboratory values ​​(severe retinal disease, intestinal paralysis, intestinal obstruction, pulmonary embolism, interstitial pneumonia or a history thereof, renal failure, hepatic failure, cerebrovascular disease, ulcers requiring transfusion, thyroid dysfunction, hypercalcemia, diabetes mellitus with poorly controlled or severe diabetic complications, epilepsy or other convulsive disorders or a history thereof) that may increase the risk associated with administration of the investigational drug or may affect the interpretation of the study results. 12) Any disease or condition (such as inflammatory bowel disease, malabsorption syndrome, or a history of GI resection) that may significantly affect the GI absorption of diparereltinib, gumarontinib, and pimitespib. 13) Any cardiac dysfunction or clinically significant cardiac disease, including any of the following: a. A history of congestive heart failure (CHF) of class III / IV according to the New York Heart Association (NYHA) functional classification b. c. Severe arrhythmias requiring treatment. Resting QTc greater than 470 msec [calculated using the Fridericia correction formula (QTcF)]. 14) (Cohort F only) Has or has a history of venous thromboembolism. 15) Has hypersensitivity to the investigational drugs used in each cohort, their excipients, or drugs of a similar structure or class. 16) Has a history of treatment with MET inhibitors including diparereltinib and gumarontinib, pimitespive and / or CD73 antagonists and / or amivantamab. 17) (Cohort F only) Unable to use or unwilling to use corticosteroids, antihistamines and / or antipyretics as premedication for amivantamab, and / or unable to use or unwilling to use apixaban during amivantamab administration. 18) (Cohort D only) Corrected visual acuity of less than 0.5 in both eyes (using the International Visual Acuity Chart). 19) The patient has a history of another primary malignant tumor within two years prior to the first dose of the investigational drug.However, this excludes cases where one or more of the following criteria are met: a. Basal cell carcinoma or squamous cell carcinoma of the skin that has been appropriately treated b. Carcinoma in situ of the chest or cervix c. A history of treatment for malignant tumors, all treatment for said malignant tumors was completed more than two years prior to the first dose of the investigational drug, and there is currently no evidence of the disease d. A patient has a concomitant malignant tumor, but is clinically stable and is considered not to require treatment for the tumor 20) Pregnant, possibly pregnant (including cases where it is determined that there is a possibility of pregnancy based on a medical interview, etc.), or breastfeeding (including cases where breastfeeding has been discontinued). 21) Female or male patients of childbearing age who do not consent to appropriate contraception during the following periods.

[0307]

[0308] 22) The clinical trial physician determined that the subject was unsuitable to participate in this study.

Claims

1. An antitumor agent comprising diparereltinib or a salt thereof as an active ingredient, to be used in combination with other antitumor agents for use in cancer patients, wherein the other antitumor agent is at least one selected from the group consisting of molecular targeted drugs, immune checkpoint inhibitors, and antibody-drug conjugates.

2. The antitumor agent according to claim 1, wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists, and antibody-drug conjugates.

3. The antitumor agent according to claim 1, wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates.

4. The antitumor agent according to claim 1, wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

5. The antitumor agent according to claim 4, characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gumarontinib once daily.

6. The antitumor agent according to claim 4, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / day or 250 mg / day of gumarontinib once daily.

7. The antitumor agent according to claim 5 or 6, characterized in that it is administered to patients having MET overexpression or MET amplification.

8. The antitumor agent according to claim 7, characterized in that, if the patient is MET overexpressing, IHC3+ is observed in 50% or more of the tumor cells collected from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS.

9. The antitumor agent according to claim 4, characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by administration of 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day, or 40 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

10. The antitumor agent according to claim 4, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

11. The antitumor agent according to claim 4, characterized by (a) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily and administering 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose or 25 mg / dose of quemrecrustat once every two weeks, or (b) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily and administering 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose or 100 mg / dose of quemrecrustat once every three weeks.

12. The antitumor agent according to claim 4, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

13. (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle lasting 28 days. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week. In subsequent cycles, 700 mg of amivantamab is administered every two weeks. (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The antitumor agent according to claim 4, characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1050 mg is administered once a week each time, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks each time, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1400 mg is administered once a week each time, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks each time.

14. (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab once every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab once every two weeks from the second cycle onward, or (c) The antitumor agent according to claim 4, characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amibantamab administered once every two weeks from the second cycle onward.

15. An antitumor agent according to claim 13 or 14, characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

16. The antitumor agent according to any one of claims 1 to 15, wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

17. The antitumor agent according to any one of claims 1 to 16, wherein the cancer patient is a lung cancer patient.

18. The antitumor agent according to any one of claims 1 to 17, wherein the cancer patient is a cancer patient having an EGFR mutation.

19. The antitumor agent according to claim 18, wherein the EGFR mutation is an exon 19 deletion mutation or an L858R mutation of exon 21 of EGFR.

20. The antitumor agent according to any one of claims 1 to 19, wherein the cancer patient is an EGFR inhibitor-resistant cancer patient.

21. The antitumor agent according to claim 20, wherein EGFR inhibitor resistance is osimertinib resistance.

22. A method for treating a tumor, comprising administering to a cancer patient in need of such treatment an effective amount of diparereltinib or a salt thereof as the active ingredient and an effective amount of another antitumor agent, which is at least one selected from the group consisting of molecularly targeted drugs, immune checkpoint inhibitors and antibody-drug conjugates.

23. The method according to claim 22, wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists, and antibody-drug conjugates.

24. The method according to claim 22, wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates.

25. The method according to claim 22, wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

26. The method according to claim 25, characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gumarontinib once daily.

27. The method according to claim 25, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / day or 250 mg / day of gumarontinib once daily.

28. The method according to claim 26 or 27, characterized in that the patient has MET overexpression or MET amplification.

29. The method according to claim 28, characterized in that, if the patient is MET overexpressing, IHC3+ is observed in 50% or more of the tumor cells taken from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS.

30. The method according to claim 25, characterized by administering 200 mg / day or 100 mg / day of dipareretinib or a salt thereof twice daily for five consecutive days, followed by administration of 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day, or 40 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

31. The method according to claim 25, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

32. The method according to claim 25, characterized by (a) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and administering 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose or 25 mg / dose of quemrecrustat once every two weeks, or (b) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and administering 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose or 100 mg / dose of quemrecrustat once every three weeks.

33. The method according to claim 25, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

34. (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle lasting 28 days. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week. In subsequent cycles, 700 mg of amivantamab is administered every two weeks. (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The method according to claim 25, characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1050 mg is administered once a week, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1400 mg is administered once a week, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks.

35. (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab every two weeks from the second cycle onward, or (c) The method according to claim 25, characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with one cycle consisting of 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amivantamab administered once every two weeks thereafter.

36. A method for an antitumor agent according to claim 34 or 35, characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

37. The method according to any one of claims 22 to 36, wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

38. The method according to any one of claims 22 to 37, wherein the cancer patient is a lung cancer patient.

39. The method according to any one of claims 22 to 38, wherein the cancer patient is a cancer patient having an EGFR mutation.

40. The method according to claim 39, wherein the EGFR mutation is an exon 19 deletion mutation or an L858R mutation of exon 21 of EGFR.

41. The method according to any one of claims 22 to 40, wherein the cancer patient is an EGFR inhibitor-resistant cancer patient.

42. The method according to claim 41, wherein the EGFR inhibitor resistance is osimertinib resistance.

43. Dipareretinib or a salt thereof, used in combination with other antitumor agents for use in cancer patients, wherein the other antitumor agent is at least one selected from the group consisting of molecularly targeted drugs, immune checkpoint inhibitors, and antibody-drug conjugates.

44. The compound or salt thereof according to claim 43, wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists, and antibody-drug conjugates.

45. The compound or salt thereof according to claim 43, wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates.

46. ​​The compound or salt thereof according to claim 43, wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

47. The compound or salt thereof according to claim 46, characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gumarontinib once daily.

48. The compound or salt thereof according to claim 46, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / day or 250 mg / day of gumarontinib once daily.

49. The compound or salt thereof according to claim 47 or 48, characterized in that the patient has MET overexpression or MET amplification.

50. The compound or salt thereof according to claim 49, characterized in that, if the patient is MET overexpressing, IHC3+ is observed in 50% or more of the tumor cells taken from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS.

51. The compound or salt thereof according to claim 46, characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by administration of 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day, or 40 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

52. The compound or salt thereof according to claim 46, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

53. The compound or salt thereof according to claim 46, characterized by (a) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and administering 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose or 25 mg / dose of quemrecrustat once every two weeks, or (b) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and administering 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose or 100 mg / dose of quemrecrustat once every three weeks.

54. The compound or salt thereof according to claim 46, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

55. (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle lasting 28 days. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week. In subsequent cycles, 700 mg of amivantamab is administered every two weeks. (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The compound or salt thereof according to claim 46, characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third and fourth weeks of the first cycle, 1050 mg is administered once a week each time, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks each time, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice a day for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third and fourth weeks of the first cycle, 1400 mg is administered once a week each time, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks each time.

56. (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab every two weeks from the second cycle onward, or (c) The compound or salt thereof according to claim 46, characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amibantamab administered once every two weeks thereafter.

57. An antitumor agent according to claim 55 or 56, characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

58. The compound or salt thereof according to any one of claims 43 to 57, wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

59. The compound or salt thereof according to any one of claims 43 to 58, wherein the cancer patient is a lung cancer patient.

60. The compound or salt thereof according to any one of claims 43 to 59, wherein the cancer patient is a cancer patient having an EGFR mutation.

61. The compound or salt thereof according to claim 60, wherein the EGFR mutation is an exon 19 deletion mutation or an L858R mutation of exon 21 of EGFR.

62. The compound or salt thereof according to any one of claims 43 to 61, wherein the cancer patient is an EGFR inhibitor-resistant cancer patient.

63. The compound or salt thereof according to claim 62, wherein EGFR inhibitor resistance is osimertinib resistance.

64. A pharmaceutical composition for treating cancer, comprising diparereltinib or a salt thereof as an active ingredient, to be used in combination with other antitumor agents for use in cancer patients, wherein the other antitumor agent is at least one selected from the group consisting of molecularly targeted drugs, immune checkpoint inhibitors, and antibody-drug conjugates.

65. The composition according to claim 64, wherein the other antitumor agent is at least one selected from the group consisting of VEGF signaling pathway antagonists, HGF / c-MET signaling pathway antagonists, ErbB / HER signaling pathway antagonists, FGF signaling pathway antagonists, adenosine signaling pathway antagonists, ubiquitin-proteasome signaling pathway antagonists, PD-1 / PD-L1 signaling pathway antagonists, and antibody-drug conjugates.

66. The composition according to claim 64, wherein the other antitumor agent is at least one selected from the group consisting of VEGF / VEGFR inhibitors, MET inhibitors, EGFR inhibitors, FGFR inhibitors, CD73 inhibitors, HSP90 inhibitors, PD-1 inhibitors, anti-TROP-2 antibody drug conjugates, anti-HER2 antibody drug conjugates, anti-HER3 antibody drug conjugates, and anti-nectin-4 antibody drug conjugates.

67. The composition according to claim 64, wherein the other antitumor agent is at least one selected from the group consisting of bevacizumab, ramucirumab, capmatinib, gumarontinib, amibantamab, futivacinib, quemriculstat, pimitespib, pembrolizumab, zimbererimab, sacituzumab govitecan, datopotamab deruxtecan, trastuzumab deruxtecan, patritumab deruxtecan, and enfortumab vedotin.

68. The composition according to claim 67, characterized by administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and 350 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, or 150 mg / day of gmarontinib once daily.

69. The composition according to claim 67, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / day or 250 mg / day of gumarontinib once daily.

70. The composition according to claim 68 or 69, characterized in that it is administered to a patient having MET overexpression or MET amplification.

71. The composition according to claim 70, characterized in that, if the patient is MET overexpressing, IHC3+ is observed in 50% or more of the tumor cells taken from the patient, and if the patient has MET gene amplification, GCN ≥ 4 or MET / CEP7 ratio ≥ 2 in FISH / NGS.

72. The composition according to claim 67, characterized by administering 200 mg / day or 100 mg / day of dipareretinib or a salt thereof twice daily for five consecutive days, followed by administration of 200 mg / day, 160 mg / day, 120 mg / day, 80 mg / day, or 40 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

73. The composition according to claim 67, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily for five consecutive days, followed by 160 mg / day, 120 mg / day, or 80 mg / day of pimitespive once daily for five consecutive days, and then a two-day rest period.

74. The composition according to claim 67, characterized by (a) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and administering 125 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose or 25 mg / dose of quemrecrustat once every two weeks, or (b) administering 200 mg / day or 100 mg / day of diparereltinib or a salt thereof twice daily, and administering 350 mg / dose, 300 mg / dose, 200 mg / dose, 150 mg / dose or 100 mg / dose of quemrecrustat once every three weeks.

75. The composition according to claim 67, characterized by administering 200 mg / day of diparereltinib or a salt thereof twice daily, and 300 mg / dose or 200 mg / dose of quemrecrustat once every three weeks.

76. (a) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, with one cycle lasting 28 days. In the first week of the first cycle, 700 mg is administered in two divided doses. In the second, third, and fourth weeks of the first cycle, 700 mg is administered once a week. In subsequent cycles, 700 mg of amivantamab is administered every two weeks. (b) Diparerertinib or a salt thereof is administered twice daily at a dose of 200 mg / day or 100 mg / day, (c) The composition according to claim 67, characterized in that one cycle is 28 days, in the first week of the first cycle, 1050 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1050 mg is administered once a week each time, and in the second cycle and beyond, 1050 mg of amibantamab is administered once every two weeks each time, or (c) 200 mg / day or 100 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, in the first week of the first cycle, 1400 mg is administered in two divided doses, in the second, third, and fourth weeks of the first cycle, 1400 mg is administered once a week each time, and in the second cycle and beyond, 1400 mg of amibantamab is administered once every two weeks each time.

77. (a) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 700 mg administered in two divided doses during the first week of the first cycle, 700 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 700 mg of amivantamab every two weeks from the second cycle onward, or (b) Administering 200 mg / day of diparereltinib or a salt thereof twice daily for 28 days as one cycle, with 1050 mg administered in two divided doses during the first week of the first cycle, 1050 mg administered once a week during the second, third, and fourth weeks of the first cycle, and continuing to administer 1050 mg of amivantamab every two weeks from the second cycle onward, or (c) The composition according to claim 67, characterized in that 200 mg / day of diparereltinib or a salt thereof is administered twice daily for 28 days, with 1400 mg administered in two divided doses during the first week of the first cycle, 1400 mg administered once a week during the second, third, and fourth weeks of the first cycle, and 1400 mg of amibantamab administered every two weeks thereafter.

78. A composition according to claim 76 or 77, characterized in that if the patient's weight is less than 80 kg, the administration schedule of (a) or (b) is applied, and if the patient's weight is 80 kg or more, the administration schedule of (b) or (c) is applied.

79. The composition according to any one of claims 64 to 78, wherein the cancer patient is a patient with head and neck cancer, brain tumor, gastrointestinal cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, bladder cancer, or skin cancer.

80. The composition according to any one of claims 64 to 79, wherein the cancer patient is a lung cancer patient.

81. The composition according to any one of claims 64 to 80, wherein the cancer patient is a cancer patient having an EGFR mutation.

82. The composition according to claim 81, wherein the EGFR mutation is an exon 19 deletion mutation or an L858R mutation of exon 21 of EGFR.

83. The composition according to any one of claims 64 to 82, wherein the cancer patient is an EGFR inhibitor-resistant cancer patient.

84. The composition according to claim 83, wherein the EGFR inhibitor resistance is osimertinib resistance.

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