HER2 inhibitor dosing schedule

Abstract

The present invention relates to a drug administration schedule for HER2 inhibitors useful in the prevention and / or treatment of cancer, particularly to their dosage and administration in second-line or subsequent lines.

Description

[Technical Field]

[0001] The present invention relates to a dosing schedule for the HER2 inhibitor N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazole-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidine-2-yl]piperidine-4-yl}prop-2-enamide, which is useful in the prevention and / or treatment of cancer. In particular, the dosing schedule may be determined by the dose of the HER2 inhibitor and / or the administration of the second or subsequent lines. [Background technology]

[0002] N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazole-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidine-2-yl]piperidine-4-yl}prop-2-enamide, also referred to herein as compound (1) or zongertinib, is a HER2 (ErbB2) inhibitor described in International Publication No. 2021 / 213800. Zongertinib is a potent and selective tyrosine kinase inhibitor of wild-type and mutant HER2 that does not affect wild-type epidermal growth factor receptor (EGFR). Therefore, it is useful for the treatment and / or prevention of diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, particularly for neoplastic and / or hyperproliferative diseases such as cancer.

[0003] There is a need to find a way to administer compound (1) that is safe, tolerable, and therapeutically effective, both on its own and in the context of treatments already performed. [Overview of the Initiative]

[0004] According to the first aspect, the following for use in cancer treatment:

[0005] [ka] A compound (1) as defined in [reference] is provided, which is administered in a daily dose of at least 30 mg. Alternatively, a method is provided for treating a patient with cancer, comprising administering compound (1) in a daily dose of at least 30 mg.

[0006] In this embodiment, compound (1) is administered in a daily dose of 30 mg to 600 mg.

[0007] In this embodiment, compound (1) is administered at a daily dose of at least 60 mg.

[0008] In this embodiment, compound (1) is administered in a daily dose of 60 mg to 300 mg.

[0009] In this embodiment, compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0010] In this embodiment, compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

[0011] In this embodiment, compound (1) is administered in a daily dose of 120 mg or 240 mg.

[0012] In this embodiment, compound (1) is administered at a daily dose of 120 mg.

[0013] In this embodiment, compound (1) is administered at a daily dose of 240 mg.

[0014] In this embodiment, compound (1) is administered once or twice daily.

[0015] In this embodiment, compound (1) is administered once daily.

[0016] In an embodiment, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg, or compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0017] In an embodiment, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, or 360 mg, or compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, or 360 mg.

[0018] In an embodiment, compound (1) is administered once daily at a daily dose of 120 mg or 240 mg.

[0019] In an embodiment, compound (1) is administered once daily at a daily dose of 120 mg.

[0020] In an embodiment, compound (1) is administered once daily at a daily dose of 240 mg.

[0021] In an embodiment, compound (1) is administered orally.

[0022] In an embodiment, compound (1) is administered as a tablet.

[0023] In an embodiment, compound (1) is administered after the administration of a systemic anti-cancer therapy agent.

[0024] Another aspect is for use in the treatment of cancer, the following

[0025]

Chemical formula

[0026] In this embodiment, the systemic anticancer therapy agent is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, taxanes, antimetabolites, immunotherapeutic agents, and combinations thereof.

[0027] In this embodiment, the systemic anticancer therapy agent is or comprises trastuzumab deruxtecan and / or trastuzumab emtansine.

[0028] In this embodiment, the systemic anticancer therapy agent includes pembrolizumab, pemetrexed, and / or platinum-based chemotherapy.

[0029] In one embodiment, the cancer is selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumors, head and neck tumors, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0030] In this embodiment, the cancer is non-small cell lung cancer.

[0031] In this embodiment, the cancer is characterized by HER2 overexpression, HER2 amplification, and / or HER2 mutation.

[0032] In this embodiment, the cancer contains a mutation in the tyrosine kinase domain of HER2.

[0033] In this embodiment, the cancer is unresectable, progressive, and / or metastatic.

[0034] In this embodiment, the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 antibody-drug conjugate.

[0035] Another embodiment is for use in the treatment and / or prevention of cancer, as follows:

[0036] [ka] The present invention relates to a defined compound (1), wherein the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 antibody-drug conjugate. Alternatively, a method is provided for treating and / or preventing cancer in a subject requiring such treatment, comprising administering compound (1), wherein the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 antibody-drug conjugate. In this embodiment, the cancer is preferably as defined in one or more of the above embodiments.

[0037] In this embodiment, the cancer is resistant to treatment with trastuzumab deruxtecan.

[0038] Another embodiment is the following for use in the treatment of cancer:

[0039] [ka] The present invention relates to a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in a daily dose of at least 30 mg. Alternatively, a method for treating a patient suffering from cancer comprises administering a pharmaceutical composition comprising compound (1) and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in a daily dose of at least 30 mg. In this embodiment, compound (1) is administered, in particular with respect to a daily dose, once / twice daily administration, and / or oral (especially tablet) administration, preferably as defined in any of the above embodiments referring to compound (1) for use. Similarly, in these embodiments, cancer may be as defined above in any embodiment.

[0040] It should be understood that any of the embodiments or aspects disclosed herein that refer to suitable characteristics (e.g., daily dose of compound (1), once / twice daily administration, oral / tablet administration, administration in addition to systemic anticancer agents, definition of cancer by location and / or HER2 abnormality and / or resistance) can be combined with each other to provide further embodiments of the present invention. [Brief explanation of the drawing]

[0041] [Figure 1A] (A) Design of dose-escalation parts of clinical trials to test various doses and schedules of compound (1) in pre-treated patients with unresectable, progressive, and / or metastatic solid tumors with HER2 gene abnormalities, as described in Examples 1 and 2. [Figure 1B] (B) Alternative notation for the dose escalation part of the clinical trial in Example 1. N = number of patients; BID = twice per day, twice daily; QD = once per day, once daily; RP2D = recommended dose for dose expansion. [Figure 2A] (A) As of March 2023 and [Figure 2B](B) Swimmer plots of response evaluations and treatment duration by patient and dose as of January 2024. Bars represent progression-free survival, not treatment duration. Each bar represents a patient in Phase Ia (see Examples 1 and 2). BID = twice daily, twice daily; QD = once daily, once daily; PR = partial response; SD = stable disease; PD = progressive disease. [Figure 3A] (A) As of March 2023 and [Figure 3B] (B) Swimmer plots of patient and dose-specific response evaluations and treatment duration in the BID schedule as of January 2024. Bars represent progression-free survival, not treatment duration. Each bar represents a patient in Phase Ia (see Examples 1 and 2). Abbreviations are defined as in Figure 2. [Figure 4A] (A) As of March 2023 and [Figure 4B] (B) Swimmer plots of patient and dose-specific response evaluations and treatment duration in the QD schedule as of January 2024. Bars represent progression-free survival, not treatment duration. Each bar represents a patient in Phase Ia (see Examples 1 and 2). Abbreviations are defined as in Figure 2. [Figure 5A] Waterfall plots for BID vs. QD schedules, showing the best change from baseline in target lesions as a percentage (RECIST v1.1). Each bar represents a patient in Phase Ia (see Examples 1 and 2). The dashed line at 20% marks the boundary for progression (above 20%). The dashed line at -30% marks the boundary for partial response (PR) (below 30%). The interval between 20% and -30% corresponds to stable disease (SD). Data are from January 2023 in Panel (A), and [Figure 5B] Panel (B) is from January 2024. [Figure 6A]Waterfall plots for BID dose levels, showing the best change from baseline in the target lesion, expressed as a percentage (RECIST v1.1). Each bar represents a patient in Phase Ia (see Examples 1 and 2). The dashed line has the same meaning as in Figure 5. Data are from March 2023 in Panel (A), and [Figure 6B] Panel (B) is from January 2024. [Figure 7A] Waterfall plot for QD dose levels, showing the best change from baseline in the target lesion, expressed as a percentage (RECIST v1.1). Each bar represents a patient in Phase Ia (see Examples 1 and 2). The dashed line has the same meaning as in Figure 5. Data are from March 2023 in Panel (A), and [Figure 7B] Panel (B) is from January 2024. [Figure 8A] As of March 2023, (A) patients with non-small cell lung cancer and [Figure 8B] (B) Waterfall plots for BID dose levels, showing the best change from baseline of the target lesion as a percentage (RECIST v1.1) in patients with other tumors. [Figure 8C] Panel (C) corresponds to Panel (A), but has a cutoff date of January 2024. Each bar represents a patient in Phase Ia (see Examples 1 and 2). The dashed lines have the same meaning as in Figure 5. [Figure 9A] As of March 2023, (A) patients with non-small cell lung cancer and [Figure 9B] (B) Waterfall plots for QD dose levels, showing the best change from baseline of the target lesion as a percentage (RECIST v1.1) in patients with other tumors. [Figure 9C]Panel (C) corresponds to Panel (A), but has a cutoff date of January 2024. Each bar represents a patient in Phase Ia (see Examples 1 and 2). The dashed lines have the same meaning as in Figure 5. [Figure 10] Figures 1(A) and (B) show an analysis of the correlation between objective response rate and total daily dose using logistic regression based on the Phase Ia dose levels and schedule. The dashed line represents the estimated relationship, and the dot area indicates the 95% confidence interval. Data are from March 2023. [Figure 11] Figures 1(A) and (B) show an analysis of the correlation between the best-case percentage change from baseline in the sum of the longest diameters of target lesions and the total daily dose, using linear regression based on the Phase Ia dose levels and schedule. Dashed lines with longer dashes (higher at baseline) represent the estimated relationship, and dashed lines with shorter dashes (lower at baseline) represent a -30% tumor reduction (defining partial response). The dot areas represent the 95% confidence interval. Data are from March 2023. [Figure 12] Kaplan-Meier plots for progression-free survival (RECIST v.1.1) by medication schedule (BID, QD) in the set of all patients treated in Phase Ia (see Examples 1 and 2), median progression-free survival (Med), and the lower and upper confidence limits (LCL, UCL) of the 95% confidence interval for the estimate of median progression-free survival. × marks on the line indicate the point at which BID patients were censored, and ○ marks indicate the point at which QD patients were censored. Data are from January 2024. [Figure 13]Kaplan-Meier plots for progression-free survival (RECIST v.1.1) by medication schedule (BID, QD) in a set of Phase Ia lung cancer patients (see Examples 1 and 2), median progression-free survival (Med), and the lower and upper confidence limits (LCL, UCL) of the 95% confidence interval for the estimate of median progression-free survival. × marks on the line indicate the point at which BID patients were censored, and ○ marks indicate the point at which QD patients were censored. Data are from January 2024. [Figure 14] Waterfall plot showing best-case change from baseline in target lesions, expressed as a percentage (RECIST v1.1). Each bar represents a patient in Phase Ib Cohort 1 who initiated treatment at least 7 weeks prior to the snapshot date, with baseline and post-baseline tumor assessments (see Example 3). Patients were treated with 120 mg QD or 240 mg QD. Data cutoff is July 2023. [Figure 15] Schematic diagram of the experiment for the data in Figure 16. T-DXd-resistant tumors were generated in vivo, collected, cultured in vitro, and then tested for sensitivity to T-DXd, the T-DXd-containing deruxtecan, and compound (1). [Figure 16A] (A) Deruxtecan in vitro [Figure 16B] (B)T-DXd, [Figure 16C] (C) Dose-response curves for parental and T-DXd-resistant NCI-N87 cells to treatment with compound (1) (i.e., songertinib) (each line represents an independent experiment). [Modes for carrying out the invention]

[0042] Detailed description of the invention The object of the present invention is to provide a safe and effective dose regime for compound (1) for use in the treatment of cancer. Surprisingly, the dose regimes according to the present invention were found to achieve clinical efficacy while providing a tolerable and manageable safety profile. Efficacy and safety results from ongoing dose escalation studies are reported in Example 1 (with the first or early cutoff date) and Example 2 (with the second or later cutoff date). Example 3 refers to a dose expansion study in patients treated with compound (1) 120 mg or 240 mg once daily.

[0043] Specifically, efficacy can be demonstrated by a partial response with an overall response rate (ORR) of 45.8% in patients with non-small cell lung cancer, along with a favorable disease control rate (DCR) of 95.8% at the initial cutoff date (excluding patients with the best overall response rate of "not quantifiable" at the data cutoff date). By the late cutoff date, compound (1) in the dosing schedule according to the present invention conferred OR and DCR of 49% and 91% in 53 patients with pre-treated HER2-abnormally positive solid tumors, and 58% and 97% in such patients with HER2-mutated NSCLC (n=36). Further preliminary evidence of efficacy is provided in Examples 1 and 2 (see particularly 1.2.4 and 2.3, and Figures 2-9 and 12-13) and Example 3 (see particularly 3.2 and Figure 14).

[0044] Additionally, the efficacy of the medication schedule according to the present invention is demonstrated by the impressive median progression-free survival (PFS) time observed by the late cutoff date, specifically approximately 8 months across all treated patients (8.0 months for the BID schedule and 8.3 months for the QD schedule), and over 1 year in NSCLC patients (13.8 months for the BID schedule and 12.3 months for the QD schedule), with the median PFS calculated using the Kaplan-Meier estimator (see 2.8 in Example 2, and Figures 12 and 13).

[0045] At the same time, the side effects resulting from the dose regimen according to the present invention are remarkably few and mild, as evidenced by the fact that only three dose-limiting toxicities (DLTs) have been observed, all of which occurred outside the maximum tolerated dose (MTD) observation period and before the first cutoff date, the MTD had been reached (see 1.2.3 in Example 1). By the second cutoff date, four patients had experienced a DLT at one point in the entire treatment period and had not yet reached the MTD (see 2.2 in Example 2). This demonstrates the good safety and tolerability of the medical use and treatment method according to the present invention, as well as a low discontinuation rate. In addition, the dose regimen according to the present invention appears to be suitable for a diverse range of patients who are already receiving other cancer-related treatments.

[0046] The positive safety profile observed with respect to the drug administration schedule of the present invention allows for the simultaneous administration of relatively large amounts of compound (1). This, in turn, may have several advantageous effects, for example, on patient adherence.

[0047] In addition, the observed efficacy and tolerability were maintained over a long period, as indicated by the duration of treatment (see 1.2.6 in Example 1 and 2.4 in Example 2), the duration of response (see 1.2.7 in Example 1 and 2.5 in Example 2), the duration of disease control (see 2.6 in Example 2), and progression-free survival (see 2.8 in Example 2, and Figures 12 and 13).

[0048] The dose-efficacy and dose-safety relationships were found to be unexpectedly flat, which may indicate a broad treatment window for the present invention (see Section 1.2.5 in Example 1). In particular, the relationship between total daily dose and objective response rate was estimated to be very flat, showing that even relatively low doses led to high response rates (see Figure 10). Similar observations were predicted regarding the relationship between total daily dose and tumor reduction (see Figure 11).

[0049] Advantageously, the drug regimen of the present invention was relatively effective in a patient population pre-treated with the anti-HER2 antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) (see 1.2.8 in Example 1 and 2.7 in Example 2). In fact, compound (1) was found to potently inhibit the proliferation of HER2-dependent cells that had acquired resistance to T-DXd (see Example 4 and Figure 16).

[0050] Compound (1) As used herein, the term "compound (1)" means the following:

[0051] [ka] This refers to compounds specified in or pharmaceutically acceptable salts thereof.

[0052] The IUPAC name for compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazole-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidine-2-yl]piperidine-4-yl}prop-2-enamide. In case of any discrepancy between the IUPAC name and the written formula, the formula shall prevail. Compound (1) is also known as songertinib. Compound (1) is disclosed in International Publication No. 2021 / 213800 as an example of compound I-01. International Publication No. 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines, including compound (1), as HER2 inhibitors and provides a synthesis procedure for compound (1). The properties of compound (1), as well as evidence of its inhibitory effects on HER2 wild-type and YVMA kinase activity without affecting EGFR, are disclosed in International Publication No. 2021 / 213800, incorporated herein by reference.

[0053] As used herein, the term "compound (1)" includes any tautomers and pharmaceutically acceptable salts and all solid forms of the compound, as well as solvates, including hydrates and solvates of its pharmaceutically acceptable salts.

[0054] In embodiments, compound (1) is used as a free base. In embodiments, a pharmaceutically acceptable salt of compound (1) is used. As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human tissue without excessive toxicity, irritation, allergic response, or other problems or complications, and that is commensurate with a reasonable benefit / risk ratio.

[0055] As used herein, “pharmaceutically acceptable salt” of compound (1) means compound (1) modified by forming an acidic or basic salt thereof. As used herein, the term pharmaceutically acceptable salt generally includes both acid and base addition salts. A pharmaceutically acceptable acid addition salt is a salt formed with an inorganic or organic acid that retains the biological efficacy and properties of the free base and is not biologically or otherwise undesirable. A pharmaceutically acceptable base addition salt includes salts derived from an inorganic base or an organic non-toxic base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and similar salts. For example, such salts include salts derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. In embodiments, pharmaceutically acceptable salts are selected from chlorides and fumarates.

[0056] A pharmaceutically acceptable salt can be synthesized from compound (1) by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of compound (1) with a sufficient amount of a suitable acid or base in water or in an organic diluent or solvent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0057] As used herein, the term “solvate” refers to an association or complex of one or more solvent molecules with compound (1). Examples of solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, tert-butyl methyl ether, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, and ethanolamine. The term “hydrate” refers to a complex in which the solvent molecule is water.

[0058] Dosage and dosage regimen The object of the present invention is to provide a safe and effective dose regime for the administration of compound (1) or a pharmaceutical composition containing compound (1) in the dose regime described herein. This dose regime is particularly useful for use in the treatment of cancer. In addition, this dose regime for compound (1) or a pharmaceutical composition containing compound (1) is particularly useful in methods of treating patients with cancer. Furthermore, this dose regime is also considered suitable for secondary or subsequent line treatment when a patient has already received one or more cancer treatments in the past.

[0059] As used herein, “dose regimen” or “medication schedule” means the administration of compound (1) according to any one or more characteristics, including but not limited to a daily dose, once or twice daily administration, oral administration, administration for a specific duration, or administration following systemic anticancer therapy.

[0060] As used herein, “daily dose” or “total daily dose” refers to the amount of the active substance, i.e., compound (1), administered to a patient within a 24-hour time frame. The 24-hour time frame does not necessarily begin at noon or midnight.

[0061] As described above and in the examples below, it was surprisingly found that the use of compound (1) in the treatment of cancer at a daily dose of at least 30 mg was safe and effective.

[0062] In a preferred embodiment, compound (1) is administered in a daily dose of at least 60 mg. Alternatively, the method for treating a patient with cancer as described above includes administering compound (1) in a daily dose of at least 60 mg.

[0063] In a preferred embodiment, compound (1) is administered in a daily dose of at least 80 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of at least 80 mg.

[0064] In a preferred embodiment, compound (1) is administered in a daily dose of at least 120 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of at least 120 mg.

[0065] In a preferred embodiment, compound (1) is administered in a daily dose of at least 180 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of at least 180 mg.

[0066] In a preferred embodiment, compound (1) is administered in a daily dose of at least 200 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of at least 200 mg.

[0067] In a preferred embodiment, compound (1) is administered in a daily dose of at least 240 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of at least 240 mg.

[0068] In a preferred embodiment, compound (1) is administered in a daily dose of at least 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of at least 300 mg.

[0069] In a preferred embodiment, compound (1) is administered in a daily dose of 30 mg to 600 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 30 mg to 600 mg.

[0070] In a preferred embodiment, compound (1) is administered in a daily dose of 60 mg to 600 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 60 mg to 600 mg.

[0071] In a preferred embodiment, compound (1) is administered in a daily dose of 80 mg to 600 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 80 mg to 600 mg.

[0072] In a preferred embodiment, compound (1) is administered in a daily dose of 120 mg to 600 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 120 mg to 600 mg.

[0073] In a more preferred embodiment, compound (1) is administered in a daily dose of 30 mg to 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 30 mg to 300 mg.

[0074] In a more preferred embodiment, compound (1) is administered in a daily dose of 60 mg to 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 60 mg to 300 mg.

[0075] In a more preferred embodiment, compound (1) is administered in a daily dose of 80 mg to 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 80 mg to 300 mg.

[0076] In a more preferred embodiment, compound (1) is administered in a daily dose of 120 mg to 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 120 mg to 300 mg.

[0077] In a preferred embodiment, compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0078] In a preferred embodiment, compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0079] In a preferred embodiment, compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

[0080] In a preferred embodiment, compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg.

[0081] In a preferred embodiment, compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

[0082] In a preferred embodiment, compound (1) is administered in a daily dose of 120 mg or 240 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) in a daily dose of 120 mg or 240 mg.

[0083] In a preferred embodiment, compound (1) is administered at a daily dose of 30 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 30 mg.

[0084] In a preferred embodiment, compound (1) is administered at a daily dose of 60 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 60 mg.

[0085] In a preferred embodiment, compound (1) is administered at a daily dose of 80 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 80 mg.

[0086] In a preferred embodiment, compound (1) is administered at a daily dose of 120 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 120 mg.

[0087] In a preferred embodiment, compound (1) is administered at a daily dose of 180 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 180 mg.

[0088] In a preferred embodiment, compound (1) is administered at a daily dose of 200 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 200 mg.

[0089] In a preferred embodiment, compound (1) is administered at a daily dose of 240 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 240 mg.

[0090] In a preferred embodiment, compound (1) is administered at a daily dose of 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 300 mg.

[0091] In a preferred embodiment, compound (1) is administered at a daily dose of 360 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 360 mg.

[0092] In a preferred embodiment, compound (1) is administered at a daily dose of 400 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 400 mg.

[0093] In a preferred embodiment, compound (1) is administered at a daily dose of 420 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 420 mg.

[0094] In a preferred embodiment, compound (1) is administered at a daily dose of 480 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 480 mg.

[0095] In a preferred embodiment, compound (1) is administered at a daily dose of 500 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 500 mg.

[0096] In a preferred embodiment, compound (1) is administered at a daily dose of 540 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 540 mg.

[0097] In a preferred embodiment, compound (1) is administered at a daily dose of 600 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) at a daily dose of 600 mg.

[0098] In preferred embodiments, compound (1) is administered once or twice daily. This means that the daily dose is administered daily as a single dose, or the daily dose is divided into two separate doses, each administered at a different time each day, i.e., within 24 hours. If compound (1) is administered twice daily, the two separate doses are preferably separated by a time interval of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours, preferably 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours, more preferably 8, 9, 10, 11, or 12 hours, and preferably approximately 12 hours.

[0099] In a preferred embodiment, compound (1) is administered once daily. In a preferred embodiment, compound (1) is administered as a single dose every 24 hours.

[0100] In a preferred embodiment, compound (1) is administered twice daily. In a preferred embodiment, compound (1) is administered twice every 24 hours.

[0101] In a preferred embodiment, each of the two daily doses of compound (1) corresponds to half of the daily dose. A simple and error-free application scheme can be provided by administering the required daily dose of compound (1) in two doses containing the same amount.

[0102] In a more preferred embodiment, compound (1) is administered for at least 21 consecutive days. In a more preferred embodiment, compound (1) is administered for 21 days multiplied by X, where X is a natural number greater than or equal to 1. As used herein, “21 days” and “3 weeks” are intended to be synonymous. In the overall cancer treatment, it is also possible to include drug-free intervals between treatment times that involve the administration of compound (1).

[0103] In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg, or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, methods for treating patients with cancer include administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg, or administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0104] In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, methods for treating patients with cancer include administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, or administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0105] In some embodiments, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, or 360 mg, or compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, or 360 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, or 360 mg, or administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, or 360 mg.

[0106] In some embodiments, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg, or compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg, or administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0107] In some embodiments, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0108] In some embodiments, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0109] In some embodiments, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[0110] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 120 mg or 240 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 120 mg or 240 mg.

[0111] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 60 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 60 mg.

[0112] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 120 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 120 mg.

[0113] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 180 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 180 mg.

[0114] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 240 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 240 mg.

[0115] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 300 mg.

[0116] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 360 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 360 mg.

[0117] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 400 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 400 mg.

[0118] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 420 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 420 mg.

[0119] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 480 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 480 mg.

[0120] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 500 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 500 mg.

[0121] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 540 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 540 mg.

[0122] In a preferred embodiment, compound (1) is administered once daily at a daily dose of 600 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) once daily at a daily dose of 600 mg.

[0123] In some embodiments, compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0124] In some embodiments, compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0125] In some embodiments, compound (1) is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, a method of treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0126] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 30 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 30 mg. Preferably, in these embodiments, each of the two daily doses is 15 mg.

[0127] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 60 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 60 mg. Preferably, in these embodiments, each of the two daily doses is 30 mg.

[0128] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 120 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 120 mg. Preferably, in these embodiments, each of the two daily doses is 60 mg.

[0129] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 200 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 200 mg. Preferably, in these embodiments, each of the two daily doses is 100 mg.

[0130] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 300 mg. Preferably, in these embodiments, each of the two daily doses is 150 mg.

[0131] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 360 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 360 mg. Preferably, in these embodiments, each of the two daily doses is 180 mg.

[0132] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 400 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 400 mg. Preferably, in these embodiments, each of the two daily doses is 200 mg.

[0133] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 420 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 420 mg. Preferably, in these embodiments, each of the two daily doses is 210 mg.

[0134] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 480 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 480 mg. Preferably, in these embodiments, each of the two daily doses is 240 mg.

[0135] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 500 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 500 mg. Preferably, in these embodiments, each of the two daily doses is 250 mg.

[0136] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 540 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 540 mg. Preferably, in these embodiments, each of the two daily doses is 270 mg.

[0137] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 600 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) twice daily at a daily dose of 600 mg. Preferably, in these embodiments, each of the two daily doses is 300 mg.

[0138] In this embodiment, compound (1) is administered orally.

[0139] In this embodiment, compound (1) is administered as a tablet.

[0140] In some embodiments, compound (1) is administered orally once daily, preferably in tablet form, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally once daily, preferably in tablet form, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0141] In some embodiments, compound (1) is administered orally once daily, preferably in tablet form, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally once daily, preferably in tablet form, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0142] In some embodiments, compound (1) is administered orally once daily, preferably in tablet form, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily, preferably in tablet form, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[0143] In some embodiments, compound (1) is administered orally once daily, preferably in tablet form, at a daily dose of 120 mg or 240 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily, preferably in tablet form, at a daily dose of 120 mg or 240 mg.

[0144] In some embodiments, compound (1) is administered orally once daily at a daily dose of 60 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 60 mg, preferably in tablet form.

[0145] In some embodiments, compound (1) is administered orally once daily at a daily dose of 120 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 120 mg, preferably in tablet form.

[0146] In some embodiments, compound (1) is administered orally once daily at a daily dose of 180 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 180 mg, preferably in tablet form.

[0147] In some embodiments, compound (1) is administered orally once daily at a daily dose of 240 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 240 mg, preferably in tablet form.

[0148] In some embodiments, compound (1) is administered orally once daily at a daily dose of 300 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 300 mg, preferably in tablet form.

[0149] In some embodiments, compound (1) is administered orally once daily at a daily dose of 360 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 360 mg, preferably in tablet form.

[0150] In some embodiments, compound (1) is administered orally once daily at a daily dose of 400 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 400 mg, preferably in tablet form.

[0151] In some embodiments, compound (1) is administered orally once daily at a daily dose of 420 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 420 mg, preferably in tablet form.

[0152] In some embodiments, compound (1) is administered orally once daily at a daily dose of 480 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 480 mg, preferably in tablet form.

[0153] In some embodiments, compound (1) is administered orally once daily at a daily dose of 500 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 500 mg, preferably in tablet form.

[0154] In some embodiments, compound (1) is administered orally once daily at a daily dose of 540 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 540 mg, preferably in tablet form.

[0155] In some embodiments, compound (1) is administered orally once daily at a daily dose of 600 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally once daily at a daily dose of 600 mg, preferably in tablet form.

[0156] In some embodiments, compound (1) is preferably administered orally twice daily in tablets at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily in tablets at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

[0157] In some embodiments, compound (1) is preferably administered orally twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, in the form of tablets. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, in the form of tablets.

[0158] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg. Alternatively, a method for treating a patient with cancer includes administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[0159] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 30 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 30 mg. Preferably, in these embodiments, each of the two daily doses is 15 mg.

[0160] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 60 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 60 mg. Preferably, in these embodiments, each of the two daily doses is 30 mg.

[0161] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 120 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily at a daily dose of 120 mg, preferably in tablet form. Preferably, in these embodiments, each of the two daily doses is 60 mg.

[0162] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 200 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 200 mg. Preferably, in these embodiments, each of the two daily doses is 100 mg.

[0163] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 300 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 300 mg. Preferably, in these embodiments, each of the two daily doses is 150 mg.

[0164] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 360 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 360 mg. Preferably, in these embodiments, each of the two daily doses is 180 mg.

[0165] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 400 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 400 mg. Preferably, in these embodiments, each of the two daily doses is 200 mg.

[0166] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 420 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 420 mg. Preferably, in these embodiments, each of the two daily doses is 210 mg.

[0167] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 480 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 480 mg. Preferably, in these embodiments, each of the two daily doses is 240 mg.

[0168] In some embodiments, compound (1) is administered orally twice daily at a daily dose of 500 mg, preferably in tablet form. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily at a daily dose of 500 mg, preferably in tablet form. Preferably, in these embodiments, each of the two daily doses is 250 mg.

[0169] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 540 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 540 mg. Preferably, in these embodiments, each of the two daily doses is 270 mg.

[0170] In some embodiments, compound (1) is administered orally twice daily, preferably in tablet form, at a daily dose of 600 mg. Alternatively, a method for treating a patient with cancer involves administering compound (1) orally twice daily, preferably in tablet form, at a daily dose of 600 mg. Preferably, in these embodiments, each of the two daily doses is 300 mg.

[0171] In preferred embodiments, it is also possible to combine the above-specified dose regimens for compound (1) and to change the daily dose during the course of treatment. For example, treatment can be initiated by administering a daily dose of 30 mg (once or twice daily), and this dose can be switched to a higher or lower daily dose (applied once or twice daily).

[0172] The dose regimens described in this paragraph are also applicable if the patient has already received one or more systemic anti-cancer treatments or therapies.

[0173] Use for cancer treatment One embodiment relates to the compound(1) and dose regimen described herein for use in the treatment and / or prevention of cancer. In addition, further embodiments relate to the compound(1) and dose regimen described herein for use in the treatment and / or prevention of cancer when the patient has previously received one or more anti-cancer treatments or therapies, particularly systemic anti-cancer agents.

[0174] According to one embodiment, a compound (1) for use as an anticancer drug in the dosage regime described herein is provided.

[0175] As used herein, cancer, in certain cases, is a “hyperproliferative disorder” and refers to a medical condition in which cell growth increases beyond normal levels. Hyperproliferative disorders include malignant diseases such as cancer, and non-malignant diseases. As used herein, cancer is also referred to, in certain cases, as a “neoplastic disorder.” A neoplastic disorder refers to a disease or medical condition associated with cancer or cancerous signs. Cancer can be classified according to the type of tissue from which it originates (histological type) and the primary site, i.e., the location in the body where the cancer first developed.

[0176] In one embodiment, compound (1) in a dose regime described herein is provided for use in the treatment and / or prevention of cancer. Further embodiments provide a pharmaceutical composition described herein in a dose regime described herein for use in the treatment and / or prevention of cancer. Further embodiments provide compound (1) or a pharmaceutical composition described herein for use in the treatment and / or prevention of cancer when the patient has already received different primary, secondary, or subsequent lines of treatment.

[0177] Different treatments include the administration of anticancer therapies, drugs, or agents that are different from and do not contain compound (1). Prior first-line, second-line, or subsequent line treatments are not correlated with the administration of compound (1), and prior first-line, second-line, or subsequent line treatments are completed or have been completed before any treatment involving the administration of compound (1) is performed.

[0178] Further embodiments relate to a method for treating and / or preventing cancer, comprising the step of administering compound (1) or a pharmaceutical composition described herein in a dose regime described herein to a patient. In one embodiment, such a method comprises administering a disclosed therapeutically effective amount of compound (1) or a pharmaceutical composition comprising compound (1) described herein to a person in need of such treatment.

[0179] Further embodiments relate to a method for treating and / or preventing cancer in a patient who has already received different primary, secondary, or subsequent line treatments, comprising the step of administering compound (1) or a pharmaceutical composition described herein in a dose regime described herein to the patient. In one embodiment, such a method comprises administering a therapeutically effective amount of compound (1) or a pharmaceutical composition containing compound (1) described herein to a person in need of such treatment, in a patient who has already received different primary, secondary, or subsequent line treatments.

[0180] One embodiment relates to the use of compound (1) or a pharmaceutical composition in a dose regime described herein in the manufacture of a pharmacopoeia for the treatment and / or prevention of cancer.

[0181] In embodiments, cancer or tumors include HER2 abnormalities. This means that the cells of cancer or tumors have HER2 abnormalities. When used herein, the expressions “HER2 abnormality,” “HER2 abnormality,” and their grammatical variations have meanings generally derived therefrom in the art and include any variation or alteration in the HER2 protein or its coding gene, such as overexpression of the HER2 protein, amplification of the HER2 coding gene, mutations in the HER2 coding gene and / or HER2 protein (in particular, non-synonymous mutations, somatic mutations, mutations in specific regions, e.g., in the tyrosine kinase domain, in exon 20, etc.), and gene rearrangements of HER2 and / or NRG1. If cancer includes HER2 abnormalities, it may be referred to as HER2 abnormality. If cancer includes overexpression of the HER2 protein, it may be referred to as HER2 overexpression. If cancer includes amplification of the HER2 coding gene, it may be referred to as HER2 amplification. If cancer includes mutations in the HER2 coding gene and / or HER2 protein, it may be referred to as HER2 mutation.

[0182] In this embodiment, the cancer is characterized by HER2 overexpression, HER2 amplification, and / or a HER2 mutation.

[0183] In one embodiment, the cancer contains a mutation in the tyrosine kinase domain of HER2. In another embodiment, the cancer is a HER2 exon 20 mutant cancer.

[0184] In this embodiment, the cancer includes gene rearrangements of HER2 and / or NRG1.

[0185] As used herein, “HER2 overexpression” refers to cancer or tumor cells that express HER2 at levels detectable by immunohistochemistry (e.g., IHC 2+ and IHC 3+) and / or ERBB2 messenger RNA assays.

[0186] As used herein, "HER2 amplification" refers to cancer or tumor cells that exhibit more than two copies of the HER2 gene ERBB2, particularly more than three, four, five, six, seven, eight, nine, or ten copies, and preferably more than six copies.

[0187] HER2 expression, gene copy number, and amplification can be measured, for example, by determining nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), insight hybridization including fluorescence insight hybridization (FISH) and chromogenic insight hybridization (CISH), ELISA, and RNA quantification using techniques such as reverse transcription-polymerase chain reaction (RT-PCR), microarray analysis, and next-generation sequencing (NGS). HER2 expression in or on cancer sample cells can be compared to reference cells. Reference cells may be non-cancer cells obtained from the same subject as the sample cells. Reference cells may be non-cancer cells obtained from a different subject or population of subjects.

[0188] If cancer cells or cells overexpress and / or amplify HER2, the cancer may be referred to as "HER2-positive."

[0189] As used herein, “HER2 mutation” refers to a cancer having at least one mutation, including but not limited to those listed below, i.e., a change in the nucleic acid sequence of the HER2 coding gene and / or a change in the amino acid sequence of the HER2 protein.

[0190] Mutations can be detected by any method known to those skilled in the art, including but not limited to molecular diagnostic methods such as polymerase chain reaction (PCR), single-stranded higher-order polymorphism (SSCP), denaturant concentration gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism (RFLP), next-generation sequencing (NGS), and whole exome sequencing.

[0191] In the embodiments of the HER2-mutated cancer described above, the mutation is a non-synonymous mutation. As used herein, the term “non-synonymous” has the meaning generally derived therefrom in the art, and in particular refers to a mutation in the nucleic acid sequence of the HER2 coding gene that alters the amino acid sequence of the HER2 protein.

[0192] In the embodiments of the HER2-mutated cancer described above, the mutation is a somatic mutation. As used herein, the term “somatic” has the meaning generally derived therefrom in the art, and in particular refers to a mutation in the nucleic acid sequence of the HER2 coding gene occurring in a gamete, germ cell, or cell other than a germ mother cell.

[0193] In the embodiment of the HER2-mutated cancer described above, the mutation is a non-synonymous cell mutation.

[0194] In the embodiment of the HER2-mutated cancer described above, the mutation is a non-synonymous cell mutation in the tyrosine kinase domain of HER2.

[0195] In the embodiment of the HER2-mutated cancer described above, the mutation is located in the tyrosine kinase domain of HER2, specifically in exon 20 of HER2. In the latter case, the cancer may be referred to as a HER2 exon 20 variant.

[0196] As used herein, "HER2 mutation" may also refer to rearrangements involving the HER2 gene ERBB2 and / or NRG1 gene.

[0197] As used herein, cancer containing a mutation in the tyrosine kinase domain of HER2 is defined as cancer in which cancer or tumor cells have at least one mutation in the tyrosine kinase domain of HER2, extending from amino acids 694 to 883 and / or exons 18 to 21.

[0198] As used herein, “carcinoma with HER2 exon 20 mutation” or “HER2 exon 20 variant carcinoma” means cancer or tumor cells having at least one HER2 exon 20 mutation, including but not limited to the mutations listed below.

[0199] ERBB2 (HER2) exon 20 encodes a portion of the kinase domain, spanning amino acids 769-835. Any mutation, insertion, duplication, or deletion within this region is classified as follows: p.A772_G773insMMAY; p.Y772_A775_dup(YVMA); p.A775_G776insYVMA; p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insSVMA; p.A775_G776insVVMA; p.A775 _G776insYVMS;p.A775_G776insC;p.A776_delinsVC;p.A776_delinsLC;p.A776_delinsVV;p.A77 6_delinsAVGC;p.A776_delinsIC;p.A776_V777delinsCVC;p.V777_insE;p.V777_G778insV;p.V77 7_G778insC;p.V777_G778insCG;p.V777_S779dup;p.V777L;p.V777M;p.G778_P780dup(GSP);p.G 778_S779insCPG;p.G778_S779insG;p.G776_delinsVC;p.G776_V777delinsAVGCV;p.G776delinsL This is defined as an exon 20 mutation including C;p.G776_V777delinsAVCV;p.G776delinsVV;p.G776_V777insL;p.G776_V777insVGC;p.G776C;p.G776A;p.G776L;p.G776V;p.P780_Y781insGSP (where "p." refers to the HER2 protein).

[0200] In addition, HER2 mutations, including the following mutations: p.S310A;p.S310F;p.S310Y;p.R678Q;p.G727A;p.T733I;p.L755S;p.L755A;p.L755F;p.L755P;p.L755S;p.V842I;p.D769Y;p.D769H;p.R103Q;p.G1056S;p.I767M;p.L869R;p.L869R;p.T733I;p.T862A;p.V697L;p.R929W;p.D277H;p.D277Y;p.G660D (where "p." refers to the HER2 protein), are located outside of exon 20.

[0201] Among these, examples of tyrosine kinase mutations include p.G727A;p.T733I;p.L755S;p.L755A;p.L755F;p.L755P;p.L755S;p.V842I;p.D769Y;p.D769H;p.I767M;p.L869R;p.L869R;p.T733I;p.T862A;p.V697L.

[0202] In these embodiments, cancer is, but is not limited to, one of the following cancers, tumors, or other proliferative disorders: Cancers / tumors / carcinomas of the head and neck: for example, tumors / carcinomas / cancers of the nasal cavity, sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar trigone, floor of the mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsils, palatine arch (tonsillar pilar), soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottic, glottis, subglottic, vocal cords), hypopharynx, and salivary glands (including minor salivary glands); Lung cancer / tumors / carcinomas: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar epithelium), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma); Mediastinal neoplasms: for example, neurogenic tumors (including neurofibromas, schwannomas, malignant schwannomas, neurosarcomas, ganglioblastomas, gangliocytomas, neuroblastomas, pheochromocytomas, and paragangliomas), germ cell tumors (including seminomas, teratomas, and nonseminomas), thymic tumors (including thymomas, thymic lipomas, thymic carcinomas, and thymic carcinoids), and mesenchymal tumors (including fibromas, fibrosarcomas, lipomas, liposarcomas, myxomas, mesotheliomas, leiomyomas, leiomyosarcomas, rhabdomyosarcomas, xanthogranulomas, mesenchymal tumors, hemangiomas, hemangioendotheliomas, hemangiopericytomas, lymphangiomas, lymphangiopericytomas, and lymphangiomyomas); Cancers / tumors / carcinomas of the gastrointestinal tract (GI): e.g., esophagus, stomach (stomach cancer), pancreas, liver, and biliary tract (hepatocellular carcinoma (HCC), e.g., pediatric HCC, fibrous HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; vascular sarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, cracking tumors), gallbladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (cecum, Tumors / carcinomas / cancers of the colon, rectum, and anus (including colorectal cancer and gastrointestinal stromal tumors (GIST)), appendix, and genitourinary system (kidneys, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal tumor, Gravitz's tumor; ureters, bladder, e.g., urachal cancer, urothelial carcinoma; urethra, e.g., distal, bulbomembranous, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), and penis); Testicular cancer / tumors / carcinomas: e.g., seminomas, nonseminomas; Gynecological cancers / tumors / carcinomas: for example, tumors / carcinomas / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine body (including endometrium and base); Breast cancer / tumors / carcinomas: e.g., breast cancer (invasive ductal, colloidal, lobular, tubular, adenocystic, papillary, medullary, mucinous), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), HER2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast; Endocrine system cancers / tumors / carcinomas: for example, endocrine glands, thyroid (thyroid cancer / tumor; papillary, follicular, undifferentiated, medullary), parathyroid (parathyroid cancer / tumor), adrenal cortex (adrenocortical carcinoma / tumor), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; nonfluorineunctional PET, PPoma, gastrinoma, insulinoma, vipoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors / carcinomas / cancers; Soft tissue sarcomas: for example, fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, vasosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumors of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granulocyte tumor, clear cell sarcoma, melaninous schwannoma, plexosarcoma, neuroblastoma, gangliblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal tumor, alveolar soft tissue sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, fibroplastic small cell tumor; Bone sarcomas: for example, myeloma, reticuloma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcoma), osteosarcoma (including paraostemic, periosteal, high-grade superficial, small cell, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma; Mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma; Skin cancers: for example, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentiginous malignancy, acral lentiginous, nodular, and intraocular melanoma), actinic keratosis, eyelid cancer; Neoplasms of the central nervous system and brain: e.g., astrocytoma (cerebral, cerebellar, diffuse, fibrous, undifferentiated, pilocytic, protoplasmic, gemistocytary), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, gangliocytoma, neuroblastoma, retinoblastoma, schwannoma (e.g., auditory), spinal axial tumor; Peripheral nervous system cancers; lymphomas and leukemias: e.g., B-cell non-Hodgkin lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), and Burkitt lymphoma (BL)), T-cell non-Hodgkin lymphoma (anaplastic large cell lymphoma (ALCL), adult T-cell leukemia) disease / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell Lymphoma (B-LBL), Immunocytoma, Chronic B-cell lymphocytic leukemia (BchlorineL), Chronic T-cell lymphocytic leukemia (TchlorineL), B-cell small lymphocytic lymphoma (B-SLL) ), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), tuberous sclerotic HD (NSHD), mixed cell type HD (MCHD), lymphocyte-rich classical HD, lymphopenic HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia ( CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML); Cancer of unknown primary site (CUP).

[0203] Characterized by their specific location / origin within the body, all cancers / tumors / carcinomas listed above are intended to include both primary tumors and metastatic tumors derived therefrom. Preferably, the cancers defined herein (including, for example, any embodiments referring to cancer types) are metastatic, progressive, and / or unresectable.

[0204] All of the cancers / tumors / carcinomas listed above can be further distinguished by their histopathological classification: Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, undifferentiated, transitional epithelium, lymphoid epithelium), adenocarcinoma (AC) (well differentiated, mucinous, papillary, pleomorphic giant cell, tubular, small cell, signet ring cell, spindle cell) , clear cell, oat cell, colloidal, adenosquamous, mucoepidermal, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumor (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma carcinoma); Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, vasosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.

[0205] In some embodiments, cancer is a solid tumor. In some embodiments, cancer manifests as at least one solid tumor.

[0206] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck tumors, lung cancer, nervous system cancer, and skin cancer.

[0207] Preferably, the brain cancer is glioblastoma or glioma.

[0208] Preferably, the breast cancer is lobular breast cancer. In addition or alternatively, the breast cancer is preferably metastatic.

[0209] Preferably, the endocrine cancer is a nerve sheath tumor, more preferably a HER2-mutated nerve sheath tumor.

[0210] Preferably, the gastrointestinal cancer is selected from the group consisting of anal cancer, appendiceal cancer, bile duct cancer, bladder cancer, colorectal cancer, esophageal and gastric cancer, stomach cancer, esophageal tumors, gastroesophageal cancer, gallbladder tumors, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, and small intestine cancer.

[0211] In addition or alternatively, the gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably with a HER2 mutation. More preferably, the gastrointestinal cancer is selected from the group consisting of gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, particularly metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[0212] Preferably, the gynecological cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer, and ovarian cancer.

[0213] As used herein, “head and neck tumor” preferably means head and neck cancer. Preferably, the head and neck tumor is salivary gland cancer or a tumor.

[0214] Preferably, the lung cancer is non-small cell lung cancer (NSCLC).

[0215] Preferably, the neurological cancer is a peripheral nervous system cancer, more preferably a HER2-amplified peripheral nervous system cancer.

[0216] Preferably, the skin cancer is not melanoma, i.e., a non-melanoma skin cancer.

[0217] In some embodiments, cancer is selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendiceal cancer, bile duct cancer, bladder cancer, colorectal cancer, esophageal and gastric cancer, stomach cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer, and non-melanoma skin cancer.

[0218] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplifying, and / or HER2-mutated (particularly HER2 exon 20 mutation) cancer selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendiceal cancer, bile duct cancer, bladder cancer, colorectal cancer, esophageal and gastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer, and non-melanoma skin cancer.

[0219] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumors, head and neck tumors, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0220] In some embodiments, the cancer is a HER2-overexpressing, HER2-amplifying, and / or HER2-mutated (particularly HER2 exon 20 mutation) cancer selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumors, head and neck tumors, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0221] In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumors, head and neck tumors, gastrointestinal cancers, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0222] In the embodiment, the cancer is a HER2-overexpressing, HER2-amplifying, and / or HER2-mutated (particularly HER2 exon 20 mutation) cancer selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0223] In other embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In further embodiments, the cancer is selected from lung cancers / tumors / carcinomas: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar epithelium), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma). In further embodiments, the cancer is NSCLC. In further embodiments, the cancer is HER2 exon 20 variant NSCLC.

[0224] In a further embodiment, the cancer is unresectable. In a further embodiment, the cancer is an unresectable HER2 exon 20 variant NSCLC.

[0225] In a preferred embodiment, the cancer is progressive or metastatic. In a more preferred embodiment, the cancer is progressive and metastatic. In a more preferred embodiment, if the cancer is metastatic, the metastases are located in the lungs, lymph nodes, bones, or liver. In a more preferred embodiment, the cancer is progressive cancer including metastases, and the metastases are located in the lungs, lymph nodes, bones, or liver. In addition or alternatively, the cancer may be unresectable.

[0226] In a preferred embodiment, the cancer is an unresectable, advanced cancer including a solid tumor and solid metastases, the metastases located in the lungs, liver, lymph node tissue, or bone.

[0227] In a preferred embodiment, the cancer is a solid, unresectable tumor and advanced NSCLC including metastases, the metastases located in the lungs, liver, lymph node tissue, or bone.

[0228] In a preferred embodiment, the cancer is a HER2 exon 20 variant progressive NSCLC including a solid, unresectable tumor and metastases, the metastases located in lung tissue, lymph node tissue, or bone.

[0229] In one embodiment, the cancer is advanced, unresectable, or metastatic NSCLC with a HER2 mutation, the HER2 mutation being located in the tyrosine kinase domain. Preferably, in this embodiment, compound (1) is administered as first-line therapy. More preferably, in this embodiment, compound (1) described herein is administered as second-line or subsequent-line therapy.

[0230] In this embodiment, the cancer is HER2-positive metastatic breast cancer. Preferably, in this embodiment, compound (1) described herein is administered as first-line therapy. More preferably, in this embodiment, compound (1) described herein is administered as second-line or subsequent-line therapy.

[0231] In this embodiment, the cancer is HER2-positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, compound (1) described herein is administered as first-line therapy. More preferably, in this embodiment, compound (1) described herein is administered as second-line or subsequent-line therapy.

[0232] In another embodiment, the cancer is resistant to treatment with an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate as defined herein. In yet another embodiment, the cancer is resistant to monotherapy with the anti-HER2 antibody or the anti-HER2 antibody-drug conjugate. In these embodiments, the resistance can be favorably overcome by treatment with compound (1), particularly when administered according to the dose / dosage regimen described herein.

[0233] The term “antibody,” which may be used interchangeably with “antibody molecule,” encompasses a variety of antibody structures, including polyclonal or monoclonal, chimeric, humanized, human, monospecific, bispecific, or multispecific antibodies, single-chain antibodies, single-domain antibodies, and fragmented antibodies (also called antibody fragments), e.g., Fab, F(ab)2, F(ab')2, Fab', single-chain variable fragments (scFv), or antibodies containing, but not limited to, the antigen-binding domain of an antibody, insofar as they exhibit the desired antigen-binding activity. The term “antibody” shall encompass complete immunoglobulins, such as those produced by lymphocytes and present in serum, e.g., monoclonal antibodies secreted by hybridoma cell lines, polypeptides produced by recombinant expression in host cells having binding specificity to immunoglobulins or monoclonal antibodies, and molecules derived from such immunoglobulins, monoclonal antibodies, or polypeptides by further processing while retaining their binding specificity. In particular, the term “antibody” includes complete immunoglobulins containing two heavy chains and two light chains. The term further encompasses immunoglobulin fragments, such as Fab fragments, and polypeptides having one or more variable domains derived from immunoglobulins, such as single-chain antibodies (scFv) and single-domain antibodies.

[0234] The term "antibody fragment" refers to a fragment of an antibody that retains its antigen-binding ability.

[0235] Antibodies may normally possess effector functions such as ADCC or CDC mediated by the antibody's Fc portion (antibody constant region), or they may lack effector functions, for example, by having an Fc portion that is absent, blocked, or masked, essentially an Fc portion that is not recognized or is poorly recognized by immune cells or components of the immune system, such as the complement system.

[0236] The antibody or its fragment may be of any type, such as IgA, IgD, IgE, IgG, or IgM. IgG is preferred.

[0237] As used herein, the terms “monoclonal antibody” or “monoclonal antibody composition” refer to an antibody molecule having a single amino acid composition, or a preparation of a homogeneous antibody population, i.e., a homogeneous population consisting of an entire immunoglobulin or its fragments or derivatives. Such antibodies may be selected from the group consisting of IgA, IgD, IgE, IgG, IgM, or their fragments.

[0238] A "recombinant antibody" is an antibody produced by a recombinant host cell. It can be optionally isolated or purified.

[0239] A "human antibody" is defined as an antibody produced by human cells, or an antibody possessing an amino acid sequence equivalent to that of an antibody derived from a non-human source utilizing the human antibody repertoire or other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0240] As used herein, the term “recombinant human antibody” is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from host cells such as NS0 or CHO cells, or from animals transgenic to human immunoglobulin genes (e.g., mice), or antibodies expressed using recombinant expression vectors transfected into host cells. Such recombinant human antibodies have variable and constant regions in their reconstituted form. Recombinant human antibodies may have been subjected to in vivo somatic hypermutation. Therefore, the amino acid sequences of the VH and VL regions of recombinant antibodies are derived from and related to human germline VH and VL sequences, but may not be naturally present in the human antibody germline repertoire in vivo.

[0241] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from a non-human hypervariable region (HVR) and amino acid residues derived from a human framework region (FR). In certain embodiments, a humanized antibody is considered to contain substantially all of at least one, typically two, variable domains, with all or substantially all of the HVR (e.g., complementarity-determining regions (CDRs)) corresponding to those of a non-human antibody, and all or substantially all of the FR corresponding to those of a human antibody. A humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0242] "Binding" of a polypeptide (such as an immunoglobulin, antibody, or generally an antigen-binding molecule, or a fragment thereof) means having "affinity for" or "specificity for" a particular epitope, antigen, or protein (or at least one part, fragment, or epitope thereof). The terms "binding" and "specific binding," referring to the binding of an antibody or antigen-binding portion to an antigen epitope, can be determined in an in vitro assay using purified wild-type antigen, preferably by a plasmon resonance assay (BIAcore®, GE Healthcare Uppsala, Sweden).

[0243] Generally, the term "specificity" refers to the number of different types of antigens or epitopes to which a particular antigen-binding molecule (such as an antibody as described herein) can bind. The specificity of an antigen-binding molecule can be determined based on its affinity and / or avidity. Affinity, expressed by the equilibrium constant (KD) for dissociation between the antigen and the antigen-binding protein, is a measure of the binding strength between the epitope and the antigen-binding site on the antigen-binding protein: the smaller the KD value, the stronger the binding strength between the epitope and the antigen-binding molecule (or affinity can also be expressed as an affinity constant (KA) of 1 / KD). As will be apparent to those skilled in the art, affinity can be determined in a manner known in the art, depending on the specific antigen of interest. Avidity is a measure of the strength of binding between the antigen-binding molecule containing it (such as an immunoglobulin, antibody, or generally an antigen-binding molecule or its fragment) and the associated antigen. Avidity relates to both the affinity between the epitope and its antigen-binding site on the antigen-binding molecule, and the number of associated binding sites present on the antigen-binding molecule.

[0244] An epitope is a region of an antigen to which an antigen-binding molecule (such as an antibody as described herein) can bind. The term “epitope” includes any polypeptide determinant that can specifically bind to an antibody or antigen-binding moiety. In certain embodiments, the epitope determinant includes a chemically active surface group of a molecule, such as an amino acid, glycan side chain, phosphoryl, or sulfonyl, and in certain embodiments, may have specific three-dimensional structural features and / or specific charge features. Stereostructural and non-stereostructural epitopes are distinguished in that binding to the former is lost in the presence of a denaturing solvent, while binding to the latter is not.

[0245] In this specification, the terms “variable domain,” “variable region,” or “Fv” refer to the respective light-chain and heavy-chain pairs directly involved in antibody binding to the antigen. The variable domain of the light chain is abbreviated as “VL,” and the variable domain of the heavy chain is abbreviated as “VH.” The variable light-chain and heavy-chain domains have the same general structure, and each domain contains four widely conserved framework (FR) regions connected by three HVRs (or CDRs). The framework regions adopt a beta-sheet three-dimensional structure, and the CDRs can form loops connecting the beta-sheet structures. The CDRs in each chain are held in their three-dimensional structure by the framework regions and, together with the CDRs from the other chain, form the antigen-binding site. The heavy-chain and light-chain CDR regions of the antibody play a particularly important role in the antibody's binding specificity / affinity.

[0246] In the context of this invention, references to CDRs are based on the definitions of Chothia (Chothia and Lesk, J. Mol. Biol. 1987, 196: 901-917) and Kabat (EA Kabat, TT Wu, H. Bilofsky, M. Reid-Miller and H. Perry, Sequence of Proteins of Immunological Interest, National Institutes of Health, Bethesda (1983)).

[0247] As used in this application, the terms “constant domain” or “constant region” refer to the totality of antibody domains other than the variable region. The constant region does not directly participate in antigen binding but exhibits various effector functions.

[0248] The “constant domains” used in the antibodies disclosed herein are preferably of human origin, and are derived from the constant heavy chain region and / or constant light chain kappa or lambda region of a human antibody of subclass IgG1, IgG2, IgG3, or IgG4. Such constant domains and regions are well known in the art and have been described, for example, by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, MD, Publication No. 91).

[0249] The "Fc portion" of an antibody, while not directly involved in the binding of the antibody to the antigen, exhibits various effector functions. The term "Fc portion of an antibody" is well-known to those skilled in the art and is defined based on the papain cleavage of the antibody. Depending on the amino acid sequence of the constant region of their heavy chain, antibodies or immunoglobulins are classified into classes IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, and IgG4, IgA1, and IgA2. According to the heavy chain constant region, the various classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The Fc portion of an antibody is directly involved in ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cell-mediated cytotoxicity) based on complement activation, C1q binding, and Fc receptor binding. Complement activation (CDC) is initiated by the binding of complement factor C1q to the Fc portion of most IgG antibody subclasses. The effect of antibodies on the complement system depends on specific conditions, but binding to C1q is triggered by a specific binding site in the Fc region. Such binding sites are known in the art, for example, Boackle, RJ, et al, Nature 282 (1979) 742-743; Lukas, TJ, et al, J. Immunol. 127 (1981) 2555-2560; Brunhouse, R., and Cebra, JJ, Mol. Immunol. 16 (1979) 907-917; Burton, DR, et al, Nature 288 (1980) 338-344; Thommesen, JE, et al, Mol. Immunol. 37 (2000) 995-1004; Idusogie, EE, et al, J. Immunol. 164 (2000) 4178-4184; Hezareh, M., et al, J. Virology 75 (2001). 12161-12168; Morgan, A., et al, Immunology 86 (1995) 319-324; described in European Patent No. 0 307 434.Such binding sites include, for example, L234, L235, D270, N297, E318, K320, K322, P331, and P329 (numbered according to the EU index of Kabat, EA; see below). Antibodies of subclasses IgG1, IgG2, and IgG3 typically exhibit complement activation and C1q and C3 binding, while IgG4 does not activate the complement system and does not bind to C1q and C3. As used herein, the term “domain” (of a polypeptide or protein) refers to a folded protein structure that has the ability to maintain its tertiary structure independently of the rest of the protein. Generally, domains are involved in the individual functional properties of a protein and can often be added to, removed from, or migrated to other proteins without loss of function of the protein and / or the rest of the domain.

[0250] The term "anti-HER2 antibody" refers to an antibody that binds to the HER2 protein, particularly specifically. Anti-HER2 antibodies inhibit HER2 activation or downstream signaling through various mechanisms. In non-limiting examples, anti-HER2 antibodies may block ligand binding, receptor activation, or receptor signaling; reduce HER2 expression or localize it to the cell surface; inhibit HER2 cleavage; or induce antibody-mediated cytotoxicity. In preferred embodiments, the term "anti-HER2 antibody" is therefore intended to be synonymous with and replaceable with "inhibitory antibody that specifically binds to HER2." Anti-HER2 antibodies used for cancer treatment are typically monoclonal, however, polyclonal antibodies are not excluded by this term. Preferably, anti-HER2 antibodies are selected from the group consisting of trastuzumab, pertuzumab, margetuximab, and combinations thereof.

[0251] Trastuzumab, also known as Herceptin, is a humanized IgG1 monoclonal antibody that binds to HER2, particularly to its extracellular domain, and especially to the HER2 domain that binds to another HER2 protein. The mechanism of action underlying the antitumor effect of trastuzumab has not yet been fully elucidated and may actually involve several different mechanisms. Trastuzumab may exert its effect by activating antibody-dependent cellular cytotoxicity, preventing HER2 dimerization, inhibiting cleavage of the extracellular domain of HER2, interacting with signal transduction pathways, arresting the cell cycle in G1 phase, inducing apoptosis, or inhibiting angiogenesis. HER2 downregulation has also been suggested as a possible mechanism. Trastuzumab is disclosed in, for example, International Publication No. WO 92 / 22653, which is incorporated herein by reference.

[0252] Pertuzumab, also known as Perjeta, is a humanized IgG1 monoclonal antibody that binds to HER2, particularly to the extracellular domain of HER2, and especially to the extracellular dimerization subdomain of the HER2 receptor. Pertuzumab reduces HER2 intracellular signaling by preventing HER2 from forming heterodimers with other HER receptors such as HER3. Pertuzumab is disclosed in, for example, U.S. Patent No. 6,949,245 and U.S. Patent No. 7,862,817, each of which is incorporated herein by reference.

[0253] Margetuximab, also known as Margenza, is a mouse / human chimeric IgG1 monoclonal antibody that binds to HER2, particularly to its extracellular domain, and especially to the HER2 domain that binds to another HER2 protein. Margetuximab is disclosed in, for example, U.S. Patent No. 8,802,093, which is incorporated herein by reference.

[0254] In another aspect, the anti-HER2 antibody is an inhibitory antibody. The expression "inhibitory antibody" is intended as a synonym for "antagonist antibody" and can be replaced by it. An "inhibitory antibody" or "antagonist antibody" within the meaning of the present invention is an antibody that inhibits the interaction between HER2 and its ligand or receptor.

[0255] In another aspect, the anti-HER2 antibody specifically binds to HER2.

[0256] In another aspect, the anti-HER2 antibody specifically binds to the extracellular domain of HER2.

[0257] In another aspect, the anti-HER2 antibody is an inhibitory antibody that specifically binds to HER2.

[0258] In another aspect, the anti-HER2 antibody is an inhibitory antibody that specifically binds to the extracellular domain of HER2.

[0259] In another aspect, the anti-HER2 antibody is selected from the group consisting of trastuzumab, pertuzumab, margetuximab, and combinations thereof.

[0260] In another aspect, the anti-HER2 antibody is selected from the group consisting of trastuzumab and pertuzumab.

[0261] The term “antibody-drug conjugate” (also abbreviated as “ADC” as used herein) is well known in the art and describes a group of therapeutic methods that combine the specificity of tumor target conjugates, such as antibodies, with the efficacy of highly cytotoxic agents. Thus, such conjugates of cytotoxic agents and / or cell proliferation inhibitors to tumor cell-specific antibodies are powerful tools for specifically targeting cancer cells for their destruction. ADCs are well known in the art and are outlined, for example, in Dumontet et al. 2023 (Dumontet, C., Reichert, JM, Senter, PD et al. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov 22, 641-661 (2023)).

[0262] In particular, as used herein, "anti-HER2 antibody-drug conjugate" refers to an ADC in which the tumor targeting conjugate is an antibody directed to, targeting, and / or binding to HER2, such as trastuzumab, pertuzumab, and margetuximab.

[0263] Therefore, the terms "anti-HER2 antibody-drug conjugate" and "anti-HER2 ADC" refer to an anti-HER2 antibody conjugated to a cytotoxic drug, also called a loading device, optionally via a linker. The anti-HER2 antibody in the ADC can deliver the loading device to HER2-expressing cells, particularly cells with high levels of HER2.

[0264] In another embodiment, the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody, which is an inhibitory antibody.

[0265] In another embodiment, the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody that specifically binds to HER2.

[0266] In another embodiment, the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody that specifically binds to the extracellular domain of HER2.

[0267] In another embodiment, the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody, which is an inhibitory antibody that specifically binds to HER2.

[0268] In another embodiment, the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody that specifically binds to the extracellular domain of HER2.

[0269] In another embodiment, the anti-HER2 antibody-drug conjugate comprises trastuzumab. In this embodiment, trastuzumab may be as defined above in any embodiment relating to the anti-HER2 antibody.

[0270] In another embodiment, the anti-HER2 antibody-drug conjugate is selected from the group consisting of trastuzumab deruxtecan and trastuzumab emtansine. In this embodiment, trastuzumab may be as defined above in any embodiment relating to the anti-HER2 antibody.

[0271] The terms “trastuzumab emtansine” or “adtrastuzumab emtansine,” also known as T-DM1 or Kadcyla, refer to an antibody-drug conjugate comprising the anti-HER2 antibody trastuzumab, a thioether linker, and the microtubule inhibitor emtansine or DM1, a derivative of maytansine, as the cytotoxic conjugate. The international generic name (INN) “trastuzumab emtansine” is published in WHO INN Recommendation List 65, which is incorporated herein by reference.

[0272] The term "trastuzumab deruxtecan," also known as T-DXd or Enhertu, refers to an antibody-drug conjugate comprising the anti-HER2 antibody trastuzumab, a linker, and deruxtecan or DXd, a topoisomerase I inhibitor derived from exatecan, as a cytotoxic conjugate. The international generic name (INN), "trastuzumab deruxtecan," is published in WHO's INN Recommendation List 78, which is incorporated herein by reference.

[0273] As used herein, INN is intended to include, but is not limited to, all biosimilar molecules having the same structure as the original (originator) antibody, particularly those having the same or substantially the same amino acid sequence, including, such biosimilar antibodies approved under 42 United States Code § 262(k) in the United States and equivalent regulations in other jurisdictions. As used herein, “biosimilar” means an antibody (isolated or as part of an ADC) or antigen-binding fragment having the same primary amino acid sequence as a reference antibody (e.g., trastuzumab) and optionally having detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) as a reference antibody (e.g., different sugar types).

[0274] As used herein, cancers that exhibit / develop or become "resistant" to therapy include cancers that are unresponsive to and / or exhibit a reduced ability to produce a significant response, such as partial response and / or complete response, to treatment with an anti-HER2 antibody or anti-HER2 antibody-drug conjugate. Resistance may be de novo (primary) resistance or acquired resistance that develops during the course of treatment. As used herein, the term "acquired resistance" indicates that a cancer becomes resistant and / or substantially less responsive to the effects of an anti-HER2 antibody or anti-HER2 antibody-drug conjugate as defined herein after exposure to it for a specific period of time.

[0275] Cancer can develop resistance to monotherapy with an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate. The mechanism of resistance can be due to the antibody or payload, can be receptor-related referring to target accessibility, or can be intracellular referring to regulation of intracellular signaling pathways and the like.

[0276] In one embodiment, the cancer is resistant to treatment with the payload of an anti-HER2 antibody-drug conjugate.

[0277] In one embodiment, the cancer is resistant to treatment with deruxtecan or emtansine.

[0278] Cancer that initially responded to an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate may relapse and become resistant to the anti-HER2 antibody or anti-HER2 antibody-drug conjugate if, for example, the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is no longer effective in treating a subject having the cancer despite administration of increased dosages.

[0279] Cancer can be refractory, recurrent, resistant or non-responsive to one or more anti-HER2 antibodies or anti-HER2 antibody-drug conjugates. Thus, a patient may have previously received prior anti-cancer therapy with one or more anti-HER2 antibodies or one or more anti-HER2 antibody-drug conjugates without having been completely cured of the disease.

[0280] Cancer having a relapse and / or having resistance to an anti-HER2 antibody or anti-HER2 antibody-drug conjugate may be particularly suitable for monotherapy with compound (1) in the second or subsequent line of treatment described herein.

[0281] Therefore, one embodiment refers to compound (1) for use in the treatment and / or prevention of cancer in which the cancer is resistant to treatment with an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate. In this embodiment, compound (1), the administration schedule (e.g., daily dose, frequency of administration, oral / tablet administration, use in a second or subsequent line, etc.), and the cancer may be described individually or together as in any embodiment or model disclosed herein.

[0282] Secondary or subsequent line of administration It was surprisingly discovered that the use of compound (1) following cancer therapy with at least one systemic anticancer agent has the potential to improve or stabilize clinical outcomes.

[0283] In preferred embodiments, at least one additional therapeutic agent is administered in the treatment line prior to or before compound (1) in the doses and dose regimens described herein. Alternatively, the method of treating a patient with cancer as described above includes administering compound (1) in the doses and dose regimens described herein in the treatment line after or following at least one additional therapeutic agent.

[0284] In a preferred embodiment, the additional therapeutic agent administered in the treatment line prior to or before the administration of compound (1) is selected from the group consisting of chemotherapeutic agents and systemic anticancer therapy agents. The additional therapeutic agent may be used in the treatment of cancer in addition to the administration of compound (1).

[0285] In preferred embodiments, systemic anticancer agents are administered in a treatment line prior to or before compound (1). In particular, one or more systemic anticancer agents may be administered in a treatment line prior to compound (1). In other words, it is preferable to treat cancer in a treatment line using compound (1) following or after the administration of a treatment line containing one or more systemic anticancer agents. These systemic anticancer agents may be administered as separate treatment lines or in combination with each other in the same line. Systemic anticancer agents administered additionally or prior to compound (1) in a treatment line may be used in combination with any other anticancer therapies different from compound (1), whether systemic or not. This means that compound (1) may be administered as a secondary line (where only one line of treatment including at least one systemic anticancer therapy is administered prior to compound (1)) or as a subsequent line (where more than one line of treatment including at least one systemic anticancer therapy is administered prior to compound (1)). In this embodiment, compound (1) is preferably administered in the doses and dosage regimens described herein.

[0286] In this context, the terms “after” and “following” mean that, provided there is no overlap between the first and second periods, an additional therapeutic agent, particularly a chemotherapeutic agent or systemic anticancer therapy agent, is administered in the first-line or preceding line of therapy during the first period, for example, over several hours, several days, or a week or more, in one or more doses, followed by the administration of compound (1) during the second period, for example, over several hours, several days, or a week or more, in one or more doses. In particular, it is preferable that the systemic anticancer therapy agent or chemotherapeutic agent and compound (1) are not administered on the same day. Also, in particular, once compound (1) has been administered, the administration of a single systemic anticancer therapy agent or chemotherapeutic agent is not restarted at the same dose (of the single systemic anticancer therapy agent or chemotherapeutic agent). The terms “after” and “following” do not require that compound (1) be administered immediately after or immediately following the line of therapy using the systemic anticancer therapy agent. Therefore, insofar as systemic anticancer therapy or chemotherapy is administered in the treatment line prior to compound (1), another line of therapy may be administered between the systemic anticancer agent or chemotherapy and compound (1). Preferably, the systemically detectable dose of the anticancer agent in the prior anticancer therapy is less than the established therapeutic effective dose before compound (1) is administered. In a more preferred embodiment, the selected daily dose and daily administration schedule of compound (1) may also be selected in accordance with one or all of the pretreatments using the systemic anticancer agent.

[0287] Those skilled in the art will recognize that the terms “before,” “prior,” “after,” and “subsequently” are used herein to refer to different and / or separate lines of therapy. In other words, any reference to the administration of compound (1) after or following systemic anticancer therapy or chemotherapy, even if this is not explicitly stated, is equivalent to a reference to the administration of compound (1) as a second or subsequent line after the administration of systemic anticancer therapy or chemotherapy.

[0288] When used herein, “secondary or subsequent line” and its grammatical variations have meanings known in the art. In particular, “secondary or subsequent line” and its grammatical variations may refer to the administration of compound (1) after, or following, a primary or preceding line of therapy that has failed, ceased to function, reduced efficacy, had unbearable side effects, or was only partially successful, in particular, the primary or preceding line of therapy which will not be administered to the patient again, according to the judgment of the attending physician. The expression “secondary or subsequent line administration” may be read as administration of a secondary line or a subsequent line of administration.

[0289] As used herein, “systemic anticancer therapy agent” may exist and be administered in the form of a single drug compound or a single active ingredient. The agent may also exist and be administered in the form of a combination of two or more drug compounds or active ingredients. Drug compounds may include small or large molecules, chemical elements such as platinum (Pt) metal complexes, biologics, and combinations thereof.

[0290] As used herein, the term "systemic anticancer therapy" includes the administration of at least one systemic anticancer therapy agent, either alone or in combination with another drug compound or active ingredient.

[0291] As used herein, the term “systemic” has a meaning that is generally derived therefrom in the art and therefore may refer to a route of administration that affects the whole body, in contrast to a local administration, in which the effect is generally local. Systemic administration may be enteral (e.g., via the gastrointestinal tract) or parenteral (e.g., via injection, infusion, implantation, etc.). Preferably, the systemic anticancer therapy is parenteral anticancer therapy.

[0292] When used herein, "chemotherapy agent" or "chemotherapeutic agent" may exist and be administered in the form of a single drug compound or a single active ingredient. The agent may also exist and be administered in the form of a combination of two or more drug compounds or active ingredients.

[0293] As used herein, the term "chemotherapy" includes the administration of at least one chemotherapeutic agent, either alone or in combination with another drug compound or active ingredient.

[0294] As used herein, the term "chemotherapy" has the meaning generally derived therefrom in the art, and therefore may refer to chemical agents or combinations of chemical agents useful in the prevention and / or treatment of cancer, in particular, such agents or combinations being or containing cytotoxic agents and / or cell proliferation inhibitors.

[0295] Preferably, the chemotherapy is administered systemically, i.e., it is systemic chemotherapy.

[0296] In preferred embodiments, the systemic anticancer therapy agent is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, taxanes, antimetabolites, immunotherapeutic agents, and combinations thereof. Preferably, the term “combinations thereof” may include separate administrations of two or more members of the list at different time intervals or at different time points as different lines of therapy, or administration of a combination of two or more members of the list in the same line of therapy. A combination may include, for example, a primary line treatment including a platinum-based chemotherapy agent preceding treatment based on compound (1), and then a secondary line treatment based on an ADC, preferably an anti-HER2-ADC, or vice versa. The combination may be in a planned order or may be performed depending on the outcome of the treatments.

[0297] As used herein, the expression “platinum-based chemotherapy” and its grammatical variations have meanings generally derived in the art and may therefore refer to one or more chemotherapeutic agents comprising platinum (Pt). Preferred platinum-based chemotherapeutic agents include oxaliplatin, carboplatin, and / or cisplatin. More preferred platinum-based chemotherapeutic agents include carboplatin and / or cisplatin.

[0298] The anti-HER2 antibody-drug conjugate may be as defined above. A preferred anti-HER2 antibody-drug conjugate includes trastuzumab deruxtecan and / or trastuzumab emtansine.

[0299] As used herein, the term “taxane” and its grammatical variations have meanings generally derived to them in the art and therefore may refer to diterpenes having a taxadiene core. Taxanes typically act as mitotic inhibitors, specifically as disruptors of microtubule function. Preferred taxanes include cabazitaxel, larotaxel, tesetaxel, docetaxel, and / or paclitaxel. More preferred taxanes include docetaxel and / or paclitaxel.

[0300] As used herein, the term “antametabolite” and its grammatical variations have meanings generally derived to them in the art and may therefore refer to one or more active substances that interfere with intracellular metabolic processes. Specifically, anantametes can inhibit metabolites. Preferred anantametes include 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, phloxuridine, fludarabine, hydroxycarbamide, methotrexate, phototrexate, gemcitabine, pemetrexed, and / or tegafur. More preferred anantametes include gemcitabine, pemetrexed, and / or tegafur.

[0301] As used herein, the terms “immunotherapy,” “immunotherapy agent,” and their grammatical variations have meanings generally derived therefrom in the art and may therefore refer to one or more active substances that interfere with (e.g., activate or suppress) the immune system and thereby contribute to the prevention and / or treatment of cancer. Preferred immunotherapy agents include semiprimab, dostallimab, trastuzumab, pertuzumab, margetuximab, pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab, and / or ramucirumab. More preferred immunotherapy agents include pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab, and / or ramucirumab.

[0302] In a preferred embodiment, the systemic anticancer therapy agent is selected from the group consisting of carboplatin, cisplatin, trastuzumab deruxtecan, trastuzumab emtansine, pemetrexed, docetaxel, paclitaxel, gemcitabine, pembrolizumab, durvalumab, tremelimumab, ramucirumab, atezolizumab, tegafur, nivolumab, ipilimumab, and combinations thereof.

[0303] In a preferred embodiment, the systemic anticancer therapy agent is selected from the group consisting of carboplatin, cisplatin, trastuzumab deruxtecan, trastuzumab emtansine, pemetrexed, docetaxel, paclitaxel, gemcitabine, pembrolizumab, durvalumab, tremelimumab, ramucirumab, atezolizumab, tegafur, nivolumab, and ipilimumab.

[0304] In a preferred embodiment, the systemic anticancer therapy agent comprises or consists of an anti-HER2 antibody-drug conjugate.

[0305] In a preferred embodiment, the systemic anticancer agent is trastuzumab deruxtecan and / or trastuzumab emtansine.

[0306] In a preferred embodiment, the systemic anticancer therapy agent includes platinum-based chemotherapy.

[0307] In a preferred embodiment, the systemic anticancer therapy agent includes pembrolizumab, pemetrexed, and / or platinum-based chemotherapy.

[0308] In a preferred embodiment, the systemic anticancer therapy agents include pembrolizumab, pemetrexed, and platinum-based chemotherapy.

[0309] In a preferred embodiment, the systemic anticancer therapy agent includes pembrolizumab, pemetrexed, and cisplatin.

[0310] In a preferred embodiment, the systemic anticancer therapy agent includes pembrolizumab, pemetrexed, and carboplatin.

[0311] In a preferred embodiment, the systemic anticancer therapy agent comprises pembrolizumab and / or pemetrexed.

[0312] In a preferred embodiment, the systemic anticancer therapy agent comprises standard care therapy, optionally followed by maintenance therapy. The standard care therapy may include a combination of pembrolizumab, pemetrexed, and platinum-based chemotherapy, which is optionally administered once every three weeks for one or more doses, preferably one, two, three, or four doses, more preferably four doses. The maintenance therapy may include a combination of pembrolizumab and pemetrexed, which is optionally administered once every three weeks for one or more doses.

[0313] In a more preferred embodiment, the following

[0314] [ka] Compound (1) as defined herein is for use in the treatment of cancer, and compound (1) is administered in the treatment line after the administration of chemotherapy or systemic anticancer therapy agents. Alternatively, in a preferred embodiment, a method of treating a patient with cancer includes administering compound (1), and compound (1) is administered in the treatment line after the administration of chemotherapy or systemic anticancer therapy agents. Preferably, in these embodiments, compound (1) is administered according to the doses and dose regimens described above herein. In addition or alternatively, in these embodiments, the cancer and / or systemic anticancer therapy agents may be as defined herein. Preferably, the systemic anticancer therapy agent is a specific HER2 systemic anticancer therapy agent, such as an anti-HER2 antibody-drug conjugate, for example, one defined above.

[0315] In preferred embodiments, compound (1) is used in the treatment of cancer at least 21 days after the last day of administration of chemotherapy or systemic anticancer therapy. Alternatively, in preferred embodiments, a method of treating a patient with cancer includes administering compound (1), which is administered at least 21 days after the last day of administration of chemotherapy or systemic anticancer therapy. In these embodiments, compound (1) is preferably administered for at least 21 consecutive days, or for 21 days multiplied by X, where X is a natural number of 1 or more.

[0316] Pharmaceutical composition The following for use in cancer treatment:

[0317] [ka] Provided herein is a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in a daily dose of at least 30 mg. Alternatively, a method is disclosed for treating a patient with cancer, comprising administering a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in a daily dose of at least 30 mg. Preferably, in these embodiments, compound (1) is administered according to the doses and dose regimens described above herein. Also preferably, in these embodiments, the cancer is as defined herein (in any aspect or embodiment). All embodiments described above relating to compound (1) for use in the treatment of cancer, or a method for treating a patient with cancer using compound (1), are applicable to pharmaceutical compositions for use in the treatment of cancer, or a method for treating a patient with cancer using a pharmaceutical composition.

[0318] The term "pharmaceutically acceptable excipient" refers to a non-toxic component that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutical compositions may contain conventional non-toxic pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that may be used in the compositions of the present invention include fillers, disintegrants, flow enhancers, lubricants, and coatings. Compositions may also contain further pharmaceutically acceptable excipients selected from buffers, dispersants, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives usable in the manufacture of pharmaceutical products.

[0319] In a preferred embodiment, compound (1) or the pharmaceutical composition is administered orally. Compound (1) or the pharmaceutical composition may be administered as tablets, hard or soft gelatin capsules, pills, granules, or suspensions. In a preferred embodiment, compound (1) or the pharmaceutical composition is in the form of tablets.

[0320] Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which the present invention pertains.

[0321] The following embodiments are helpful in illustrating the present invention in more detail, but do not constitute a limitation thereof. [Examples]

[0322] Example 1 - An open-label Phase I dose-escalation study, combined with dose confirmation and expansion, of compound (1) as monotherapy in patients with unresectable, progressive, and / or metastatic solid tumors with HER2 abnormalities. 1.1 Protocol: This is a first-in-human dose-escalation and expansion study to determine the maximum tolerated dose (MTD) of compound (1) as monotherapy in patients with HER2-positive, unresectable, advanced, and / or metastatic solid tumors, and to investigate the safety, pharmacokinetics, pharmacodynamics, and first signs of efficacy.

[0323] The dose-escalation part of the study (also referred to as Phase Ia) includes a successive cohort of patients treated with the escalating dose of compound (1).

[0324] 1.1.1 Purpose: The main objectives of the dose escalation portion of the study are as follows: - To investigate the safety, tolerability, and pharmacokinetics (PK) of compound (1) as an orally administered monotherapy twice daily (BID) or once daily (QD) in patients with advanced and / or metastatic solid tumors with HER2 abnormalities; - Determine the MTD and / or recommended Phase II dose (RP2D, equivalent to the dose recommended for dose expansion in Phase Ib, see Example 3) of orally administered compound (1) monotherapy for each study regimen.

[0325] 1.1.2 Evaluation Criteria: The primary endpoints for the dose-escalation portion of the study are as follows: - MTD is defined as the highest dose with a risk of less than 25% during the MTD evaluation period in any research regimen, where the true dose-limiting toxicity (DLT) rate is 33% or greater; - Number of patients with DLT during the MTD evaluation period.

[0326] The MTD evaluation period is defined as the first 21 days of treatment (first cycle).

[0327] The secondary endpoints for the dose escalation portion of the study are as follows: - Number of patients who experienced DLT during the entire treatment period; - The following PK parameters for compound (1) after the first and subsequent doses of the compound on days 1 and 15 (if feasible): ·C max : Maximum measurable concentration of compound (1) in plasma; AUC 0-t2 Area under the concentration-time curve of compound (1) in plasma.

[0328] If evaluable and applicable, the following further evaluation criteria will be assessed: - Number of patients who experienced adverse events (AEs) during the treatment period; - Objective response (OR) is defined as the best overall response of complete response (CR) or partial response (PR), determined according to RECIST version 1.1, assessed by the principal investigator from the first treatment dose to the earliest of disease progression, death, last evaluable tumor assessment before initiation of subsequent anticancer therapy, loss of follow-up, or withdrawal of consent; - Disease control (DC) is defined as the best overall response of complete response (CR), partial response (PR), or stable disease (SD), as defined in RECIST version 1.1, where the best overall response is assessed by the principal investigator until the earliest of disease progression, death, the last evaluable tumor assessment before the initiation of subsequent anticancer therapy, loss of follow-up, or withdrawal of consent; - Duration of Objective Response (DoR), defined as the time from the first documented complete response (CR) or partial response (PR) to the earliest occurrence of disease progression or death among patients with an objective response; - Duration of Disease Control (DoDC), defined as the time from the first administration of treatment to the earliest occurrence of disease progression or death among patients with disease control; - Tumor shrinkage according to RECIST 1.1, defined as the best (smallest) percentage change from baseline in the sum of the longest diameters of target lesions evaluated by the investigator for all tumor assessments during treatment; - If data permit, PK parameters to be calculated for compound (1) as monotherapy shall include the following: · AUC 0-∞ : Area Under the Curve of the plasma concentration-time curve over the time interval extrapolated from 0 to infinity; · AUC 0-tz : Area Under the Curve of the plasma concentration-time curve over the time interval from 0 to the last measurement time point (t z ); · C min : Minimum measured plasma concentration in plasma; · t 1 / 2 : Terminal phase half-life of the analyte in plasma; · t max : Time from dosing to C max in plasma.

[0329] 1.1.3 Dose Escalation Dose escalation will be conducted according to the open-label design. Data obtained from the trial will be used to determine the MTD estimate based on a Bayesian logistic regression model with overdose control (BLRM) (Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008; 27:2420-2439). The BLRM estimates the MTD by updating the estimate of the probability of observing DLT during the MTD evaluation period for each dose level in the trial, taking into account updated DLT information from both schedules as patient information becomes available. At any point in the trial, dose escalation to a dose that does not satisfy the EWOC principle is not permitted. Dose escalation is limited to the maximum 100% increase from the previous dose. Dose escalation and cohort size will be based on decisions of the Dose Elevation Committee (DEC), guided by the BLRM.

[0330] The dose-escalation part of the study tests BID and QD dosing schedules for compound (1) within a single BLRM using a covariate (to distinguish between BID and QD). In the BID schedule, the cycle has a duration of 3 weeks (i.e., 21 days) and compound (1) is administered twice daily (BID), while in the QD schedule, the cycle has a duration of 3 weeks (i.e., 21 days) and compound (1) is administered once daily. The study begins with the BID schedule; the QD schedule is initiated after a dose level one level above the predicted human treatment dose is determined to be safe by DEC. If this QD cohort is deemed safe, the next BID dose level is released.

[0331] From this point onward, all dose-level cohorts are alternately released between BID and QD schedules (see Figures 1A and 1B). The BID dose cohorts are filled first, and then moved down to the equivalent QD cohorts.

[0332] A successive cohort of patients receives increasing doses of compound (1) until the MTD is reached. After all patients in the cohort have experienced a DLT, or have been observed for 21 days without experiencing a DLT, the BLRM is updated with newly accumulated data from both schedules. The risk of overdose is then calculated for each dose, and dose escalation is permitted for all doses that meet the EWOC criteria. For each dosing schedule, based on the model and additional information (PK, pharmacodynamics, patient profiles, and information from the other dosing schedule), members of the DEC reach a joint decision regarding the next dose level and the size of the next cohort to be considered. The pre-specified dose levels are provisional, and intermediate levels may be examined if the DEC deems it necessary.

[0333] All cohorts include at least three patients. If only two patients in a cohort are evaluable (i.e., one patient is unevaluable) and neither has experienced a DLT within the MTD evaluation period, dose escalation may occur based on these two patients.

[0334] If a dose level (DLT) is observed in the first two consecutive patients at a previously untested dose level, subsequent enrollment in that cohort will be discontinued. The BLRM will be updated to confirm that the dose level still meets the EWOC principle. Based on this information, the DEC will evaluate whether to enroll subsequent patients at the same dose level or at a lower dose level.

[0335] No further dose escalation will be performed after the criteria for MTD are met. Additional patients may be included to confirm this MTD estimate, i.e., to confirm that the EWOC criteria are still met. The DEC may declare any dose that meets the EWOC criteria as the RP2D, regardless of the MTD estimate. The RP2D will not exceed the MTD. Any DLTs that occur after the MTD evaluation period will be taken into consideration in the evaluation of the RP2D for compound (1). If no DLTs are observed, the DEC may decide to declare the RP2D based on the PK / pharmacodynamic endpoints and the overall safety profile. MTD and RP2D are defined separately for both schedules.

[0336] If a selective dose for dose expansion is declared at the end of dose escalation, and if agreed upon with the DEC, the dose escalation may remain open to the inclusion of patients who are not eligible for dose expansion at the selective dose in the clinical setting participating in the dose escalation.

[0337] The RP2D for compound (1) administered as monotherapy in BID and QD is determined based on DLT / MTD (if reached), all safety data, and, where data allows, PK and PK / pharmacodynamics collected during the study. If DLT or MTD is not reached, the RP2D is determined based on safety data (i.e., overall tolerability and incidence of severe toxicity), and, where data allows, PK and PK / pharmacodynamics. The RP2D does not need to be the same in the two schedules (BID and QD). BLRM is performed based on extended data including all DLT-like events throughout the entire treatment period, as well as on each treatment schedule individually, to further guide the selection of the RP2D.

[0338] Before reaching the MTD / before the dose escalation is complete, the RP2D may be defined and the dose expansion phase may be initiated.

[0339] Patients may continue treatment with compound (1) until disease progression (PD) occurs according to RECIST, or until there is another reason requiring the discontinuation of treatment.

[0340] 1.1.4 Dosage: The starting dose for the dose escalation phase of the study is as follows: - BID schedule: 15 mg twice daily (i.e., a total daily dose of 30 mg) - QD schedule: 60 mg once daily (unless otherwise suggested by DEC)

[0341] The dose escalation process is determined by DEC.

[0342] Predicted human doses for compound (1) were derived from a quantitative pharmacokinetic / tumor growth inhibition (PK / TGI) model. This preclinical mathematical model was constructed using input data from internal in vitro experiments and in vivo data from efficacy experiments in PC-9 YVMA xenografts. The model was trained using unbound in vitro cell efficacy, plasma exposure, and tumor growth inhibition data from mice. Comprehensive pharmacokinetic profiling of compound (1) in vitro and in vivo using mice, rats, dogs, and miniature pigs enabled the prediction of human PK parameters. Using the predicted human PK parameters, human plasma profiles were simulated and incorporated into the preclinical PK / TGI model. In this setting, the PK / TGI model was used to predict and identify the required human dose to achieve TGI > 100%. This was predicted for 40 mg BID and 80 mg QD (predicted human effective dose). In other words, exposure to human doses of 40 mg BID and 80 mg QD was estimated to be sufficient to achieve >100% tumor growth inhibition in patients.

[0343] 1.1.5 Patient The dose-escalation part enrolls patients with advanced, unresectable, and / or metastatic solid tumors that are refractory to or unsuitable for standard therapy for the disease and are eligible. Patients must also have exhausted all known treatment options for extending their survival for the disease. These patients should also show a confirmed positive diagnosis of HER2 abnormality (described as overexpression according to standard diagnostic criteria, or gene amplification according to standard diagnostic criteria, or non-synonymous somatic mutation, or gene rearrangement involving HER2 or NRG1).

[0344] Based on provisional dose levels and escalation schemes, the initial plan was to enroll approximately 66 patients in the dose escalation part of the study (approximately 36 patients for the BID and approximately 30 patients for the QD dosing schedule). This increased to approximately 96 patients (approximately 36 patients for the BID and approximately 60 patients for the QD dosing schedule). The total number of patients depends on the number of dose escalations required.

[0345] All patients, including those deemed eligible for the study based on field testing, must provide tumor samples for confirmation of their HER2 status.

[0346] Main inclusion criteria: - Patients with a confirmed diagnosis of progressive, unresectable, and / or metastatic nonhematological malignancy, having at least one measurable or evaluable lesion. Patients must demonstrate the presence of at least one measurable lesion according to RECIST 1.1. - Eastern Cooperative Oncology Group score of 0 or 1 - Availability and willingness to provide samples of formalin-fixed paraffin-embedded (FFPE) tumor tissue material from the archive to confirm the patient's HER2 status. - The patient must be willing and capable of complying with blood sampling and tumor biopsy requirements for PK, pharmacodynamics, and biomarker analysis. - Appropriate organ function measured routinely in the field - At the start of treatment, recovery from any previous therapy-related toxicity to ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 (except for alopecia, stable sensory neuropathy, and hypothyroidism (in patients undergoing thyroid replacement therapy), which must be ≤ CTCAE Grade 2). - In the opinion of the principal investigator, the mean life expectancy at least 12 weeks at the start of the procedure. - At least 18 years old at the time of consent, or older in countries where the legal age of consent is higher than 18. - Informed consent signed and dated in accordance with the International Council on Harmonisation for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Good Clinical Practice (ICH-GCP) and local laws prior to enrollment in the trial. - Male or female patients. Women of childbearing age (WOCBP) and men capable of fathering children must be prepared and able to use highly effective methods of contraception that, when used consistently and correctly, result in a low failure rate of less than 1% per year, in accordance with ICH M3(R2). - Patients with documented abnormalities of the HER2 gene, including overexpression by immunohistochemistry (IHC), gene copy number increase by insight hybridization (ISH), non-synonymous gene mutations, or gene fusion of the HER2 or NRG-1 gene. - Patients who have failed conventional treatments, for whom no proven effective therapy exists, or who are ineligible for established treatment options. Patients must have exhausted all known and available treatment options to extend their survival for their disease, or for which there are no suitable candidates.

[0347] Main exclusion criteria: - Major surgery (as determined by the investigator) performed within 4 weeks prior to the first study procedure, or planned within 6 months after screening. - Previous or concurrent malignancies within the past two years that were not treated in this study, except for the following: ○ Effectively treated non-melanoma skin cancer, ○ Effectively treated intraepithelial carcinoma of the cervix ○ Effectively treated ductal carcinoma in situ ○ Other malignant tumors that have been effectively treated and are considered to be curable by local treatment. - Systemic anticancer therapy or treatment with the investigational drug within 21 days of the first treatment with compound (1) or within 5 half-lives (whichever is shorter) - Patients who must or wish to continue taking restricted medications or any medications that are thought to potentially interfere with the safe conduct of the study.

[0348] As those skilled in the art will recognize, further inclusion and exclusion criteria may apply.

[0349] Patients may, as a whole, discontinue the study treatment or withdraw their consent to participate in the study.

[0350] 1.1.6 Compounds: Compound (1) is administered as a film-coated tablet. This formulation was developed in three dose strengths: 5 mg (approximately 10 mm round), 20 mg (approximately 10 mm round), and 100 mg (oval, approximately 16 x 7 mm). In addition to the drug substance, the tablets contain standard pharmaceutical excipients in typical amounts.

[0351] 1.1.7 Assessment of efficacy: Tumor evaluation should include computed tomography (CT) scans (or PET / CT) of the chest, abdomen / pelvis, and brain MRI at screening. Where clinically indicated, imaging of any other known or suspected disease sites (e.g., bone) should be performed using an appropriate method (CT scan, MRI, PET / CT, or bone scan). The same radiological procedure must be used throughout the trial. Evaluations should be performed at screening (≤28 days before the start of the procedure), every two cycles (6 weeks ± 5 days), at the end-of-treatment (EOT) examination (if not performed within the past 3 weeks), and, at the discretion of the principal investigator, by the principal investigator, with copies to be collected by the sponsor or designated. The evaluation schedule should not be altered whenever possible, but if there is a pause or delay in the procedure, changes to the tumor evaluation schedule to align with clinical evaluations are permitted. Additional unscheduled tumor evaluations may be performed at the discretion of the principal investigator. If a patient discontinues the investigational drug for reasons other than disease progression, tumor assessment in accordance with RECIST v1.1 will continue until disease progression occurs (or until one of the following occurs: death, loss of follow-up, or termination of the study).

[0352] The patient's clinical condition will be assessed on-site by each principal investigator. Clinical deterioration must be due to underlying tumor progression and not to comorbidities or concomitant medications. In cases of tumor-related clinical exacerbation, all efforts should be made to confirm disease progression through imaging tests.

[0353] Tumor response is assessed according to RECIST version 1.1 (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228-247). RECIST 1.1 is used for a) systemic assessment (classical RECIST 1.1) and b) tumor assessment of non-CNS areas. Assessment according to classical RECIST 1.1 by the principal investigator and / or on-site radiologist is the basis for continuing or discontinuing the study in individual patients (in addition to safety). Systemic RECIST assessment is not performed in the dose-escalation part.

[0354] Baseline imaging should include images of all known or suspected disease sites using an appropriate method. The principal investigator (or designated investigator) should record targeted and non-target lesions in a case report form (CRF or eCRF). Lesions in previously irradiated areas may not be considered measurable at baseline unless the lesions arose after irradiation. Throughout the procedure and during follow-up, the same assessment methods and imaging techniques must be used at each subsequent point in time to characterize each reported lesion.

[0355] 1.1.8 Safety Assessment: Physical examinations, including height (screening only) and weight measurements, are performed at screening, on day 1 of each treatment cycle, at the end-of-treatment (EOT) examination, and at the 30-day safety follow-up examination. However, patients will have a brief physical examination (focusing on specific diseases, at the discretion of the principal investigator) on day 1 of cycle 1 (if the previous physical examination was performed within 72 hours of the start of treatment) and on day 15 of cycle 1.

[0356] A thorough physical examination helps assess overall health and also serves as a clinical tumor assessment, and may include, but is not limited to, cardiopulmonary examination, regional lymph node and abdominal examination, as well as assessment of mental and neurological status. Any additional symptoms not reported during the previous examination should be identified. Whenever possible, the same principal investigator should perform this examination.

[0357] A limited physical examination should include cardiopulmonary examination, clinical tumor assessment, local lymph node examination, and abdominal examination.

[0358] 1.1.9 Assessment of adverse events: An adverse event (AE) is defined as any troubling medical event in a patient or clinical trial participant who has been administered a drug, and it does not necessarily have to be causally related to the treatment.

[0359] Therefore, an adverse event (AE) can be any undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of a drug, whether or not it is considered to be related to the drug.

[0360] A serious adverse event (SAE) is defined as any AE that meets at least one of the following criteria: - to cause death - This refers to an event in which the patient was at risk of death at the time of the event; in more severe cases, it does not refer to an event that could have potentially caused death, but is fatal. - Patients requiring hospitalization or extension of existing hospitalization, - resulting in a permanent or serious physical disability or incapacity, - It is a congenital anomaly / birth defect. - Any other reason that, based on appropriate medical judgment, is a significant medical event that could endanger the patient and require medical or surgical intervention to prevent one of the other consequences listed above, shall be considered serious.

[0361] Examples of such events include intensive care in an emergency room or at home for allergic bronchospasm, blood disorders, or seizures that do not result in hospitalization or the development of dependence or abuse.

[0362] Using medical judgment, a reasonable possibility of a causal relationship between the adverse event and compound (1) should be determined by considering all relevant factors, including confounding factors such as the pattern of the reaction, the temporal relationship, discontinuation or readmission of the drug, concomitant medications, comorbidities, and relevant medical history.

[0363] The following arguments may suggest a reasonable possibility of causality: - The phenomenon is consistent with the known pharmacological properties of the drug. - It is publicly known that the event is caused by or resulting from a class of drugs. - The reasonable time from drug exposure to the onset of an event. - Evidence that the event is reproducible if the drug is reintroduced. - There is no medically plausible alternative etiology that could explain the event (e.g., pre-existing or co-existing conditions, or concomitant medications). - The event is typically drug-related and rare in the general population that has not been exposed to drugs (e.g., Stevens-Johnson syndrome). - A measure of dose-response (i.e., a larger effect size when the dose increases, and a smaller effect size when the dose decreases).

[0364] The following arguments may suggest that there is no reasonable possibility of a causal relationship: - The reasonable time interval between drug exposure and the onset of an event is not clear (e.g., diagnosis of cancer or chronic disease within a few days / weeks of drug administration before treatment; allergic reaction several weeks after discontinuation of the drug in question). - Persistence of the event despite the withdrawal of the drug, taking into account the pharmacological properties of the compound (e.g., after 5 half-lives). It should be noted that this criterion may not be applicable to events where the time course is prolonged despite the removal of the original trigger. - Additional arguments to those previously mentioned, such as alternative explanations (for example, situations in which another drug or underlying condition is thought to offer a more plausible explanation for the observed event than the drug in question). - Disappearance of the event despite the continued or unchanged treatment with the test drug.

[0365] The principal investigator will maintain and store detailed records of all adverse events (AEs) in the patient profile.

[0366] 1.1.10 Pharmacokinetic assessment: The pharmacokinetic (PK) profile of compound (1) will be examined after the initial dose and after repeated doses. Standard PK parameters will be calculated where the data allows and where it is scientifically reasonable.

[0367] Individual concentration data and their calculated PK parameters will be presented in tables and graphs. Statistical analysis will be performed. In the event of protocol violations related to PK evaluation (which should be decided without delay beyond the reporting planning meeting) or in the event of inability to evaluate PK (which will become apparent during data analysis based on the criteria specified below), the patient's PK data will be flagged and excluded from the statistical analysis. The reasons for excluding patient data will be documented in the Clinical Trial Report (CTR).

[0368] If the data allows, the pharmacokinetic parameter C of compound (1) should be used to reach a steady state. max ( ,ss ), AUC 0-t2 ( ,ss The drug interactions (PK) are evaluated from the perspective of dose-proportionality. If deemed necessary, additional PK parameters may be used in these evaluations.

[0369] A preliminary PK analysis may be performed as needed for DEC determination. The final preliminary analysis is performed at the end of the dose escalation phase, before proceeding to the dose expansion phase. In contrast to the final PK analysis, the preliminary analysis is based on planned sampling times rather than actual times; supplemental patient information, such as adverse events or concomitant medications, is not used in these analyses, and the outputs are not validated. Therefore, slight differences may occur between the preliminary and final results.

[0370] 1.1.11 Compliance: Patients are asked to bring all remaining test medication, including empty packaging materials, with them when they visit the clinic.

[0371] Based on the number of tablets taken, adherence to the treatment is calculated as shown in the formula below. Medication interruptions in accordance with the protocol (e.g., medication interruptions due to adverse events) are not included in the calculation. Adherence is verified by a Clinical Research Monitor (CRA) approved by the sponsor or agent.

[0372]

number

[0373] A compliance rate of 80-120% is considered good.

[0374] 1.1.12 Statistical methods: Dose escalation is guided by BLRM with overdose control (EWOC) fitted to binary toxicity outcomes (DLT). As data accumulates using BLRM, parameter estimates are updated. At the end of the dose escalation period, toxicity probabilities at each dose level are calculated to determine the estimated MTD.

[0375] 1.1.13 Clinical Trial Plan All patients should adhere to their appointment schedule. If a treatment administration is delayed at any point, the schedule for all subsequent appointments / cycles will be recalculated based on the actual date of treatment. For business planning reasons, appointments may extend over more than one day, provided that all evaluations fall within the window defined by the sponsor, i.e., within ±1 or ±2 days of the scheduled evaluation.

[0376] Each examination and evaluation will be conducted within the permitted window. Additional flexibility (e.g., to accommodate holidays and patient inconvenience) may be permitted if agreed upon between the principal investigator and the sponsor.

[0377] If a patient misses an appointment, the appointment should be rescheduled as soon as possible, and the missed appointment should be documented along with the actual date and reason for the delay. Since subsequent appointment schedules should not be altered, rescheduling before the next planned appointment is not possible, and the missed appointment should be skipped.

[0378] If a patient is hospitalized for administrative reasons to allow for treatment and PK sampling, this is not considered a SAE unless any other criteria for SAE are met.

[0379] In addition to scheduled assessments, unscheduled consultations and assessments for safety reasons may be performed at any time as needed.

[0380] In the event of force majeure or other catastrophic circumstances (e.g., pandemic, war), the field should adhere to the required protocol procedures as much as possible. However, if a patient is unable or unwilling to receive a clinic consultation (due to force majeure or other catastrophic circumstances such as a pandemic or war), the principal investigator must assess the risk-benefit ratio for the individual patient and may decide to conduct the consultation remotely if this is in the best interest of the patient and agreed upon with the sponsor. All deviations from the original schedule of consultations and procedures will be documented, and the anticipated impact will be taken into consideration in the analysis of the trial data.

[0381] Following informed consent, the patient undergoes a screening assessment. The assessment must fall within an acceptable screening consultation window, but does not need to be performed on the same day. Screening assessments may be repeated, provided they fall within the screening consultation window. If more than one screening assessment is available, eligibility must be assessed using the most recent assessment prior to the commencement of treatment.

[0382] If a patient meets the eligibility criteria during screening, an initial treatment consultation will be scheduled. Any baseline conditions present at the time of the screening consultation should be reported to the eCRF.

[0383] Eligible patients will receive compound (1) daily until the criteria for discontinuation of treatment are met.

[0384] The patient may continue treatment in unlimited cycles until the criteria for discontinuing the treatment are met, for example, as long as the patient experiences clinical benefit, or until excessive drug toxicity occurs or consent is withdrawn, whichever comes first.

[0385] If a decision is made to permanently discontinue a treatment during the trial, no further administration of the investigational drug should be given, and an end-of-treatment (EOT) examination should be conducted within 7 days of the decision. If a decision to permanently discontinue the investigational treatment is made during a scheduled examination, an EOT examination should be conducted instead of the scheduled examination.

[0386] In the dose-escalation phase of the study, follow-up consultations (FUs) are conducted at least 30 days after permanent discontinuation of compound (1) and are primarily for collecting follow-up safety information. Individual patients who complete a follow-up consultation are considered to have completed the study.

[0387] 1.2. Results: The study design is shown in Figure 1. The data related to the trial are summarized as a whole and pooled against the QD and BID schedules, as well as against the doses selected for the dose expansion part of the trial. The data lock point is March 2023 in the following paragraphs under 1.2.1, 1.2.2, 1.2.3, 1.2.4, 1.2.5, 1.2.6, and 1.2.7, including Tables 1-7.

[0388] 1.2.1 Safety At the data lockpoint, safety data were available from 43 patients (Tables 1-3). Patients were treated with compound (1) monotherapy administered in escalating doses using either a twice-daily (BID, 17 patients) or once-daily (QD, 26 patients) schedule. In the BID schedule, the starting dose was 15 mg twice daily (N=3), with 30 mg BID (N=3), 60 mg BID (N=4), 100 mg BID (N=4), and 150 mg BID (N=3) also being investigated. In the QD schedule, the starting dose was 60 mg once daily (N=5), with 120 mg QD (N=4), 180 mg QD (N=6), 240 mg QD (N=6), and 300 mg QD (N=5) also being investigated.

[0389] At the time of data lock-up, 17 out of 43 treated patients (39.5%) had discontinued the study treatment for 11 (25.6%) due to objective disease progression, 3 (7.0%) due to clinical disease progression, and 1 (2.3%) due to patient withdrawal and "other" reasons. 26 patients (60.5%) were still undergoing treatment.

[0390] 1.2.2 Exposure and Population Composition A total of 43 patients were treated with compound (1). Overall, the median treatment duration at the data snapshot date was 126.0 days; exposure ranged from 9 to 417 days. The median number of initiated treatment cycles was 4.0 (range: 1 to 15).

[0391] Of the 26 patients (60.5%), the population was Asian, and of the 17 patients (39.5%), the population was Caucasian. The median age of the patients was 58 years (range 32–79); 23 patients (53.5%) were male. The primary diagnosis was NSCLC (27 patients; 62.8%). The median time from the first histological diagnosis was 34.46 months (range 7.2–137.7 months). All patients had metastatic disease at the time of screening, with the primary sites of metastasis being the lungs, lymph nodes, and bones.

[0392] Of the patients tested for HER2 (or NRG1 mutations), 10 out of 42 (23.8%) showed HER2 overexpression; 25 out of 42 (59.5%) showed non-synonymous somatic mutations; and 9 out of 42 (21.4%) showed HER2 or NRG1 gene rearrangements.

[0393] 1.2.3 Safety Overview Across all doses and schedules, no serious unexpected safety findings were observed at the data cutoff time, and reported adverse events (AEs) were manageable. Observed Ae and DLT considerations are summarized below.

[0394] Of the 43 patients, a total of 38 (88.4%) experienced one or more adverse events (AEs). For 28 patients (65.1%), at least one AE was considered procedure-related by the principal investigator. Two patients (4.7%) experienced AEs that led to a dose reduction of compound (1).

[0395] The most common adverse event was diarrhea (15 patients, 34.9%), followed by elevated ALT (8 patients, 18.6%), anemia (8 patients, 18.6%), and elevated serum creatinine (7 patients, 16.3%).

[0396] In total, 11 patients (25.6%) had a maximum CTCAE grade of 1, 11 patients (25.6%) had a grade of 2, 10 patients (23.2%) had a grade of 3, 1 patient (2.3%) had a grade of 4, and 5 patients (11.6%) had a grade of 5 Ae.

[0397] Based on priority terms (PTs) as defined in the Medical Dictionary for Regulatory Activities (MedDRA), Grade 3 events included elevated ALT (5 patients, 11.6%), elevated AST (2 patients, 4.7%), anemia (2 patients, 4.7%), diarrhea, pneumonia, elevated GGT, hypertriglyceridemia, hypocalcemia, limb pain, pleural effusion, atrial flutter, basal cell carcinoma, lymphopenia, pericardial effusion, and sepsis (1 patient, 2.3%) each. One patient (2.3%) had a Grade 4 event (COVID-19). All coded (one uncoded) Grade 5 (i.e., fatal) events were related to underlying cancer (malignant neoplasm progression: 3 patients, 7.0%; malignant lung neoplasm: 1 patient, 2.3%).

[0398] In total, 18 patients (41.9%) had drug-related adverse events (AEs) of the highest grade 1, 6 patients (14.0%) had grade 2, 4 patients (9.3%) had grade 3, 0 patients had grade 4, and 0 patients had grade 5. As of the data lock date, patients with drug-related AE grade 3 included one patient with drug-related AST and ALT elevation grade 3, two patients with drug-related ALT elevation grade 3, and one patient with hypocalcemia grade 3.

[0399] Overall, 14 patients (32.6%) experienced severe adverse events (SAEs). One patient (2.3%) had a drug-related SAE considered by the principal investigator: grade 3 ALT elevation and grade 3 AST elevation.

[0400] Eleven of the fourteen patients had SAEs considered to be related to an underlying disease or external cause: progression of malignant neoplasm in one patient, progression of malignant neoplasm and basal cell carcinoma in one patient, progression of malignant neoplasm and pleural effusion in one patient, malignant lung neoplasm and metastasis to the central nervous system in one patient, pericardial effusion, pneumonia, and pleural effusion in one patient, anemia and "not yet coded" (reported as "death"; investigation of the cause was ongoing at the time of data lock), sepsis in one patient, elevated ALT in one patient, diarrhea in one patient, peritumoral edema in one patient, and cerebral edema in one patient.

[0401] In addition, three patients had SAEs, and the principal investigator did not report any association with underlying disease or external causes. These SAEs were grade 2 / 3 atrial flutter in one patient, grade 2 pneumonia in one patient, and grade 4 (fatal) COVID-19 in one patient. All three patients recovered from the SAEs.

[0402] At the time of data lock, four patients had experienced dose-limiting toxicity: one of these patients (QD 60 mg) had an AE that was misreported by the principal investigator as DLT (not drug-related grade 3 anemia on day 213); the error had not yet been corrected at the time of the data snapshot. One patient (60 mg BID cohort) had grade 2 edema (drug-related, not serious) on day 58. One patient (150 mg BID cohort) had grade 2 diarrhea (drug-related, not serious) on day 155. One patient (180 mg QD cohort) had grade 3 ALT elevation (drug-related, not serious) and grade 2 ALT elevation (drug-related, not serious) on day 84.

[0403] In the 240 mg QD and 300 mg QD dose cohorts, no DLTs were reported in any of the cycles from cycle 1 onward.

[0404] Regarding doses administered up to 150 mg BID and 300 mg QD, no patients experienced DLT during the MTD evaluation period (first cycle; 21 days) in the dose escalation part of the study. Therefore, MTD was not reached in either of the two schedules involving a total of 43 treated patients.

[0405] [Table 1] TIFF2026513532000011.tif106165

[0406] [Table 2] TIFF2026513532000013.tif95165

[0407] [Table 3]

[0408] 1.2.4 Overview of Effects Of all treated patients, tumor response assessments were available for 34 out of 43 patients, with 16 treated with BID and 18 treated with QD. Overall, regardless of confirmation, the best tumor response, partial response (PR), was reported in 13 out of 34 patients (38.2%) who were evaluable for analysis. Stability was achieved in 18 patients (52.9%); 3 patients (8.8%) had disease progression (PD); and no complete response (CR) was reported in any patient. Among patients with NSCLC, tumor response assessments were available for 24 out of 32 patients. Among evaluable NSCLC patients, 11 reported the best overall response, PR (45.8% of 24 evaluable patients, regardless of confirmation), while 12 patients (50%) had a best overall response of stable disease (SD), and 1 patient (4.2%) had a best response of PD. For this assessment, a patient will be considered to have NSCLC if their primary diagnosis for participation in the study is entered as either NSCLC or a common lung cancer not classified as small cell lung cancer.

[0409] [Table 4]

[0410] [Table 5]

[0411] [Table 6]

[0412] [Table 7]

[0413] Further preliminary evidence regarding efficacy is provided in Figures 2–9. According to Figure 2(A), 13 out of 35 patients (37.14%) treated for at least one cycle of 21 days showed at least one PR evaluation. When considering the QD schedule, as shown in Figures 2A and 4A, this increases to 7 out of 18 patients (38.89%). In Figures 2–9 and 12, each bar represents a different patient. Bars represent patients whose indicators are screened by maximum reduction %. Change from baseline was calculated as the difference between lesion size at screening and at the end of two cycles (day 42). Negative values ​​indicate a decrease in the total target lesion diameter, and positive values ​​indicate an increase.

[0414] 1.2.5 Exposure Plasma exposure increased with increasing dose without any apparent deviation from dose-proportional pharmacokinetics. However, substantial intra-patient and inter-patient variability in pharmacokinetics was observed with respect to overlapping exposures among dose groups, e.g., 180 mg QD, 240 mg QD, and 300 mg QD.

[0415] The relationship between dose level (total daily dose) and objective response rate was evaluated using a (conventional / non-Bayesian) logistic regression model based on a set of patients with at least one post-baseline tumor assessment. The estimated relationship and 95% confidence interval are reported in Figure 10. The relationship between dose level (total daily dose) and the best-case percentage change in the sum of the longest diameters of target tumor lesions from baseline (tumor reduction) was evaluated using a (conventional / non-Bayesian) linear regression model based on a set of patients with at least one post-baseline tumor assessment. The estimated relationship and 95% confidence interval are reported (Figure 11).

[0416] A flat exposure-response / safety relationship was observed, and in particular, the exposure-response curves for tumor reduction and ORR were flattened, showing no substantial improvement in efficacy over the higher dose range (180 mg to 300 mg).

[0417] Exposure-toxicity analysis was also performed. From the perspective of toxicity assessment items, the occurrence of grade 2 or higher AEs and grade 3 or higher AEs was considered. For all considered exposure assessment items, the general exposure-toxicity relationship considering all AEs was relatively flat, and there was no indication of a higher incidence of grade 2 / 3 (and higher) general AEs in patients with higher exposure. However, for specific AEs, such as diarrheal AEs, a trend of potentially higher incidence with higher exposure was observed.

[0418] 1.2.6 Duration of treatment Twenty-four patients were being treated for a relatively long duration up to the cutoff date and in higher dose cohorts (≥100 mg BID and ≥180 mg QD). For these patients, the median total duration of treatment was >6 months at data lock for the 150 mg BID cohort and approximately 5 months for the 100 mg BID and 180 mg QD cohorts, as shown below. Most of these patients were still being treated at the time of data cut.

[0419] 100mg BID for 147 days (still in progress at the time of data lock: 2 / 4 points) 150mg BID for 185 days (still in treatment at the time of data lock: 2 / 3 points) 180mg QD 146 days (still in treatment at the time of data lock: 6 / 6 points) 240mg QD 72 days (still in treatment at the time of data lock: 5 / 6 points) 300mg QD 57 days (still in treatment at the time of data lock: 5 / 5 points)

[0420] Overall, the median treatment duration on the data snapshot date was 126.0 days. The median number of initiated treatment cycles was 4.0 (range: 1–15).

[0421] 1.2.7 Duration of response Based on all treated patients, the median duration of response (Kaplan-Meier estimate) was 7 months.

[0422] Based on all treated patients with NSCLC, the median duration of response (Kaplan-Meier estimate) was 6.9 months (95% CI: 1.4–7.0).

[0423] 1.2.8 Patients pre-treated with trastuzumab deruxtecan As of the data cutoff in July 2023, 50 patients had been treated. Five patients (10.0%) had received trastuzumab deruxtecan prior to compound (1). These patients had NSCLC. In these patients, a maximum tumor reduction of -53% (mean -22.5%, median -16.1%) was observed.

[0424] Since many patients were still undergoing treatment at the time of filing this application, the results presented herein are only preliminary.

[0425] Example 2 - Update of the results from Example 1 (Section 1.2 and subsections) This example provides an update to the results of Example 1, with data reported up to the January 2024 cutoff. The study design and protocol are identical to Example 1, except for the addition of a 360 mg QD dose level (see paragraph 1.1 and subsections). It is noted that the dose expansion part of the study was opened in April 2023. From this point onward, patients with NSCLC with HER2 tyrosine kinase domain mutations were no longer permitted to enroll in Phase Ia of the study, but were instead enrolled in Phase Ib (dose expansion, see Example 3). NSCLC patients who were not eligible for Phase Ib were permitted to participate in Phase Ia, provided they met the remaining criteria for enrollment in Phase Ia. Furthermore, after the dose expansion was opened, investigators were permitted to enroll patients in Phase Ia at dose levels of their choice within the DEC's review and deemed safe in the QD schedule, i.e., doses up to 360 mg QD.

[0426] 2.1 Exposure and Population Composition By the data cutoff date for Example 2, a total of 83 patients had been treated with compound (1) in the dose escalation phase. Overall, the median treatment duration at the data snapshot date was 4.2 months, with exposures ranging from 0 to 24 months.

[0427] Thirty-nine patients (47%) were Asian, and 35 patients (42.2%) were Caucasian. The median age of the patients was 59 years (range 31–81); 38 patients (45.8%) were male. The primary diagnoses were NSCLC (33 patients; 39.8%) and unspecified lung cancer (10 patients; 12%). The median time from the first histological diagnosis was 36.2 months (range 6–237.5 months). All patients who provided data on this had metastatic disease at the time of screening (76 patients), with the primary sites of metastasis being the lungs, lymph nodes, bones, and liver. For the remaining seven patients, there was no information regarding the presence of metastasis.

[0428] Among patients for whom data on HER2 abnormalities test results were available, 28 out of 75 patients (37.3%) exhibited HER2 overexpression; 42 out of 75 patients (56%) exhibited non-synonymous somatic mutations; and 12 out of 75 patients (16%) exhibited HER2 or NRG1-related gene rearrangements.

[0429] 2.2 Safety Overview At the time of data locking in this example, 7 out of 83 patients (8.4%) experienced dose-limiting toxicity (DLT) at any point during the entire treatment period (from the start of treatment to the end of the residual effect period). In addition to those reported in Example 1 (see subsection 1.2.3), the following DLTs were observed: In the 240 mg QD cohort, one patient had grade 4 thrombocytopenia and the other had grade 3 diarrhea. One patient (300 mg QD cohort) had grade 4 hypokalemia and grade 4 neutropenia, which were considered DLTs. One patient (360 mg QD) had grade 3 thrombocytopenia.

[0430] In the 120 mg QD and 60 mg QD dose cohorts, no dose-limiting trials (DLTs) were reported in any of the dose-escalation parts of the study from cycle 1 onward.

[0431] Three of the above patients experienced DLTs during the MTD evaluation period (first cycle, 21 days): one in the 360 ​​mg QD, one in the 300 mg QD, and one in the 240 mg QD. Therefore, the DLT rates during the MTD evaluation period were 5.9% for the 240 mg QD, 5% for the 300 mg QD, and 16.7% for the 360 ​​mg QD, and no DLTs occurred during the MTD evaluation period for all other doses. In addition, based on the analysis of BLRM, MTD was not reached in either of the two schedules using a total of 83 treated patients at the data cutoff point.

[0432] Notably, across all doses, the proportion of adverse events leading to dose reduction of compound (1) was very low (9.6%), and the proportion of patients experiencing adverse events leading to temporary discontinuation of compound (1) was limited (26.5%). Additionally, only two patients (2.4%) experienced serious adverse events that the investigator considered to be related to compound (1). Overall, the tested dosing regimens of compound (1) surprisingly demonstrated a very tolerable and manageable safety profile. While other tyrosine kinase inhibitors that inhibit HER2 are typically expected to cause a high rate of toxicity associated with off-target inhibition of wild-type EGFR, the dosing schedule of compound (1) was surprisingly found to lead to a relatively low rate of such EGFR-related AEs (common AEs with HER2 tyrosine kinase inhibitors such as pirotinib and poziotinib, e.g., rash, stomatitis, paronychia, as reported in Song Z et al, BMC Med 20:42, 2022; Zhou C et al, J Clin Oncol 38:2753-2761, 2020; Elamin YY, J Clin Oncol 40:702-709, 2022; Le X, J Clin Oncol 40:710-718, 2022).

[0433] [Table 8] TIFF2026513532000020.tif113165

[0434] [Table 9] TIFF2026513532000022.tif102165

[0435] [Table 10]

[0436] 2.3 Overview of Effects Regarding the updated analysis of data obtained within the dose-escalation phase of the study, longer follow-up studies allowed for the analysis of the confirmed best overall response rather than the objective response, regardless of the confirmation of the previous data cutoff presented in Example 1. In other words, in contrast to Example 1, if partial response was assessed in two subsequent tumor assessments for the patient, i.e., if the second tumor assessment confirmed the initial partial response at a later point in time, the patient was considered to have only a partial response.

[0437] Of all treated patients, 74 out of 83 were evaluable for tumor response assessment, with 17 treated with BID and 57 with QD. Patients were considered unevaluable (NE) for response in this analysis if the duration of treatment was too short to be evaluated and still ongoing, meaning they did not have a post-baseline tumor assessment to allow for the allocation of a confirmed overall response, rather than an NE resulting from SD assessment prior to day 36 of treatment. Overall, the best tumor response, a partial response (PR), meeting the criteria for confirmation, was reported in 26 out of 74 evaluable patients (35.1%) for analysis. Stability was achieved in 37 patients (50%); 5 patients (6.7%) experienced PD; and no complete response (CR) was reported in any patient.

[0438] Of the 43 patients with NSCLC, 41 were evaluable for the defined best overall response as defined above. Of the evaluable NSCLC patients, 18 reported a best overall response of PR (43.9% of the 41 evaluable patients), while 20 patients (48.8%) had a best overall response of SD, and 1 patient (2.4%) had a best overall response of PD. Furthermore, two patients had a best overall response of "unevaluable," even though they were not continuing treatment and the duration of treatment was not too short to be evaluated. This can occur, for example, if the patient discontinued treatment before tumor imaging was taken (such patients should be included in the analysis as non-responders).

[0439] [Table 11]

[0440] [Table 12]

[0441] [Table 13]

[0442] [Table 14]

[0443] 2.4 Duration of treatment Of the 83 patients treated in this example, 38 (45.8%) were still continuing treatment at the data cutoff. The majority of patients in the QD cohort (34 out of 66 patients, 51.5%) were still continuing treatment. At data lock, the median treatment duration (time to discontinuation) based on Kaplan-Meier estimates was 8.3 months, while the third quartile (the time at which 75% of patients are expected to discontinue treatment) was 20.3 months. In addition, Kaplan-Meier estimates for treatment duration / time to discontinuation suggest that 25% of patients were expected to be treated for 20 months prior to discontinuing treatment with the test dosing regimen of compound (1), indicating long-term, overall tolerable treatment. Up to the data cutoff, the longest individual treatment duration for a patient was approximately 2 years (24 months for a patient on the 30 mg BID). Due to the study design, patients at higher dose levels were recruited later than those at lower dose levels, and therefore, by design, patients at higher dose levels were treated for a shorter period compared to those at lower dose levels. Nevertheless, the longest treatment duration was 18 months for the 120 mg QD and 13 months for the 240 mg QD at the cutoff date, and many patients in these higher dose levels were still receiving treatment, indicating that higher dose levels are well tolerated by patients.

[0444] 2.5 Duration of response Based on all treated patients, the median duration of confirmed response (Kaplan-Meier estimate) was 12.7 months (95% confidence interval: 5.6 months to 15.8 months). Overall, this demonstrates strong persistence of response across the investigated dose range and schedule, even starting at very low dose levels. For example, at 60 mg BID, one patient had a confirmed response with a duration of 12.7 months, and at 120 mg QD, two patients with confirmed responses showed durations exceeding 12 months (14.1 and 15.8 months at the data cutoff). At higher dose levels, patients were also observed with longer durations of response, such as those with durations close to 12 months for confirmed responses at 240 mg QD. Due to the study design, patients at higher dose levels were recruited later than those at lower doses, meaning that, on average, patients at higher doses had a shorter time for follow-up regarding the persistence of response at the data cutoff. Nevertheless, the results demonstrate an excellent duration of response across the entire dose range investigated.

[0445] Based on all treated patients with NSCLC, the median duration of response (Kaplan-Meier estimate) was 15.8 months (95% confidence interval: 5.6–15.8 months).

[0446] 2.6 Duration of disease control Among all treated patients, the median duration of disease control from Kaplan-Meier estimates was 8.7 months (95% confidence interval: 7.2–13.9 months). The median duration was 8.4 months in the BID cohort and 10.3 months in the QD cohort. Overall, long-lasting disease control was observed across a wide range of doses, including lower dose levels. For example, in the 120 mg QD group, a median duration of disease control of 17.2 months was observed across three patients with disease control, and in the 30 mg BID group, one patient had a duration of disease control of 20.8 months at the data cutoff.

[0447] In patients with NSCLC, the median duration of disease control from Kaplan-Meier estimates was 12.3 months (95% confidence interval: 8.3 to NC months, where NC means "cannot be calculated due to lack of events"). The median duration of disease control was 12.3 months in the QD schedule and 13.8 months in the BID schedule. Overall, longer duration of disease control was observed in NSCLC patients compared to the entire patient population treated.

[0448] 2.7 Patients pre-treated with trastuzumab deruxtecan Of the 83 treated patients (22.9%), 19 had received trastuzumab deruxtecan prior to compound (1). Of these, 15 patients already had post-baseline tumor assessments at the data cutoff and were considered evaluable for objective response, regardless of the following confirmations.

[0449] Of the 15 evaluable patients who had received prior treatment with trastuzumab deruxtecan, 5 achieved a partial response (33.3%, regardless of confirmation), 8 (53.3%) had stable disease, and 2 (12.3%) had disease progression. Therefore, an 86.7% disease control rate was observed in these patients. In this group of patients, a maximum tumor reduction of -90.6% was observed, with a mean tumor reduction of -19.1% and a median reduction of -12.5%.

[0450] 2.8 Progression-free survival At the time of data cut, 36 out of 83 treated patients (43.4%) had a progression-free survival (PFS) event, meaning they either died or had documented progression. For 30 patients (36.1%), progression was the PFS event, and for 6 patients (7.2%), the event was death. The remaining 47 patients did not have a PFS event and were censored for analysis: 8 (9.6%) were censored due to early discontinuation, and 1 patient (1.2%) was censored due to initiation of subsequent anticancer therapy. Of the remaining patients, 12 (14.5%) were censored on day 1 because they did not (yet) have a post-baseline evaluation, and 26 patients (31.3%) were ongoing at the time of data lock and will be censored at the time of the last tumor evaluation currently available. Based on Kaplan-Meier analysis, the median PFS in the BID schedule was 8.0 months (95% confidence interval: 2.8 months to NC, where NC means it was not possible to calculate the value due to the absence of events), as plotted in Figure 12. Overall, similar PFS was observed across various dose levels. Patients already showed very promising PFS outcomes in the low-dose group (e.g., 30 mg BID with patients having PFS exceeding 20 months).

[0451] Of the 43 treated patients with lung cancer, including NSCLC, 19 (44.2%) had already experienced a PFS event (for 17 patients, the event was disease progression; for 2 patients, death), and the remaining patients were censored for analysis. Sixteen (37.2%) of the lung cancer patients were ongoing at the time of data lock and censored at the time of the last available tumor assessment, and four patients (9.3%) were censored on day 1 because they had not yet had a post-baseline tumor assessment. For patients with lung cancer, PFS was estimated to be higher than in the set of all treated patients, as plotted in Figure 13, based on Kaplan-Meier analysis: for the BID schedule, the estimated median PFS was 13.8 months (confidence interval: 2.3 months to NC), and for the QD schedule, it was 12.3 months (confidence interval: 7.6 to 17.2 months). Similar PFS was observed across the dose ranges examined in lung cancer patients.

[0452] Further preliminary evidence regarding efficacy is provided in Figures 2–9. Since many patients were still undergoing treatment as of the filing date of this application, the results presented herein are only preliminary.

[0453] Example 3 - Dose expansion part of the clinical trial of Examples 1 and 2 (Phase Ib) This example focuses on the dose-expansion portion (Phase Ib) of the Phase I study described in Examples 1 and 2. Approximately 275 patients diagnosed with progressive or metastatic refractory NSCLC with HER2 gene mutations will be enrolled. Phase Ib-specific elements are reported in the protocol below. For other elements not specified, the protocol remains the same as in Example 1. Patients will be divided into five cohorts according to the main inclusion criteria listed below.

[0454] 3.1 Protocol The objectives of Phase Ib include the following: - For Cohort 1, Cohort 2, and Cohort 5, the objective tumor response rate will be evaluated by a central independent review board; - For Cohort 3, the objective tumor response rate will be evaluated by the principal investigator; - For all cohorts, further investigate the safety, tolerability, and pharmacokinetics of the investigated doses of compound (1) in patients with HER2 mutation-positive advanced / metastatic NSCLC; - Continue to evaluate safety and patient-reported outcomes for all cohorts.

[0455] The primary endpoints for Phase Ib include the following: - Regarding cohorts 1, 2, and 5: ORs will be assessed by an independent central review board in accordance with RECIST version 1.1; - Regarding Cohort 3: OR as assessed by the principal investigator.

[0456] Secondary endpoints include the following: Regarding cohorts 1, 2, and 5: - Duration of objective response (DoR) according to RECIST 1.1 by the Central Independent Review Board; - Disease control (DC) according to RECIST 1.1 by a central independent review board; - PFS in accordance with RECIST 1.1 by the Central Independent Review Board; Regarding Cohort 3 only: - Duration of the Operations Review (OR) according to RECIST 1.1 as assessed by the principal investigator; - DCs as assessed by the principal investigator, in accordance with RECIST 1.1; - PFS as assessed by the principal investigator, according to RECIST 1.1; Regarding all cohorts: - Number of patients who experienced DLT during the entire treatment period; - Changes in the EORTC QLQ-C30 physical function domain score from baseline to C5D1 (cycle 5, day 1); - Change in NSCLC-SAQ total score from baseline to C5D1; - Change in EORTC IL46-item score from baseline to C5D1.

[0457] EORTC QLQ-C30, NSCLC-SAQ, and EORTC IL46 are patient-reported outcome measures (PROMs). Specifically, the EORTC QLQ-C30 (IL19) Physical Function Domain Score is a five-item function scale from the EORTC QLQ-C30, a questionnaire specific to assessing health-related quality of life (QoL) in patients with cancer. The NSCLC-SAQ is a seven-item PROM for adult use to assess symptoms of progressive NSCLC. It includes five domains and associated items identified as symptoms of NSCLC: cough (1 item), pain (2 items), dyspnea (1 item), fatigue (2 items), and appetite (1 item). EORTC IL46 (item 168) is a validated single-item question that assesses the overall adverse effect. Other PROMs may be measured during the course of the study.

[0458] The main inclusion criteria include the following: - Patients with a confirmed diagnosis of progressive, unresectable, and / or metastatic nonhematological malignancy having at least one measurable lesion (same as in Example 1); - Availability and willingness to provide samples of formalin-fixed paraffin-embedded (FFPE) tumor tissue material from the archive (similar to Example 1); - The patient must be willing to comply with blood sampling and tumor biopsy requirements for PK, pharmacodynamic, and biomarker analysis (same as in Example 1); - Regarding Cohort 1: Patients with documented HER2 tyrosine kinase domain (TKD) mutation-positive non-squamous NSCLC who had received at least one line of systemic therapy, including platinum-based combination chemotherapy, in the advanced / metastatic setting; - Regarding Cohort 2: Patients with documented HER2 tyrosine kinase domain (TKD) mutation-positive non-squamous NSCLC who have not received any prior line of therapy (neo- or adjuvant chemotherapy, chemoradiotherapy, or radiotherapy is permitted if at least 6 months have passed since disease progression); - Regarding Cohort 3: Patients with documented HER2 non-TKD mutation-positive NSCLC and HER2 TKD mutation-positive squamous cell NSCLC who received at least one line of systemic therapy, including platinum-based combination chemotherapy, in the advanced / metastatic setting; - Patients in these cohorts 1-3 must not have received prior therapy with HER2-targeted antibody-drug conjugates (ADCs); - Regarding Cohort 5: Patients with documented HER2 TKD mutation-positive non-squamous NSCLC who have received prior therapy with HER2-targeted ADCs in the progressive / metastatic setting and have experienced disease progression during or after this therapy.

[0459] As those skilled in the art will recognize, further inclusion and exclusion criteria may apply.

[0460] Compound (1) is administered orally in doses of 120 mg or 240 mg QD.

[0461] The treatment consists of repeated 3-week cycles, as long as the patient experiences clinical benefit, or until excessive drug toxicity occurs or consent is withdrawn, whichever comes first (as in Example 1).

[0462] For Cohort 1, the analysis of the primary endpoint OR by the Central Independent Review Board will be performed using a one-sided z-test at a one-sided alpha level of 0.0125 (considering the two doses examined).

[0463] For cohorts 2 and 5, the central independent review board will perform an analysis of the primary outcome measure (OR) using a one-sided z-test at a one-sided alpha level of 0.025.

[0464] For Cohort 3, no confirmatory tests will be performed. Only descriptive analysis will be conducted in terms of observed ORR and 95% CI using the Wilson method. In addition, the primary endpoint OR, as assessed by the principal investigator, will be analyzed using a Bayesian hierarchical model (BHM) for ORR, thereby utilizing the available concurrent data from Cohorts 1, 2, and 3 in a Bayesian metaanalysis.

[0465] 3.2 Results As of July 2023, 42 patients were treated in Phase Ib Cohort 1 (randomized to 120 / 240 mg QD). Treatment-related adverse events (TRAEs) (all / grade ≥ 3) were observed in 67% / 10% of patients. The most common TRAEs were diarrhea (29% / 0%), rash (21% / 0%), increased aspartate aminotransferase (10% / 2%), decreased appetite (10% / 0%), and dysgeusia (10% / 0%). There were no AEs leading to treatment discontinuation. The ORR / DCR in 23 evaluable patients (who had received 2–5 cycles at the cutoff) was 74% / 91%. The median best-case percentage change from baseline in the target lesion was -41.2%. The best-case change from baseline in the target lesion is shown in Figure 14. All responding patients remained in treatment at the data cutoff.

[0466] Example 4 - Efficacy of compound (1) (songertinib) in NSCLC cells resistant to T-DXd Zongertinib (i.e., compound (1)) is involved in the downstream signaling of HER2, and HER2 WT It consistently inhibits the proliferation of cancer cells that rely on the high expression of HER2, and its mechanism of action differs from that of antibody-based treatments, giving an opportunity to address resistance. Therefore, this example demonstrates that zongertinib inhibits HER2 WT We investigated whether it is effective against human cancer cells that are resistant to HER2-targeted ADCs, depending on the high expression of [specific gene]. First, we generated a tumor model resistant to trastuzumab deruxtecan (T-DXd).

[0467] 4.1. Materials and Methods 4.1.1. Emission of T-DXd-resistant tumors in vivo To generate a T-DXd resistance model, the NCI-N87 model was used, as shown in Figure 15. Mice with tumors were treated with T-DXd for three cycles, the regrowing tumors were harvested, and the tumor cells were then cultured in vitro. Parental and T-DXd-resistant NCI-N87 cells were treated with deruxtecan, T-DXd, or songertinib.

[0468] NCI-N87 cells were placed in PBS (Gibco, #14190-094) containing 5% FBS (Gibco, #26140-079) at a rate of 2.5 × 10⁶ 7 Suspend the cells individually. Then, add 100 μl of the cell suspension (2.5 × 10⁶ cells per mouse). 6 The solution is administered subcutaneously to the right flank of BomTac:NMRI-Foxn1nu mice in individual cell volume. After 15 days, the 120 mm 3 Mice are randomized based on the average size of the sc tumor volume. Treatment is initiated on this day with 3 mg / kg T-DXd IV. From this point onward, tumor size is measured three times a week using a measuring instrument. On day 22 after the first treatment, a second treatment is administered by injection with 10 mg / kg T-DXd. Treatment is continued on days 43, 64, 85, and 106 with 7 mg / kg IV. Growth is then observed. The tumor size is measured on day 174 (514.09 mm). 3 #18) and day 209 (626.21mm) 3 Collect the sample in #17) and culture it in PBS on ice.

[0469] 4.1.2. Tumor growth in vitro Tumor 1mm 3Cut the cells into halves and homogenize them using the Tumor Dissociation Kit, mouse (Miltenyi Biotec, #130-096-730) in combination with the gentleMACS® Octo Dissociator (Miltenyi). Resuspend the cells in 3 ml of RPMI medium (PAN-Biotech, #P04-18047) supplemented with 10% FBS (Gibco, #26140-079), 1×GlutaMAX® (Gibco, #35050-038), and 1×Pen Strep (Gibco, #15140-122), and count the cells. 6.8×10 6 Individual cells are seeded in 3 ml of medium per well in a TC-treated 6-well cell culture plate (Corning, #3506) and grown in a humidified incubator at +37°C and 5% CO2. For the next two days, cells are washed daily with 3 ml of PBS (Gibco, #14190-094) to remove non-adherent cells and replace the medium. Cells are washed with 1 ml of PBS, then dissociated with 500 μL of trypsin (PAN-Biotech, #P10-0210300), and the cells are subcultured at 60–80% density by incubation at 37°C until the cells detach. Trypsin is blocked with 1 ml of medium, and 500 μL of cell suspension is seeded back into a 6-well plate with 3 ml of medium or a T25 cell culture flask with 7 ml of medium (Corning, #353109). The cells are passed through five passages until no residual fibroblasts are visible, and then, immediately after drug treatment, a growth assay is performed.

[0470] 4.1.3. Growth assay method Seed 1000 cells per well in 40 μL of medium in a sterile white 384-well culture plate (TC treated; PerkinElmer #6007680) and incubated overnight in a humidified incubator at 37°C and 5% CO2. Add a 0.1% DMSO control or a triple dilution of the compound. Dilute T-DXd in 0.3% Tween solution and add it to the cells. Five days after incubation with the test compound, immediately after adding CellTiter Glo Luminescent Cell Viability Reagent (Promega, #G9243), measure the cell plate to assess cell viability. Place the plate on a shaker for 5 minutes and incubate additionally at room temperature for 10 minutes to induce cell lysis and stabilize the luminescence signal. Measure the luminescence signal in each well using an EnSpire Multilabel Plate Reader 658 (PerkinElmer). The dose-response curve is fitted and visualized using Boehringer Ingelheim's proprietary software, MegaLab and PRISM (GraphPad Inc.).

[0471] 4.2. Results In this example, using a cell line model, it was demonstrated that songertinib potently inhibits the proliferation of HER2-dependent cells with acquired resistance to T-DXd. Parental NCI-N87 cells were sensitive to both T-DXd and deruxtecan, while T-DXd-resistant cells were resistant to both T-DXd and deruxtecan, and their IC 50 There was at least a 100-fold difference (Figures 16A and 16B). On the other hand, both parental and resistant NCI-N87 cells were sensitive to songertinib, and their IC 50 The difference was less than 10 times (Figure 16C). Therefore, zongertinib inhibits the growth of HER2-dependent human NSCLC cells that are resistant to trastuzumab deruxtecan.

[0472] The data presented in this example raise exciting possibilities that zoneginib may be effective in treating HER2-dependent tumors that are resistant to ADCs.

Claims

1. The following for use in cancer treatment: 【Chemistry 1】 Compound (1) as defined in [reference], which is administered in a daily dose of at least 30 mg.

2. Compound (1) for use according to claim 1, administered in a daily dose of 30 mg to 600 mg.

3. Compound (1) for use according to claim 1 or 2, administered in a daily dose of at least 60 mg.

4. A compound (1) for use according to any one of claims 1 to 3, administered in a daily dose of 60 mg to 300 mg.

5. Compound (1) for use according to any one of claims 1 to 4, administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

6. A compound (1) for use according to any one of claims 1 to 5, administered in a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

7. A compound (1) for use according to any one of claims 1 to 6, administered in a daily dose of 120 mg or 240 mg.

8. A compound (1) for use according to any one of claims 1 to 7, administered in a daily dose of 120 mg.

9. A compound (1) for use according to any one of claims 1 to 7, administered in a daily dose of 240 mg.

10. A compound (1) for use according to any one of claims 1 to 9, administered once or twice daily.

11. A compound (1) for use according to any one of claims 1 to 10, which is administered once daily.

12. Compound (1) for use according to any one of claims 1 to 11, administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg, or administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg.

13. Compound (1) for use according to any one of claims 1 to 12, administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, or 360 mg, or administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, or 360 mg.

14. A compound (1) for use according to any one of claims 1 to 13, administered once daily in a daily dose of 120 mg or 240 mg.

15. Compound (1) for use according to any one of claims 1 to 14, administered once daily at a daily dose of 120 mg.

16. Compound (1) for use according to any one of claims 1 to 14, administered once daily at a daily dose of 240 mg.

17. A compound (1) for use according to any one of claims 1 to 16, which is administered orally.

18. A compound (1) for use according to any one of claims 1 to 17, administered as a tablet.

19. A compound (1) for use according to any one of claims 1 to 18, which is administered after the administration of a systemic anticancer therapy agent.

20. The following for use in cancer treatment: 【Chemistry 2】 Compound (1) as defined in [reference], which is administered after the administration of a systemic anticancer therapy agent.

21. Compound (1) for use according to claim 19 or 20, wherein the systemic anticancer therapy agent is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, taxanes, antimetabolites, immunotherapy agents, and combinations thereof.

22. Compound (1) for use according to any one of claims 19 to 21, wherein the systemic anticancer therapy agent is trastuzumab deruxtecan and / or trastuzumab emtansine, or comprises the same.

23. Compound (1) for use according to any one of claims 19 to 21, wherein the systemic anticancer therapy agent comprises pembrolizumab, pemetrexed, and / or platinum-based chemotherapy.

24. Compound (1) for use according to any one of claims 1 to 23, wherein the cancer is selected from the group consisting of brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

25. The compound for use according to any one of claims 1 to 24, wherein the cancer is non-small cell lung cancer.

26. A compound for use according to any one of claims 1 to 25, wherein the cancer is characterized by HER2 overexpression, HER2 amplification, and / or a HER2 mutation (1).

27. A compound for use according to any one of claims 1 to 26, wherein the cancer comprises a mutation in the tyrosine kinase domain of HER2 (1).

28. A compound for use according to any one of claims 1 to 27, wherein the cancer is unresectable, progressive, and / or metastatic cancer.

29. A compound for use according to any one of claims 1 to 28, wherein the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 antibody-drug conjugate (1).

30. For use in the treatment and / or prevention of cancer, the following 【Transformation 3】 Compound (1) as defined in, wherein the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 antibody-drug conjugate.

31. The compound for use according to claim 30, wherein the cancer is as defined in any one of claims 24 to 28.

32. A compound for use according to any one of claims 29 to 31, wherein the cancer is resistant to treatment with trastuzumab deruxtecan (1).

33. The following for use in cancer treatment: 【Chemistry 4】 A pharmaceutical composition comprising compound (1) as defined in and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in a daily dose of at least 30 mg.

34. A pharmaceutical composition for use according to claim 33, wherein compound (1) is administered as prescribed in any one of claims 2 to 23.

35. A pharmaceutical composition for use according to claim 33 or 34, wherein the cancer is as defined in any one of claims 24 to 29.

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