ESQUEMA DE DOSAGEM DE UM INIBIDOR DE HER2

Abstract

The present invention relates to a dosing schedule of a HER2 inhibitor useful in the prevention and / or treatment of cancer, in particular to its doses and second or further line administration.

Description

1 / 141 “DOSAGE SCHEME FOR A HER2 INHIBITOR” FIELD OF THE INVENTION

[001] The present invention relates to a dosing regimen of the HER2 inhibitor, N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2enamide, which is useful in the prevention and / or treatment of cancer. In particular, the dosing regimen can be defined by doses and / or administration of the HER2 inhibitor as a second-line or subsequent dose. BACKGROUND

[002] N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2enamide, also referred to in this application as compound (1) or zongertinib, is a HER2 (ErbB2) inhibitor described in WO 2021 / 213800. Zongertinib is a potent and selective inhibitor of wild-type and mutant HER2 tyrosine kinase that spares the wild-type epidermal growth factor receptor (EGFR). Therefore, it is useful for the treatment and / or prevention of diseases and / or conditions where inhibition of wild-type and / or mutant HER2 is of therapeutic benefit, especially oncological and / or hyperproliferative diseases such as cancer.

[003] There is a need to find a way to administer compound (1) that is therapeutically effective and also safe and tolerable as such and in the context of treatments already performed. BRIEF DESCRIPTION OF THE FIGURES Figure 1. (A) Design of the dose-escalation portion of a clinical trial testing different doses and regimens of compound (1) in pre-treated patients with unresectable, advanced, and / or metastatic solid tumors with a HER2 gene aberration, as described in Examples 1 and 2. (B) Alternative representation of the dose-escalation portion of the clinical trial of Example 1. N = number of Petition 870250085375, dated 09 / 22 / 2025, page 13 / 198 2 / 141 patients; BID = bis in die, twice a day; QD = quaque die, once a day; RP2D = recommended dose for dose expansion. Figure 2. Swimmer plot (treatment duration and response assessments by patient and by dose) of response assessments and treatment duration by patient and dose (A) in March 2023 and (B) in January 2024. Bars represent progression-free survival duration, not treatment duration. Each bar represents a patient in Phase Ia (see Examples 1 and 2). BID = bis in die, twice daily; QD = quaque die, once daily; RP = partial response; DE = stable disease; PD = disease progression = progressive disease. Figure 3. Swimmer plot of response and treatment duration assessments by patient and dose in the BID regimen (A) in March 2023 and (B) in January 2024. Bars represent progression-free survival duration, not treatment duration. Each bar represents a patient in Phase Ia (see Examples 1 and 2). Abbreviations are defined as in Figure 2. Figure 4. Swimmer plot of response and treatment duration assessments by patient and dose in the QD regimen (A) in March 2023 and (B) in January 2024. Bars represent progression-free survival duration, not treatment duration. Each bar represents a patient in Phase Ia (see Examples 1 and 2). Abbreviations are defined as in Figure 2. Figure 5. Cascade graph of BID vs QD schemes showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage. Each bar represents a patient in Stage Ia (see Examples 1 and 2). The dashed line at 20% delimits progressive disease (above 20%). The dashed line at -30% delimits partial response (PR) (below 30%). The range between 20% and -30% corresponds to stable disease (SD). The data are Petition 870250085375, dated 09 / 22 / 2025, page 14 / 198 3 / 141 January 2023 on panel (A) and January 2024 on panel (B). Figure 6. Cascade graph of BID dose levels showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage. Each bar represents a patient in Phase Ia (see Examples 1 and 2). Dashed lines have the same meaning as in Figure 5. Data are from March 2023 in panel (A) and January 2024 in panel (B). Figure 7. Cascade graph of QD dose levels showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage. Each bar represents a patient in Phase Ia (see Examples 1 and 2). Dashed lines have the same meaning as in Figure 5. Data are from March 2023 in panel (A) and January 2024 in panel (B). Figure 8. Cascade graph of BID dose levels showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage in (A) patients with non-small cell lung cancer and (B) patients with other tumors in March 2023. Panel (C) corresponds to panel (A), but with a cutoff date of January 2024. Each bar represents a patient in Stage Ia (see Examples 1 and 2). Dashed lines have the same meaning as in Figure 5. Figure 9. Cascade plot of QD dose levels showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage in (A) patients with non-small cell lung cancer and (B) patients with other tumors in March 2023. Panel (C) corresponds to panel (A), but with a cutoff date of January 2024. Each bar represents a patient in Stage Ia (see Examples 1 and 2). Dashed lines have the same meaning as in Figure 5. Figure 10. Analysis of the correlation between objective response rate and dose. Petition 870250085375, dated 09 / 22 / 2025, p. 15 / 198 4 / 141 total daily dose using logistic regression, based on the dose levels and Phase Ia regimens shown in Figure 1 (A) and (B). The dashed line represents the estimated relationship, and the dotted area shows the 95% confidence interval. Data are from March 2023. Figure 11. Analysis of the correlation between the best percentage change from baseline in the sum of the largest target lesion diameters (i.e., tumor reduction) and the total daily dose using linear regression, based on the dose levels and Phase Ia regimens shown in Figure 1(A) and (B). The dashed line with longer dashes (higher at the beginning) represents the estimated relationship, the dashed line with shorter dashes (lower at the beginning) indicates a tumor reduction of -30% (defining partial response), and the dotted area shows the 95% confidence interval. Data are from March 2023. Figure 12. Kaplan-Meier plot of progression-free survival (RECIST v.1.1) by dosage regimen (BID, QD) in the set of all treated Phase Ia patients (see Examples 1 and 2), median progression-free survival (Med), and lower and upper confidence limits (LCL, UCL) of the 95% confidence interval for the median progression-free survival estimate. Crosses on the line indicate points in time when a BID patient was considered censored, and circles indicate points in time when a QD patient was considered censored. Data are from January 2024. Figure 13. Kaplan-Meier plot of progression-free survival (RECIST v.1.1) by dosage regimen (BID, QD) in the cluster of Stage Ia lung cancer patients (see Examples 1 and 2), median progression-free survival (Med), and lower and upper confidence limits (LCL, UCL) of the 95% confidence interval for the median progression-free survival estimate. Crosses on the line indicate points in time when a BID patient was considered censored, and circles indicate points in time when a QD patient was considered censored. Petition 870250085375, dated 09 / 22 / 2025, page 16 / 198 5 / 141 was considered censored. The data is from January 2024. Figure 14. Waterfall plot showing the best change from baseline in target lesions (RECIST v1.1) expressed as a percentage. Each bar represents a patient in Cohort 1 of Phase 1. Ib that initiated treatment at least 7 weeks prior to the cutoff date with baseline and post-baseline tumor assessments (see the Example 3). Patients were treated with 120 mg QD or 240 mg QD. The data cutoff is July 2023. Figure 15. Schematic representation of the experiment for the data in Figure 16. T-DXd resistant tumors are generated in vivo, collected and cultured in vitro and then tested for sensitivity to T-DXd, T-DXd payload, deruxtecan, and compound (1). Figure 16. Dose-response curves (each line represents an independent experiment) of parental and T-DXd-resistant NCI-N87 cells in relation to in vitro treatment with (A) deruxtecan, (B) TDXd, and (C) compound (1) (i.e., zongertinib). SUMMARY OF THE INVENTION

[004] According to a first aspect, compound (1) is provided as defined below (1) for use in the treatment of cancer, wherein compound (1) is administered at a daily dose of at least 30 mg. Alternatively, a method of treating a cancer patient is provided comprising administering compound (1) at a daily dose of at least 30 mg. Petition 870250085375, dated 09 / 22 / 2025, page 17 / 198 6 / 141

[005] In some embodiments, compound (1) is administered at a daily dose of 30 mg to 600 mg.

[006] In some embodiments, compound (1) is administered at a daily dose of at least 60 mg.

[007] In some embodiments, compound (1) is administered at a daily dose of 60 mg to 300 mg.

[008] In some embodiments, compound (1) is administered at 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.

[009] In some embodiments, compound (1) is administered at a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

[0010] In some embodiments, compound (1) is administered at a daily dose of 120 mg or 240 mg.

[0011] In some embodiments, compound (1) is administered at a daily dose of 120 mg.

[0012] In some embodiments, compound (1) is administered at a daily dose of 240 mg.

[0013] In some modalities, compound (1) is administered once or twice daily.

[0014] In some modalities, compound (1) is administered once daily.

[0015] 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 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.

[0016] In some embodiments, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, Petition 870250085375, dated 09 / 22 / 2025, page 18 / 198 7 / 141 300 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.

[0017] In some embodiments, compound (1) is administered once daily at a daily dose of 120 mg or 240 mg.

[0018] In some embodiments, compound (1) is administered once daily at a daily dose of 120 mg.

[0019] In some embodiments, compound (1) is administered once daily at a daily dose of 240 mg.

[0020] In some embodiments, compound (1) is administered orally.

[0021] In some embodiments, compound (1) is administered as a tablet.

[0022] In some embodiments, compound (1) is administered after administration of a systemic anticancer therapy agent.

[0023] Another aspect relates to a compound (1) as defined below (1) for use in the treatment of cancer, wherein compound (1) is administered after the administration of a systemic anticancer therapy agent. Alternatively, a method of treating a cancer patient is provided comprising administering compound (1) after the administration of a systemic anticancer therapy agent. In this respect, compound (1) is preferably administered as defined above, especially with regard to daily dose, once / twice daily administration and / or oral administration. Petition 870250085375, dated 09 / 22 / 2025, page 19 / 198 8 / 141 (particularly compressed).

[0024] In some modalities, the systemic anticancer therapy agent is selected from the group consisting of platinum-based chemotherapy, anti-HER2 drug-antibody conjugates, taxanes, antimetabolites, immunotherapeutic agents, and combinations thereof.

[0025] In some embodiments, the systemic anticancer therapy agent is or comprises trastuzumab deruxtecan and / or trastuzumab emtansine.

[0026] In some modalities, the systemic anticancer therapy agent comprises pembrolizumab, pemetrexed, and / or platinum-based chemotherapy.

[0027] In some modalities, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric 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.

[0028] In some forms, the cancer is non-small cell lung cancer.

[0029] In some forms, the cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant.

[0030] In some forms, the cancer involves a mutation in the tyrosine kinase domain of HER2.

[0031] In some forms, the cancer is unresectable, advanced and / or metastatic.

[0032] In some forms, the cancer is resistant to treatment with an anti-HER2 antibody and / or a drug conjugate. Petition 870250085375, dated 09 / 22 / 2025, page 20 / 198 9 / 141 anti-HER2 antibody.

[0033] Another aspect refers to compound (1) as defined below (1) for use in the treatment and / or prevention of cancer, wherein the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 antibody-drug conjugate. Alternatively, a method of treatment and / or prevention of cancer is provided in an individual in need thereof, comprising the administration of compound (1), wherein the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 antibody-drug conjugate. In this respect, cancer is preferably as defined in any one or more of the above embodiments.

[0034] In some forms, the cancer is resistant to treatment with trastuzumab deruxtecan.

[0035] Another aspect relates to a pharmaceutical composition comprising compound (1) as defined below. (1) and at least one excipient that is pharmaceutically acceptable for use in the treatment of cancer, wherein compound (1) is administered at a daily dose of at least 30 mg. Alternatively, a method of treating a cancer patient comprises administering Petition 870250085375, dated 09 / 22 / 2025, page 21 / 198 10 / 141 a pharmaceutical composition comprising compound (1) and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered at a daily dose of at least 30 mg. In this respect, compound (1) is preferably administered as defined in any of the above embodiments relating to compound (1) for use, especially with regard to daily dose, once / twice daily administration and / or oral administration (particularly tablet). Similarly, in these respects, the compound may be as defined above in any embodiment.

[0036] It should be understood that any of the embodiments or aspects disclosed in this application relating to compatible features (e.g., a daily dose of compound (1), once / twice daily administration, oral / tablet administration, administration after systemic anticancer therapy agent, cancer definition by location and / or aberration and / or HER2 resistance, etc.) may be combined with each other to provide other embodiments of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0037] One of the objectives of the present invention is to provide a safe and effective dosing regimen for compound (1) for use in cancer treatment. Surprisingly, the dosing regimen according to the invention has been found to achieve clinical efficacy while providing a tolerable and manageable safety profile. Efficacy and safety results from an ongoing dose escalation study are reported in Example 1 (with a first cutoff date or an earlier cutoff date) and Example 2 (with a second cutoff date or a later cutoff date). Example 3 relates to a dose expansion trial in patients treated with 120 mg or 240 mg of compound (1) once daily.

[0038] Specifically, effectiveness can be demonstrated by Petition 870250085375, dated 09 / 22 / 2025, page 22 / 198 11 / 141 partial responses with an overall response rate (ORR) of 45.8% in patients with non-small cell lung cancer with a good disease control rate (DCR) of 95.8% (excluding patients who had a better overall response of “not evaluable” at the time of data cutoff) at the earlier cutoff date. At the later cutoff date, compound (1) in the dosing regimens according to the present invention conferred OR and DCR of 49% and 91% in 53 patients with previously treated HER2-aberrant solid tumors, and of 58% and 97% in those patients with HER2-mutant positive NSCLC (n=36). Further preliminary evidence of efficacy is provided in Examples 1 and 2 (see in particular 1.2.4 and 2.3 and Figures 2 to 9 and 12 to 13) and in Example 3 (see in particular 3.2 and Figure 14).

[0039] Furthermore, the effectiveness of the dosing regimen according to the invention is evidenced by the impressive median progression-free survival (PFS) times observed to the later cutoff date, specifically around 8 months in all treated patients (8.0 months in the BID regimen and 8.3 months in the QD regimen) and over 1 year in NSCLC patients (13.8 months in the BID regimen and 12.3 months in the QD regimen), where median PFS was calculated using a Kaplan-Meier estimate (see 2.8 in Example 2 and Figures 12 and 13).

[0040] At the same time, the side effects brought about by the dosage regimen according to the invention are surprisingly few and mild, as demonstrated by the fact that only 3 dose-limiting toxicities (DLTs) were observed, all of them occurring outside the maximum tolerated dose (MTD) observation period, and the MTD had not yet been reached at the first cutoff date (see 1.2.3 in Example 1). At the second cutoff date, four patients experienced a DLT at some point during the entire treatment period and the MTD had not yet been reached (see 2.2 Petition 870250085375, dated 09 / 22 / 2025, page 23 / 198 12 / 141 in Example 2). This indicates good safety and tolerability of the medical uses and treatment methods according to the invention, as well as a low discontinuation rate. Furthermore, the dosage regimen according to the invention also appears to be suitable for a variety of patients who have already received other cancer-related treatments.

[0041] The positive safety profile observed with the dosage regimens of the invention allows relatively high amounts of compound (1) to be administered at the same time. This, in turn, can have several advantageous effects, for example, on patient adherence.

[0042] Furthermore, the observed efficacy and tolerability were maintained for long periods of time, as indicated by the duration of treatment (see 1.2.6 in Example 1 and 2.4 in Example 2), duration of response (see 1.2.7 in Example 1 and 2.5 in Example 2), 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).

[0043] The dose-efficacy and dose-safety relationships were unexpectedly found to be flat, which may be indicative of a wide therapeutic window for the invention (see Section 1.2.5 in Example 1). In particular, the relationship between the total daily dose and the objective response rate was estimated to be very flat, indicating that even relatively low doses lead to high response rates (see Figure 10). Similar observations were predicted for the relationship between the total daily dose and tumor reduction (see Figure 11).

[0044] Advantageously, the dosing regimen of the invention was comparatively effective in the patient population pre-treated with the anti-HER2 antibody conjugate (ADC) trastuzumab deruxtecan. Petition 870250085375, dated 09 / 22 / 2025, page 24 / 198 13 / 141 (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 have acquired resistance to T-DXd (see Example 4 and Figure 16). Compound (1)

[0045] As used in this application, the term “compound (1)” refers to the compound as defined below or to a pharmaceutically acceptable salt thereof: (1).

[0046] The IUPAC name of compound (1) is N-{1-[8-({3-methyl-4-[(1 methyl-1 H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4 d]pirimidin-2-yl]piperidin-4-yl}prop-2-enamide. In case of discrepancy between the IUPAC name and the represented formula, the formula shall prevail. Compound (1) is also known as zongertinib. Compound (1) is disclosed in WO 2021 / 213800 as exemplary compound I-01. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines, such as compound (1), as HER2 inhibitors and provides a synthesis procedure for compound (1). Properties of compound (1) and evidence of inhibitory effect on wild-type HER2 kinase and YVMA activity, while not significantly affecting EGFR, are also disclosed in WO 2021 / 213800, which is incorporated herein by reference.

[0047] The term “compound (1)” as used in this application also covers any pharmaceutically acceptable tautomers and salts and all solid-state forms of the compound, as well Petition 870250085375, dated 09 / 22 / 2025, page 25 / 198 14 / 141 as solvates, including hydrates and solvates of pharmaceutically acceptable salts thereof.

[0048] In the embodiments, compound (1) is used as a free base. In the embodiments, pharmaceutically acceptable salts of compound (1) are used. The term “pharmaceutically acceptable” as used in this application refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response or other problem or complication, and proportionate to a reasonable benefit / risk ratio.

[0049] As used in this application, “pharmaceutically acceptable salts” of compound (1) refers to compound (1) wherein the compound is modified by the production of acidic or basic salts thereof. The term pharmaceutically acceptable salts, as used in this application, generally includes both acidic and basic addition salts. Pharmaceutically acceptable acidic addition salts refer to salts that retain the biological efficacy and properties of the free base and that are not biologically or otherwise undesirable, formed with inorganic acids or organic acids. Pharmaceutically acceptable basic addition salts include salts derived from non-toxic inorganic or organic bases. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids from basic residues, such as amines; alkaline or organic salts from acidic residues, such as carboxylic acids; and the like.For example, such salts include salts of 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. Petition 870250085375, dated 09 / 22 / 2025, page 26 / 198 15 / 141 In some embodiments, pharmaceutically acceptable salts are selected from among chloride and fumarate salts.

[0050] Pharmaceutically acceptable salts 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 the appropriate 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.

[0051] The term “solvate”, as used in this application, refers to an association or complex of one or more solvent and compound molecules (1). Examples of solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, methyl tert-butyl ether, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone and ethanolamine. The term “hydrate” refers to a complex where the solvent molecule is water.

[0052] Doses and dosage regimens

[0053] One of the objectives of the present invention is to provide a safe and effective dosing regimen for the administration of compound (1) or a pharmaceutical composition comprising compound (1) in the dosing regimen described. This dosing regimen is especially useful for use in the treatment of cancer. Furthermore, this dosing regimen of compound (1) or a pharmaceutical composition comprising compound (1) is especially useful in a method of treating a cancer patient. In addition, the dosing regimen also appears to be suitable as a second-line or post-line treatment, where the patient has previously received one or more types of cancer treatments.

[0054] As used in this application, “dosage regimen” or “dosage schedule” refers to the administration of compound (1) of Petition 870250085375, dated 09 / 22 / 2025, page 27 / 198 16 / 141 according to one or more characteristics, including, but not limited to: daily dose, once / twice daily administration, oral administration, administration for a certain duration, administration after systemic anticancer therapy, etc.

[0055] As used in this application, “daily dose” or “total daily dose” refers to the amount of active substance, i.e., compound (1), that is administered to the patient within a 24-hour period. The 24-hour period does not necessarily begin at noon or midnight.

[0056] It was surprisingly found that the use of compound (1) in the treatment of cancer at a daily dose of at least 30 mg is safe and effective, as described above and in the example below.

[0057] In preferred embodiments, compound (1) is administered at a daily dose of at least 60 mg. Alternatively, the treatment method for a cancer patient described above comprises administering compound (1) at a daily dose of at least 60 mg.

[0058] In preferred embodiments, compound (1) is administered at a daily dose of at least 80 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of at least 80 mg.

[0059] In preferred embodiments, compound (1) is administered at a daily dose of at least 120 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of at least 120 mg.

[0060] In preferred embodiments, compound (1) is administered at a daily dose of at least 180 mg. Alternatively, the method of treating a cancer patient Petition 870250085375, dated 09 / 22 / 2025, page 28 / 198 17 / 141 involves administering compound (1) at a daily dose of at least 180 mg.

[0061] In preferred embodiments, compound (1) is administered at a daily dose of at least 200 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of at least 200 mg.

[0062] In preferred embodiments, compound (1) is administered at a daily dose of at least 240 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of at least 240 mg.

[0063] In preferred embodiments, compound (1) is administered at a daily dose of at least 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of at least 300 mg.

[0064] In preferred embodiments, compound (1) is administered at a daily dose of 30 mg to 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 30 mg to 600 mg.

[0065] In preferred embodiments, compound (1) is administered at a daily dose of 60 mg to 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 60 mg to 600 mg.

[0066] In preferred embodiments, compound (1) is administered at a daily dose of 80 mg to 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 80 mg to 600 mg.

[0067] In preferred embodiments, compound (1) is Petition 870250085375, dated 09 / 22 / 2025, page 29 / 198 18 / 141 administered at a daily dose of 120 mg to 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 120 mg to 600 mg.

[0068] In another preferred embodiment, compound (1) is administered at a daily dose of 30 mg to 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 30 mg to 300 mg.

[0069] In another preferred embodiment, compound (1) is administered at a daily dose of 60 mg to 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 60 mg to 300 mg.

[0070] In another preferred embodiment, compound (1) is administered at a daily dose of 80 mg to 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 80 mg to 300 mg.

[0071] In another preferred embodiment, compound (1) is administered at a daily dose of 120 mg to 300 mg.Alternatively, the treatment method for a cancer patient involves administering compound (1) at a daily dose of 120 mg to 300 mg.

[0072] In preferred embodiments, compound (1) is administered at 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, the method of treating a cancer patient comprises administering compound (1) at 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.

[0073] In preferred embodiments, compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, Petition 870250085375, dated 09 / 22 / 2025, page 30 / 198 19 / 141 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at 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.

[0074] In preferred embodiments, compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

[0075] In preferred embodiments, compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg.

[0076] In preferred embodiments, compound (1) is administered at a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg. Alternatively, the method of treating a cancer patient comprises administering compound (1) at a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

[0077] In preferred embodiments, compound (1) is administered at a daily dose of 120 mg or 240 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 120 mg or 240 mg.

[0078] In preferred embodiments, compound (1) is administered at a daily dose of 30 mg. Alternatively, the method Petition 870250085375, dated 09 / 22 / 2025, page 31 / 198 20 / 141 of treatment of a cancer patient comprises the administration of compound (1) at a daily dose of 30 mg.

[0079] In preferred embodiments, compound (1) is administered at a daily dose of 60 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 60 mg.

[0080] In preferred embodiments, compound (1) is administered at a daily dose of 80 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 80 mg.

[0081] In preferred embodiments, compound (1) is administered at a daily dose of 120 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 120 mg.

[0082] In preferred embodiments, compound (1) is administered at a daily dose of 180 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 180 mg.

[0083] In preferred embodiments, compound (1) is administered at a daily dose of 200 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 200 mg.

[0084] In preferred embodiments, compound (1) is administered at a daily dose of 240 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 240 mg.

[0085] In preferred embodiments, compound (1) is administered at a daily dose of 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 300 mg. Petition 870250085375, dated 09 / 22 / 2025, page 32 / 198 21 / 141

[0086] In preferred embodiments, compound (1) is administered at a daily dose of 360 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 360 mg.

[0087] In preferred embodiments, compound (1) is administered at a daily dose of 400 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 400 mg.

[0088] In preferred embodiments, compound (1) is administered at a daily dose of 420 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 420 mg.

[0089] In preferred embodiments, compound (1) is administered at a daily dose of 480 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 480 mg.

[0090] In preferred embodiments, compound (1) is administered at a daily dose of 500 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 500 mg.

[0091] In preferred embodiments, compound (1) is administered at a daily dose of 540 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 540 mg.

[0092] In preferred embodiments, compound (1) is administered at a daily dose of 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) at a daily dose of 600 mg.

[0093] In a preferred embodiment, compound (1) is administered once or twice daily. This means that the daily dose Petition 870250085375, dated 09 / 22 / 2025, page 33 / 198 22 / 141 is administered daily as a single dose or the daily dose is divided into two separate administrations, each administered at a different time each day, i.e., within 24 hours. When compound (1) is administered twice daily, the two separate administrations 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, still preferably 8, 9, 10, 11 or 12 hours, also preferably approximately 12 hours.

[0094] In a preferred embodiment, compound (1) is administered once daily. In a preferred embodiment, compound (1) is administered as a single dose every 24 h.

[0095] In a preferred embodiment, compound (1) is administered twice daily. In a preferred embodiment, compound (1) is administered twice every 24 h.

[0096] In preferred embodiments, each of the two daily administrations of compound (1) corresponds to half the daily dose. An easy and error-proof application scheme can be provided by administering the required daily dose of compound (1) in two doses comprising the same quantity.

[0097] In another preferred embodiment, compound (1) is administered for at least 21 consecutive days. In other preferred embodiments, compound (1) is administered for 21 days multiplied by X, where X is a natural number equal to or greater than 1. As used in this application, “21 days” and “3 weeks” are considered synonymous. It is also possible that in the overall cancer treatment, a dose-free interval may be included between treatment times, including administration of compound (1).

[0098] In some embodiments, compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, Petition 870250085375, dated 09 / 22 / 2025, page 34 / 198 23 / 141 300 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. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180mg, 240mg, 300mg, 360mg, 400mg, 420mg, 480mg, 500mg, 540 mg or 600 mg or administration of 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.

[0099] 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 or 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, the method of treating a cancer patient comprises 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.

[00100] 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, the treatment method for a cancer patient comprises 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. Petition 870250085375, dated 09 / 22 / 2025, page 35 / 198 24 / 141

[00101] 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, the treatment method for a cancer patient comprises 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.

[00102] 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, the treatment method for a cancer patient comprises 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.

[00103] 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, the treatment method for a cancer patient comprises 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.

[00104] 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, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg.

[00105] In preferred embodiments, compound (1) is administered once daily at a daily dose of 120 mg or 240 mg. Petition 870250085375, dated 09 / 22 / 2025, page 36 / 198 25 / 141 Alternatively, the treatment method for a cancer patient involves administering compound (1) once daily at a daily dose of 120 mg or 240 mg.

[00106] In preferred embodiments, compound (1) is administered once daily at a daily dose of 60 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 60 mg.

[00107] In preferred embodiments, compound (1) is administered once daily at a daily dose of 120 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 120 mg.

[00108] In preferred embodiments, compound (1) is administered once daily at a daily dose of 180 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 180 mg.

[00109] In preferred embodiments, compound (1) is administered once daily at a daily dose of 240 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 240 mg.

[00110] In preferred embodiments, compound (1) is administered once daily at a daily dose of 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 300 mg.

[00111] In preferred embodiments, compound (1) is administered once daily at a daily dose of 360 mg. Petition 870250085375, dated 09 / 22 / 2025, page 37 / 198 26 / 141 Alternatively, the treatment method for a cancer patient involves administering compound (1) once daily at a daily dose of 360 mg.

[00112] In preferred embodiments, compound (1) is administered once daily at a daily dose of 400 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 400 mg.

[00113] In preferred embodiments, compound (1) is administered once daily at a daily dose of 420 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 420 mg.

[00114] In preferred embodiments, compound (1) is administered once daily at a daily dose of 480 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 480 mg.

[00115] In preferred embodiments, compound (1) is administered once daily at a daily dose of 500 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 500 mg.

[00116] In preferred embodiments, compound (1) is administered once daily at a daily dose of 540 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) once daily at a daily dose of 540 mg.

[00117] In preferred embodiments, compound (1) is administered once daily at a daily dose of 600 mg. Petition 870250085375, dated 09 / 22 / 2025, page 38 / 198 27 / 141 Alternatively, the treatment method for a cancer patient involves administering compound (1) once daily at a daily dose of 600 mg.

[00118] 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, the treatment method for a cancer patient comprises 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.

[00119] 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, the treatment method for a cancer patient comprises 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.

[00120] 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, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg.

[00121] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 30 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 30 mg. Preferably, in these embodiments, each of the two daily administrations is 15 mg.

[00122] In preferred forms, compound (1) is Petition 870250085375, dated 09 / 22 / 2025, page 39 / 198 28 / 141 administered twice daily at a daily dose of 60 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 60 mg. Preferably, in these modalities, each of the two daily administrations is 30 mg.

[00123] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 120 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 120 mg. Preferably, in these embodiments, each of the two daily administrations is 60 mg.

[00124] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 200 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 200 mg. Preferably, in these embodiments, each of the two daily administrations is 100 mg.

[00125] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 300 mg. Preferably, in these embodiments, each of the two daily administrations is 150 mg.

[00126] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 360 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 360 mg. Preferably, in these embodiments, each of the two daily administrations is 180 mg.

[00127] In preferred forms, compound (1) is Petition 870250085375, dated 09 / 22 / 2025, page 40 / 198 29 / 141 administered twice daily at a daily dose of 400 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 400 mg. Preferably, in these modalities, each of the two daily administrations is 200 mg.

[00128] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 420 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 420 mg. Preferably, in these embodiments, each of the two daily administrations is 210 mg.

[00129] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 480 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 480 mg. Preferably, in these embodiments, each of the two daily administrations is 240 mg.

[00130] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 500 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 500 mg. Preferably, in these embodiments, each of the two daily administrations is 250 mg.

[00131] In preferred embodiments, compound (1) is administered twice daily at a daily dose of 540 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 540 mg. Preferably, in these embodiments, each of the two daily administrations is 270 mg.

[00132] In preferred forms, compound (1) is Petition 870250085375, dated 09 / 22 / 2025, page 41 / 198 30 / 141 administered twice daily at a daily dose of 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) twice daily at a daily dose of 600 mg. Preferably, in these modalities, each of the two daily administrations is 300 mg.

[00133] In some embodiments, compound (1) is administered orally.

[00134] In some embodiments, compound (1) is administered as a tablet.

[00135] In some embodiments, compound (1) is administered orally, preferably as a tablet, 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, the method of treating a cancer patient comprises administering compound (1) orally, preferably as a tablet, 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.

[00136] In some embodiments, compound (1) is administered orally, preferably in tablet form, 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, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, 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.

[00137] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg. Alternatively, the method of treating a cancer patient Petition 870250085375, dated 09 / 22 / 2025, page 42 / 198 31 / 141 comprises the administration of compound (1) orally, preferably in tablet form, once daily, at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg.

[00138] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 120 mg or 240 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 120 mg or 240 mg.

[00139] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 60 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 60 mg.

[00140] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 120 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 120 mg.

[00141] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 180 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 180 mg.

[00142] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 240 mg. Alternatively, the method of Petition 870250085375, dated 09 / 22 / 2025, page 43 / 198 32 / 141 treatment of a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 240 mg.

[00143] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 300 mg.

[00144] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 360 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 360 mg.

[00145] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 400 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 400 mg.

[00146] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 420 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 420 mg.

[00147] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 480 mg. Alternatively, the method of Petition 870250085375, dated 09 / 22 / 2025, page 44 / 198 33 / 141 treatment of a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 480 mg.

[00148] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 500 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 500 mg.

[00149] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 540 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 540 mg.

[00150] In some embodiments, compound (1) is administered orally, preferably in tablet form, once daily, at a daily dose of 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, once daily, at a daily dose of 600 mg.

[00151] In some embodiments, compound (1) is administered orally, preferably as a tablet, 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, the method of treating a cancer patient comprises administering compound (1) orally, preferably as a tablet, 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. Petition 870250085375, dated 09 / 22 / 2025, page 45 / 198 34 / 141

[00152] In some embodiments, compound (1) is administered orally, preferably in tablet form, 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, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, 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.

[00153] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.

[00154] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 30 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 30 mg. Preferably, in these embodiments, each of the two daily administrations is 15 mg.

[00155] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 60 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 60 mg. Preferably, Petition 870250085375, dated 09 / 22 / 2025, page 46 / 198 35 / 141 in these modalities, each of the two daily administrations is 30 mg.

[00156] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 120 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 120 mg. Preferably, in these embodiments, each of the two daily administrations is 60 mg.

[00157] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 200 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 200 mg. Preferably, in these embodiments, each of the two daily administrations is 100 mg.

[00158] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 300 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 300 mg. Preferably, in these embodiments, each of the two daily administrations is 150 mg.

[00159] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 360 mg. Alternatively, the treatment method for a cancer patient comprises the administration of Petition 870250085375, dated 09 / 22 / 2025, page 47 / 198 36 / 141 compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 360 mg. Preferably, in these forms, each of the two daily administrations is 180 mg.

[00160] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 400 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 400 mg. Preferably, in these embodiments, each of the two daily administrations is 200 mg.

[00161] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 420 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 420 mg. Preferably, in these embodiments, each of the two daily administrations is 210 mg.

[00162] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 480 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 480 mg. Preferably, in these embodiments, each of the two daily administrations is 240 mg.

[00163] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice a day. Petition 870250085375, dated 09 / 22 / 2025, page 48 / 198 37 / 141 day, at a daily dose of 500 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 500 mg. Preferably, in these modalities, each of the two daily administrations is 250 mg.

[00164] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 540 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 540 mg. Preferably, in these embodiments, each of the two daily administrations is 270 mg.

[00165] In some embodiments, compound (1) is administered orally, preferably in tablet form, twice daily, at a daily dose of 600 mg. Alternatively, the treatment method for a cancer patient comprises administering compound (1) orally, preferably in tablet form, twice daily, at a daily dose of 600 mg. Preferably, in these embodiments, each of the two daily administrations is 300 mg.

[00166] In a preferred embodiment, it is also possible to combine dosage regimens defined above for compound (1) and to change the daily doses during the course of treatment. Therefore, it is possible, for example, to start treatment by administering a daily dose of 30 mg (once or twice a day) and change the dose to higher or lower daily doses (applied once or twice a day).

[00167] The dosage regimens described in this paragraph are also applicable in cases where the patient has already received one or more Petition 870250085375, dated 09 / 22 / 2025, page 49 / 198 38 / 141 systemic anticancer treatments or therapies. Use for cancer treatment

[00168] One aspect relates to compound (1) and the dosing regimen described in this application for use in the treatment and / or prevention of cancer. In addition, a further aspect relates to compound (1) and the dosing regimen described in this application for use in the treatment and / or prevention of cancer, wherein the patient has previously received one or more anticancer treatments or therapies, in particular a systemic anticancer therapy agent.

[00169] According to one aspect, compound (1) is provided for use as an anticancer drug, in the dosage regimen as described in this application.

[00170] As used in this application, cancer is, in certain cases, a “hyperproliferative disease” and refers to conditions in which cell growth is increased relative to normal levels. Hyperproliferative diseases include malignant diseases, such as cancer, and non-malignant diseases. As used in this application, cancer is, in certain cases, also referred to as an “oncological disease.” An oncological disease refers to a disease or medical condition associated with cancer or an indication of cancer. Cancers can be classified by the type of tissue in which they originate (histological type) and by the primary site, that is, the location in the body where the cancer initially developed.

[00171] In one embodiment, compound (1) is provided in the dosage regimen as described in this application for use in the treatment and / or prevention of cancer. Another embodiment provides the pharmaceutical composition as described in this application in the dosage regimen as described in this application for use in the treatment and / or prevention of cancer. Yet another embodiment provides compound (1) or the pharmaceutical composition as described in this application for use in Petition 870250085375, dated 09 / 22 / 2025, page 50 / 198 39 / 141 treatment and / or prevention of cancer, where the patient has already received first-line, second-line or other additional treatment. A different treatment comprises the administration of a different therapy, drug or anticancer agent and does not include compound (1). The first-line, second-line or additional treatment previously administered is not correlated with the administration of compound (1) and the first-line, second-line or additional treatment previously administered was completed or ended before a treatment comprising the administration of compound (1) was administered.

[00172] Another aspect relates to a method of treating and / or preventing cancer, wherein the method comprises the step of administering compound (1) in the dosage regimen described in this application or the pharmaceutical composition as described in this application in the dosage regimen described in this application to a patient. In one embodiment, such method comprises administering to a human being in need of such treatment the disclosed therapeutically effective amount of compound (1) or pharmaceutical composition comprising compound (1) as described in this application.

[00173] Another aspect relates to a method of treating and / or preventing cancer, wherein the method comprises the step of administering compound (1) in the dosage regimen described in this application or the pharmaceutical composition as described in this application in the dosage regimen described in this application to a patient, wherein the patient has already received first-line, second-line or additional-line treatment. In one embodiment, such method comprises administering to a human being in need of such treatment a therapeutically effective amount of compound (1) or pharmaceutical composition comprising compound (1) as described in this application, wherein the patient has already received first-line treatment, Petition 870250085375, dated 09 / 22 / 2025, page 51 / 198 40 / 141 second line or additional line.

[00174] An embodiment refers to the use of compound (1) in the dosage regimen described in this application or the pharmaceutical composition in the dosage regimen described in this application in the manufacture of a medicament for the treatment and / or prevention of cancer.

[00175] In some embodiments, the cancer or tumor comprises a HER2 aberration. This means that the cancer or tumor cells harbor a HER2 aberration. As used in this application, the terms “HER2 aberration,” “HER2 aberration,” and their grammatical variants have the meaning commonly ascribed to them in the art and include any variation or alteration in the HER2 protein or its encoding gene, such as: overexpression of the HER2 protein, amplification of the HER2 encoding gene, mutations in the HER2 encoding gene and / or the HER2 protein (in particular non-synonymous mutations, somatic mutations, mutations in specific regions, e.g., in the tyrosine kinase domain, exon 20, etc.), as well as HER2 and / or NRG1 gene rearrangements. When the cancer comprises a HER2 aberration, it may be called HER2 aberrant. When cancer exhibits overexpression of the HER2 protein, it can be called HER2 overexpressed.When cancer involves an amplification of the gene that codes for HER2, it can be called HER2-amplified cancer. When cancer has a mutation in the gene that codes for HER2 and / or in the HER2 protein, it can be called HER2-mutant cancer.

[00176] In some forms, the cancer is HER2 overexpressed, HER2 amplified, and / or HER2 mutant.

[00177] In some forms, the cancer comprises a mutation in the tyrosine kinase domain of HER2. In some forms, the cancer is HER2 exon 20 mutant cancer.

[00178] In modalities, cancer comprises a gene rearrangement Petition 870250085375, dated 09 / 22 / 2025, page 52 / 198 41 / 141 of HER2 and / or NRG1.

[00179] “HER2 overexpressed”, as used in this application, refers to a cancer where the cancer or tumor cells express HER2 at levels detectable by immunohistochemistry (e.g., IHC 2 and IHC 3) and / or methods that analyze ERBB2 messenger RNA.

[00180] “Amplified HER2”, as used in this application, refers to a cancer in which the cancerous or tumor cells exhibit more than 2, in particular more than 3, 4, 5, 6, 7, 8, 9 or 10, preferably more than 6, copies of the HER2 ERBB2 gene.

[00181] HER2 expression, gene copy number, and amplification can be measured, for example, by determining nucleic acid sequencing (e.g., genomic DNA or cDNA sequencing), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), in situ hybridization—including fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH)—ELISAs, and RNA quantification using techniques such as reverse transcription polymerase chain reaction (RT-PCR), microarray analysis, and next-generation sequencing (NGS). HER2 expression in cancer sample cells can be compared to a reference cell. The reference cell can be a non-cancerous cell obtained from the same individual as the sample cell.The reference cell can be a non-cancerous cell obtained from a different individual or from a population of individuals.

[00182] When cancer is HER2 overexpressed and / or HER2 amplified within or on a cell, the cancer may be called “HER2-positive”.

[00183] The term “HER2 mutant”, as used in this application, refers to a cancer that has at least one mutation, that is, a Petition 870250085375, dated 09 / 22 / 2025, page 53 / 198 42 / 141 alteration in the nucleic acid sequence of the gene encoding HER2 and / or an alteration in the amino acid sequence of the HER2 protein, including, but not limited to, those listed below. Mutations may be identified by any method known to those skilled in the art, such as molecular diagnostic methods including, but not limited to, polymerase chain reaction (PCR), single-strand conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism (RFLP), next-generation sequencing (NGS), and whole-exome sequencing.

[00184] In HER2 mutant cancer modalities, the mutation is a non-synonymous mutation. As used in this application, the term “non-synonymous” has the meaning commonly ascribed to it in the art and, in particular, refers to a mutation in the nucleic acid sequence of the gene encoding HER2 that alters the amino acid sequence of the HER2 protein.

[00185] In HER2 mutant cancer modalities, the mutation is a somatic mutation. As used in this application, the term “somatic” has the meaning commonly ascribed to it in the art and, in particular, refers to a mutation in the nucleic acid sequence of the gene encoding HER2 that occurs in a cell other than a gamete, a germ cell, or a gametocyte.

[00186] In HER2-mutant cancer forms, the mutation is a non-synonymous somatic mutation.

[00187] In HER2-mutant cancer modalities, the mutation is a non-synonymous somatic mutation in the tyrosine kinase domain of HER2.

[00188] In HER2-mutant cancer forms, the mutation is in the tyrosine kinase domain of HER2, specifically in exon 20 of HER2. In the latter case, the cancer can be called exon-mutant. Petition 870250085375, dated 09 / 22 / 2025, page 54 / 198 43 / 141 of HER2.

[00189] As used in this application, “HER2 mutant” may also refer to a rearrangement involving the HER2 gene ERBB2 and / or the gene NRG1.

[00190] As used in this application, a cancer comprising a mutation in the HER2 tyrosine kinase domain is a cancer in which the cancerous or tumor cells harbor at least one mutation in the HER2 tyrosine kinase domain, ranging from amino acids 694 to 883 and / or exons 18 to 21.

[00191] “HER2 exon 20 mutation cancer” or “HER2 exon 20 mutant cancer”, as used in this application, refers to a cancer in which the cancerous or tumor cells harbor at least one HER2 exon 20 mutation, including but not limited to the mutations listed below.

[00192] Exon 20 of ERBB2 (HER2) encodes a portion of the kinase domain and ranges from amino acids 769 to 835. Each mutation, insertion, duplication, or deletion mutation of exon p.A772_G773insMMAY; p.A775_G776insYVMA; p.A775_G776insSVMA; p.A775_G776insYVMS; p.A776_delinsLC; p.A776_delinsIC; p.V777_G778insV; within this region is defined as a 20, including the following mutations: p.Y772_A775_dup (YVMA); p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insVVMA; p.A775_G776insC; p.A776_delinsVC; p.A776_delinsVV; p.A776_delinsAVGC; p.A776_V777delinsCVC; p.V777_insE; p.V777_G778insC; p.V777_G778insCG; p.V777_S779dup; p.V777L; p.V777M; p.G778_P780dup (GSP); p.G778_S779insCPG; p.G778_S779insG; p.G776_delinsVC; p.G776_V777delinsAVGCV; p.G776delinsLC; p.G776_V777delinsAVCV; p.G776delinsVV; p.G776_V777insL; p.G776_V777insVGC; p.G776C; p.G776A; p.G776L; p.G776V; Petition 870250085375, dated 09 / 22 / 2025, p. 55 / 198 44 / 141 p.P780_Y781insGSP (“p.” refers to the HER2 protein).

[00193] In addition, there are HER2 mutations outside exon 20, 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 (“p.” refers to the HER2 protein).

[00194] 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.

[00195] In some modalities, cancer is one of, but not limited to, the following cancers, tumors, or other proliferative diseases:

[00196] Cancers / tumors / carcinomas of the head and neck: for example, tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of the mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of the tongue, tonsil, tonsillar pillar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands);

[00197] 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), small cell lung cancer (SCLC) (non-small cell cancer, intermediate cell cancer, combined non-small cell cancer); Petition 870250085375, dated 09 / 22 / 2025, page 56 / 198 45 / 141 mediastinal neoplasms: for example, neurogenic tumors (including neurofibroma, neurilemmoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma);Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: for example, tumors / carcinomas / cancers of the esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), for example, infantile HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma-type HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gallbladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, tumor of gastrointestinal stromal tumor (GIST), appendix, genitourinary system (including kidney, for example, renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor; ureter;urinary bladder, for example, urachal cancer, urothelial cancer; urethra, for example, distal, bulbomembranous, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis); Petition 870250085375, dated 09 / 22 / 2025, page 57 / 198 46 / 141

[00198] cancers / tumors / carcinomas of the testicle: for example, seminomas, non-seminomas;

[00199] Gynecological cancers / tumors / carcinomas: for example, tumors / carcinomas / cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus);

[00200] Breast cancers / tumors / carcinomas: for example, breast carcinoma (invasive ductal, colloid, invasive 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;

[00201] Endocrine system cancers / tumors / carcinomas: for example, tumors / carcinomas / cancers of the endocrine glands, thyroid gland (thyroid carcinomas / tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (adrenocortical carcinomas / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglioma, pancreatic endocrine tumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors;

[00202] Soft tissue sarcomas: for example, fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, giant cell sarcoma Petition 870250085375, dated 09 / 22 / 2025, page 58 / 198 47 / 141 clear, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft tissue sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor.

[00203] bone sarcomas: for example, myeloma, reticular cell sarcoma, chondrosarcoma (including central, peripheral, clear cell chondrosarcoma, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell osteosarcoma, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, histiocytoma (fibrous), fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[00204] mesothelioma: for example, pleural mesothelioma, peritoneal mesothelioma;

[00205] skin cancers: for example, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer;

[00206] Neoplasms of the central nervous system and brain: for example, astrocytoma (cerebral, cerebellar, diffuse, fibrillar, anaplastic, pilocytic, protoplasmic, gemistocytic), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, Petition 870250085375, dated 09 / 22 / 2025, page 59 / 198 48 / 141 retinoblastomas, neurinomas (e.g., acoustic), spinal axis tumors;

[00207] cancer of the peripheral nervous system; Lymphomas and leukemias: for example, non-Hodgkin B-cell lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL)), non-Hodgkin T-cell lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), T-cell lymphoblastic lymphoma (T-LBL), adult T-cell lymphoma, B-cell lymphoblastic lymphoma (B-LBL), immunocytoma, chronic lymphocytic leukemia of B cells (B-CLL), chronic lymphocytic leukemia of T cells (T-CLL), small lymphocytic lymphoma of B cells (B-SLL), lymphoma cutaneous T-cell lymphoma (CTCL), primary central nervous system lymphoma (PCNSL), immunoblastoma,Hodgkin's disease (HD) (including nodular lymphocytic predominant Hodgkin's disease (NLPHD), nodular sclerosis Hodgkin's disease (NSHD), mixed cellularity Hodgkin's disease (MCHD), classic lymphocyte-rich Hodgkin's disease, lymphocyte-depleted Hodgkin's disease (LDHD)), large granular lymphocyte 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 syndromes (MDS), leukemia Chronic myelomonocytic leukemia (CMML);

[00208] cancers of unknown primary site (CUP).

[00209] All cancers / tumors / carcinomas mentioned above, which are characterized by their specific location / origin in Petition 870250085375, dated 09 / 22 / 2025, page 60 / 198 49 / 141 body, should include both primary tumors and metastatic tumors derived from them. Preferably, the cancer as defined in this application (including in any modality referring to, for example, cancer types) is metastatic, advanced and / or unresectable.

[00210] All the cancers / tumors / carcinomas mentioned above can be further differentiated by their histopathological classification:

[00211] Epithelial cancers, for example, squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, small oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma;

[00212] Non-epithelial cancers, for example, sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological malignancies, mixed and undifferentiated carcinomas.

[00213] In some forms, the cancer is a solid tumor. In some forms, the cancer is manifested by at least one solid tumor.

[00214] In some modalities, the cancer is selected from the group Petition 870250085375, dated 09 / 22 / 2025, page 61 / 198 50 / 141 which consists of brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck tumor, lung cancer, nervous system cancer, and skin cancer.

[00215] Preferably, brain cancer is a glioblastoma or a glioma.

[00216] Preferably, the breast cancer is lobular breast cancer. In addition or alternatively, said breast cancer is preferably metastatic.

[00217] Preferably, the endocrine cancer is a nerve sheath tumor, more preferably a HER2 mutant nerve sheath tumor.

[00218] Preferably, said gastrointestinal cancer is selected from the group consisting of anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, and small bowel cancer. In addition or alternatively, said gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably HER2 mutant. Also preferably, said gastrointestinal cancer is selected from the group consisting of gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, in particular metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[00219] Preferably, gynecological cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer, and ovarian cancer.

[00220] As used in this application, “head and neck tumor” Petition 870250085375, dated 09 / 22 / 2025, page 62 / 198 51 / 141 refers primarily to head and neck cancer. Preferably, the head and neck tumor is a salivary gland cancer or tumor.

[00221] Preferably, the said lung cancer is non-small cell lung cancer (NSCLC).

[00222] Preferably, cancer of the nervous system is cancer of the peripheral nervous system, more preferably cancer of the peripheral nervous system amplified by HER2.

[00223] Preferably, the skin cancer is not melanoma, that is, a non-melanoma skin cancer.

[00224] In some modalities, the cancer is selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, renal cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, gastrointestinal neuroendocrine cancer, metastatic gastric adenocarcinoma, metastatic adenocarcinoma of the gastroesophageal junction, 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.

[00225] In some modalities, the cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant (in particular, mutant in exon 20 of HER2), selected from the group consisting of glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, nerve sheath tumor, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, Petition 870250085375, dated 09 / 22 / 2025, page 63 / 198 52 / 141 gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, renal cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, gastrointestinal neuroendocrine cancer, metastatic gastric adenocarcinoma, metastatic adenocarcinoma of the gastroesophageal junction, 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.

[00226] In some modalities, the cancer is selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric 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.

[00227] In some modalities, the cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant (in particular mutant in exon 20 of HER2), selected from the group consisting of brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, renal cancer, liver cancer, lung cancer and prostate cancer.

[00228] In some modalities, 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, gastric cancer, tumor Petition 870250085375, dated 09 / 22 / 2025, page 64 / 198 53 / 141 of esophagus, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

[00229] In modalities, the cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant (in particular, mutant in exon 20 of HER2), selected from the group consisting of brain cancer, breast cancer, biliary tract 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.

[00230] In other modalities, the cancer is selected from the group consisting of breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In other modalities, 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), small cell lung cancer (SCLC) (non-small cell cancer, intermediate cell cancer, combined non-small cell cancer); In other modalities, the cancer is NSCLC. In other modalities, the cancer is a HER2 exon 20 mutant NSCLC.

[00231] In other modalities, the cancer is unresectable. In other modalities, the cancer is an unresectable HER2 exon 20 mutant NSCLC.

[00232] In one preferred modality, the cancer is advanced or metastatic. In another preferred modality, the cancer is both advanced and metastatic. In yet another preferred modality, Petition 870250085375, dated 09 / 22 / 2025, page 65 / 198 54 / 141 when the cancer is metastatic, the metastases are located in the lung, lymph node, bone, or liver. In another preferred modality, the cancer is an advanced cancer, including metastases, and the metastases are located in the lung, lymph node, bone, or liver. In addition, or alternatively, this cancer may be unresectable.

[00233] In a preferred embodiment, the cancer is an advanced unresectable cancer comprising solid tumors and solid metastases, and the metastases are located in the lung, liver, lymph node tissue, or bone.

[00234] In a preferred embodiment, the cancer is an advanced NSCLC comprising solid, unresectable tumors and metastases, and the metastases are located in the lung, liver, lymph node tissue, or bone.

[00235] In a preferred embodiment, the cancer is an advanced NSCLC mutant of exon 20 of HER2, comprising unresectable solid tumors and metastases, and the metastases are located in lung tissue or lymph nodes or bone.

[00236] In one embodiment, the cancer is an advanced, unresectable, or metastatic NSCLC harboring a HER2 mutation, wherein the HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, compound (1) is administered as first-line therapy. Also preferably, in this embodiment, compound (1) as described in this application is administered as second-line or add-on therapy.

[00237] In some embodiments, the cancer is HER2-positive metastatic breast cancer. Preferably, in this embodiment, compound (1) as described in this application is administered as first-line therapy. Also preferably, in this embodiment, compound (1) as described in this application is administered as Petition 870250085375, dated 09 / 22 / 2025, page 66 / 198 55 / 141 second line of therapy or additional line.

[00238] In some embodiments, the cancer is HER2-positive metastatic gastric adenocarcinoma, metastatic adenocarcinoma of the gastroesophageal junction, or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, compound (1) as described in this application is administered as first-line therapy. Also preferably, in this embodiment, compound (1) as described in this application is administered as second-line therapy or add-on therapy.

[00239] In another aspect, the cancer is resistant to treatment with an anti-HER2 antibody or an antibody-drug-antiHER2 conjugate, as defined in this application. In another aspect, the cancer is resistant to single-agent treatment with said anti-HER2 antibody or antibody-drug-anti-HER2 conjugate. In these aspects, resistance can be advantageously overcome by treatment with compound (1), in particular when administered according to the doses / dosing regimens described in this application.

[00240] The term “antibody,” which may be used interchangeably with “antibody molecule,” encompasses various antibody structures, including but not limited to polyclonal or monoclonal antibodies, chimeric, humanized, human, mono-, bispecific or multispecific antibodies, single-chain antibodies, single-domain antibodies, and fragmented antibodies (also called antibody fragments), such as Fab, F(ab)2, F(ab')2, Fab', single-chain variable fragments (scFv), or antigen-binding domains of an antibody, provided they exhibit the desired antigen-binding activity. The term “antibody” will encompass complete immunoglobulins, as produced by lymphocytes and, for example, present in blood sera, monoclonal antibodies secreted by hybridoma cell lines, polypeptides produced by expression Petition 870250085375, dated 09 / 22 / 2025, page 67 / 198 56 / 141 recombinant antibodies in host cells that have the binding specificity of immunoglobulins or monoclonal antibodies, and molecules that have been derived from such immunoglobulins, monoclonal antibodies, or polypeptides by further processing while maintaining their binding specificity. In particular, the term "antibody" includes complete immunoglobulins comprising two heavy chains and two light chains. The term also encompasses a fragment of an immunoglobulin, such as Fab fragments, and polypeptides having one or more variable domains derived from an immunoglobulin, such as single-chain antibodies (scFv), single-domain antibodies, and the like.

[00241] The term “antibody fragment” should refer to fragments of such an antibody that retain antigen-binding capabilities.

[00242] The antibody may have an effector function, such as ADCC or CDC, which is usually mediated by the Fc portion (constant region of the antibody) of the antibody, or it may not have an effector function, for example, by not having an Fc portion or by having a blocked and masked Fc portion; in essence, an Fc portion that is not or is insufficiently recognized by immune cells or components of the immune system, such as the complement system.

[00243] The antibody or its fragment can be of any type, for example, IgA, IgD, IgE, IgG, IgM. IgG is preferred.

[00244] The terms “monoclonal antibody” or “monoclonal antibody composition,” as used in this application, refer to a preparation of antibody molecules of a single amino acid composition or of a homogeneous population of antibodies, that is, a homogeneous population consisting of a whole immunoglobulin, or a fragment or derivative thereof. Such antibody may be selected from the group consisting of IgA, IgD, IgE, Petition 870250085375, dated 09 / 22 / 2025, p. 68 / 198 57 / 141 IgG, IgM, or a fragment thereof.

[00245] A “recombinant antibody” is an antibody that has been produced by a host cell modified by recombinant engineering. It is optionally isolated or purified.

[00246] A “human antibody” is one that has an amino acid sequence that corresponds to that of an antibody produced by a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-coding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

[00247] The term “recombinant human antibody,” as used in this application, is intended to include all human antibodies that are prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from a host cell, such as an NS0 or CHO cell, or from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes, or antibodies expressed using a recombinant expression vector transfected into a host cell. These recombinant human antibodies have variable and constant regions in a rearranged form. Recombinant human antibodies may have undergone somatic hypermutation in vivo. Thus, the amino acid sequences of the VH and VL regions of recombinant antibodies are sequences that, while derived from and related to the VH and VL sequences of the human germline, may not naturally exist in the germline repertoire of human antibodies in vivo.

[00248] A “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human hypervariable regions (HVRs) and amino acid residues from human structural regions (FRs). In certain embodiments, a Petition 870250085375, dated 09 / 22 / 2025, p. 69 / 198 58 / 141 A humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all HVRs (e.g., complementarity-determining regions (CDRs)) correspond to those of a non-human antibody, and all or substantially all FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, for example, a non-human antibody, refers to an antibody that has undergone humanization.

[00249] “Binding” of a polypeptide (such as an immunoglobulin, an antibody, or generally an antigen-binding molecule or a fragment thereof) means “having affinity for” or “having specificity for” a particular epitope, antigen, or protein (or for at least a part, fragment, or epitope thereof). The terms “binding” and “specific binding” referring to the binding of the antibody or antigen-binding fraction to an antigen epitope can be determined in an in vitro assay, preferably in a plasmonic resonance assay (BIAcore®, GE Healthcare Uppsala, Sweden) with purified wild-type antigen.

[00250] Generally, the term “specificity” refers to the number of different types of antigens or epitopes to which a specific antigen-binding molecule (such as an antibody described in this application) can bind. The specificity of an antigen-binding molecule can be determined based on its affinity and / or avidity. Affinity, represented by the equilibrium constant for the dissociation of an antigen from an antigen-binding protein (KD), is a measure of the binding strength between an epitope and an antigen-binding site on the antigen-binding protein: the lower the KD value, the stronger the binding strength between an epitope and the antigen-binding molecule. Petition 870250085375, dated 09 / 22 / 2025, page 70 / 198 59 / 141 antigen binding (alternatively, affinity can also be expressed as the affinity constant (KA), which is 1 / KD). As will become clear 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 binding strength between an antigen-binding molecule (such as an immunoglobulin, an antibody, or generally an antigen-binding molecule or a fragment thereof) containing it and the relevant antigen. Avidity is related to the affinity between an epitope and its antigen-binding site on the antigen-binding molecule and to the number of relevant binding sites present on the antigen-binding molecule.

[00251] An epitope is a region of an antigen that is bound by an antigen-binding molecule (such as an antibody described in this application). The term “epitope” includes any polypeptide determinant capable of specific binding to an antibody or antigen-binding moiety. In certain embodiments, epitope determinants include chemically active surface clusters of molecules such as amino acids, glycan side chains, phosphoryl or sulfonyl groups, and in certain embodiments, they may have specific three-dimensional structural features and / or specific charge characteristics. Conformational and non-conformational epitopes are differentiated because binding to the former, but not the latter, is lost in the presence of denaturing solvents.

[00252] The terms “variable domain” or “variable region” or Fv, as used in this application, denote each of the pairs of light and heavy chains that are directly involved in antibody binding to antigen. The variable domain of a light chain is abbreviated as “VL” and the variable domain of a heavy chain is abbreviated as “VH”. The light and heavy chain variable domains have the same general structure and each domain comprises four Petition 870250085375, dated 09 / 22 / 2025, page 71 / 198 60 / 141 structure regions (FRs) whose sequences are largely conserved, connected by three HVRs (or CDRs). The structure regions adopt a beta-sheet conformation, and the CDRs can form loops connecting the beta-sheet structure. The CDRs in each chain are maintained in their three-dimensional structure by the structure regions and, together with the CDRs of the other chain, form the antigen-binding site. The CDR regions of the antibody heavy and light chains play a particularly important role in the specificity / affinity of antibody binding.

[00253] In the context of this invention, the reference to CDRs is based on the definition of Chothia (Chothia and Lesk, J. Mol. Biol. 1987, 196: 901-917), together with 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)).

[00254] The term “constant domains” or “constant region,” as used in this application, denotes the sum of the domains of an antibody other than the variable region. The constant region is not directly involved in antigen binding but exhibits various effector functions.

[00255] The “constant domains”, as used in the antibodies disclosed in this application, are preferably of human origin, that is, a constant heavy chain region of a human antibody of the IgG1, IgG2, IgG3 or IgG4 subclass and / or a constant kappa or lambda light chain region. These constant domains and regions are well known in the state of the art and, for example, described by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, MD, Publication No. 91).

[00256] The “Fc portion” of an antibody is not directly involved in the binding of an antibody to an antigen, but it exhibits various effector functions. An “Fc portion of an antibody” is a well-known term. Petition 870250085375, dated 09 / 22 / 2025, p. 72 / 198 61 / 141 by those skilled in the art and defined based on the papain cleavage of antibodies. Depending on the amino acid sequence of the constant region of their heavy chains, antibodies or immunoglobulins are divided into the following classes: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, and IgG4, IgA1 and IgA2. According to the constant regions of the heavy chain, the different 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 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.Although the influence of an antibody on the complement system depends on certain conditions, binding to C1q is caused by defined binding sites in the Fc portion. These binding sites are known in the state of the art and described, for example, by 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. Virologia 75 (2001) 12161-12168; Morgan, A., et al, Immunologia 86 (1995) 319-324; EP 0 307 434. These binding sites are, for example, L234, L235, D270, N297, E318, K320, K322, P331 and P329 (numbering according to the EU index of Kabat, EA, see below).IgG1, IgG2, and IgG3 subclass antibodies generally show complement activation and binding to Clq and C3, while IgG4 does not activate the complement system and does not bind to Clq and C3. The term "domain" (of a polypeptide or protein), as used herein. Petition 870250085375, dated 09 / 22 / 2025, page 73 / 198 62 / 141 application, refers to a folded protein structure that has the ability to retain its tertiary structure independently of the rest of the protein. Generally, domains are responsible for discrete functional properties of proteins and, in many cases, can be added, removed, or transferred to other proteins without loss of function of the rest of the protein and / or the domain.

[00257] The expression “anti-HER2 antibody” refers to an antibody that binds, in particular binds specifically, to the HER2 protein. Anti-HER2 antibodies inhibit HER2 activation or subsequent signaling by several mechanisms. As non-limiting examples, anti-HER2 antibodies can prevent ligand binding, receptor activation or receptor signal propagation, result in reduced HER2 expression or localization on the cell surface, inhibit HER2 cleavage, or induce antibody-mediated cytotoxicity.In preferred embodiments, the expression “anti-HER2 antibody” is therefore understood as synonymous and may be replaced by “inhibitory antibody that binds specifically to HER2”. Anti-HER2 antibodies used for cancer treatment are normally monoclonal, although polyclonal antibodies are not excluded by the term. Preferably, the anti-HER2 antibody is selected from the group consisting of: trastuzumab, pertuzumab, margetuximab and combinations thereof.

[00258] Trastuzumab, also known as Herceptin, is a humanized IgG1 monoclonal antibody that binds to HER2, in particular to its extracellular domain, especially the HER2 domain that binds to another HER2 protein. The mechanism of action underlying the antitumor effect of trastuzumab has not yet been fully determined and may, in fact, involve several different mechanisms. Trastuzumab may exert its effects by activating antibody-dependent cellular cytotoxicity, preventing Petition 870250085375, dated 09 / 22 / 2025, page 74 / 198 63 / 141 HER2 dimerization, inhibition of HER2 extracellular domain cleavage, interactions with signaling pathways, cell cycle arrest during the G1 phase, induction of apoptosis, or inhibition of angiogenesis. HER2 downregulation has also been suggested as a possible mechanism. Trastuzumab is disclosed, for example, in WO 92 / 22653, which is incorporated herein by reference.

[00259] Pertuzumab, also known as Perjeta, is a humanized IgG1 monoclonal antibody that binds to HER2, in particular to the extracellular domain of HER2, especially to the extracellular dimerization subdomain of the HER2 receptor. Pertuzumab reduces intracellular HER2 signaling by preventing HER2 from forming heterodimers with other HER receptors, such as HER3. Pertuzumab is disclosed, for example, in US documents 6949245 and US 7862817, each of which is incorporated herein by reference.

[00260] Margetuximab, also known as Margenza, is a chimeric mouse / human IgG1 monoclonal antibody that binds to HER2, in particular to its extracellular domain, especially to the HER2 domain that binds to another HER2 protein. Margetuximab is disclosed, for example, in US document 8802093, which is incorporated herein by reference.

[00261] In another aspect, the anti-HER2 antibody is an inhibitory antibody. The expression “inhibitory antibody” is intended to be synonymous with “antagonist antibody” and may be substituted for the latter. An “inhibitory antibody” or “antagonist antibody”, within the meaning of this invention, is an antibody that inhibits the interaction of HER2 with its ligand(s) or receptor(s).

[00262] In another aspect, the anti-HER2 antibody binds specifically to HER2.

[00263] In another aspect, the anti-HER2 antibody binds Petition 870250085375, dated 09 / 22 / 2025, p. 75 / 198 64 / 141 specifically to the extracellular domain of HER2.

[00264] In another aspect, the anti-HER2 antibody is an inhibitory antibody that binds specifically to HER2.

[00265] In another aspect, the anti-HER2 antibody is an inhibitory antibody that binds specifically to the extracellular domain of HER2.

[00266] In another aspect, the anti-HER2 antibody is selected from the group consisting of trastuzumab, pertuzumab, margetuximab and a combination thereof.

[00267] In another aspect, the anti-HER2 antibody is selected from the group consisting of trastuzumab and pertuzumab.

[00268] The term “antibody-drug conjugate” (also abbreviated in this application as “ADC”), as used in this application, is well known in the art and describes a group of therapeutic agents that combine the specificity of tumor-targeted ligands, such as antibodies, with the potency of highly cytotoxic agents. Consequently, such conjugates of cytotoxic and / or cytostatic agents with antibodies specific for tumor cells are powerful tools for specifically targeting cancer cells and destroying them. ADCs are well known in the field and have been reviewed, 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)).

[00269] In particular, “anti-HER2 drug-antibody conjugate”, as used in this application, refers to an ADC whose tumor target ligand is an antibody directed to, targeted for, and / or that binds to HER2, such as trastuzumab, pertuzumab, and margetuximab.

[00270] The expressions “anti-HER2 drug-antibody conjugate” and “anti-HER2 ADC” therefore refer to an anti-HER2 antibody conjugated to a cytotoxic drug, also called a payload, optionally via a ligand. The anti-HER2 antibody in the ADC Petition 870250085375, dated 09 / 22 / 2025, p. 76 / 198 65 / 141 can deliver the payload to cells that express HER2, especially to cells with high levels of HER2.

[00271] In another aspect, the anti-HER2 drug-antibody conjugate comprises an anti-HER2 antibody that is an inhibitory antibody.

[00272] In another aspect, the anti-HER2 drug-antibody conjugate comprises an anti-HER2 antibody that binds specifically to HER2.

[00273] In another aspect, the anti-HER2 drug-antibody conjugate comprises an anti-HER2 antibody that binds specifically to the extracellular domain of HER2.

[00274] In another aspect, the anti-HER2 drug-antibody conjugate comprises an anti-HER2 antibody that is an inhibitory antibody that binds specifically to HER2.

[00275] In another aspect, the anti-HER2 drug-antibody conjugate comprises an anti-HER2 antibody that binds specifically to an extracellular domain of HER2.

[00276] In another aspect, the anti-HER2 antibody-drug conjugate comprises trastuzumab. In this aspect, trastuzumab may be as defined above in any of the aspects relating to the anti-HER2 antibody.

[00277] In another aspect, the anti-HER2 antibody drug conjugate is selected from the group consisting of trastuzumab deruxtecan and trastuzumab emtansine. In this aspect, trastuzumab may be as defined above in any of the aspects relating to the anti-HER2 antibody.

[00278] The term “trastuzumab emtansine” or “ado-trastuzumab emtansine”, also known as T-DM1 or Kadcyla, refers to the antibody-drug conjugate comprising the anti-HER2 antibody trastuzumab, a thioether ligand, and the microtubule inhibitor emtansine or DM1 – a derivative of maytansine – as the cytotoxic payload. The Name Petition 870250085375, dated 09 / 22 / 2025, page 77 / 198 66 / 141 The International Nonproprietary Name (INN) “trastuzumab emtansine” is published in the WHO Recommended List 65 of INNs, which is incorporated into this application by reference.

[00279] The term “trastuzumab deruxtecan”, also known as T-DXd or Enhertu, refers to the antibody-drug conjugate comprising the anti-HER2 antibody trastuzumab, a ligand, and the topoisomerase I inhibitor deruxtecan or DXd – an exatecan derivative – as a cytotoxic payload. The International Nonproprietary Name (INN) “trastuzumab deruxtecan” is published in the WHO Recommended List 78 of INNs, which is incorporated into this application by reference.

[00280] The INNs, as used in this application, must also encompass all biosimilar molecules with the same structure, in particular those comprising the same, or substantially the same, amino acid sequences as the original antibody, including, but not limited to, biosimilar antibodies authorized under Regulation 42 USC §262 subsection (k) in the US and equivalent regulations in other jurisdictions. A “biosimilar,” as used in this application, refers to an antibody (isolated or as part of an ADC) or antigen-binding fragment that has the same primary amino acid sequence compared to a reference antibody (e.g., trastuzumab) and may optionally have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) compared to the reference antibody (e.g., a different glycoform).

[00281] Cancer that exhibits / develops “resistance” or is / is becoming “resistant” to a therapy, as used in this application, includes cancer that does not respond and / or exhibits a reduced capacity to produce a significant response, for example, partial response and / or complete response, to treatment with the anti-HER2 antibody or the anti-HER2 drug-antibody conjugate. Resistance may Petition 870250085375, dated 09 / 22 / 2025, page 78 / 198 67 / 141 being de novo (primary) or acquired, which arises in the course of a treatment method. The term “acquired resistance,” as used in this application, indicates that the cancer becomes resistant and / or substantially less responsive to the effects of the anti-HER2 antibody or the anti-HER2 drug-antibody conjugate as defined in this application after exposure to it for a specified period of time.

[00282] Cancer can develop resistance to single-agent treatment, anti-HER2 antibody or anti-HER2 drug-antibody conjugate. Resistance mechanisms can be attributed to the antibody or the payload and can be receptor-related, referring to target accessibility, or intracellular, as referring to the regulation of intracellular signaling pathways.

[00283] In one embodiment, the cancer is resistant to treatment with the payload of an anti-HER2 drug-antibody conjugate.

[00284] In one form, the cancer is resistant to treatment with deruxtecan or emtansine.

[00285] A cancer that initially responded to an anti-HER2 antibody or an anti-HER2 drug-antibody conjugate may relapse and become resistant to the anti-HER2 antibody or the anti-HER2 drug-antibody conjugate when the anti-HER2 antibody or the anti-HER2 drug-antibody conjugate is no longer effective in treating an individual with cancer, for example, despite the administration of higher dosages.

[00286] Cancer can be recurrent, relapsing, resistant, or refractory to one or more anti-HER2 antibodies or to an anti-HER2 drug-antibody conjugate. Therefore, patients may have received prior anticancer therapies with one or more anti-HER2 antibodies or one or more anti-HER2 drug-antibody conjugates that did not completely cure the disease.

[00287] Cancer with recurrence and / or resistance to anti-antibody Petition 870250085375, dated 09 / 22 / 2025, page 79 / 198 68 / 141 HER2 or an anti-HER2 antibody-drug conjugate may be particularly amenable to single-agent treatment with compound (1) in a second-line or additional-line treatment, as described in this application.

[00288] Therefore, one aspect relates to compound (1) for use in the treatment and / or prevention of cancer, wherein the cancer is resistant to treatment with an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate. In this aspect, compound (1), the dosing regimen (e.g., daily dose, frequency of administration, oral / tablet administration, second-line or additional-line use, etc.) and the cancer may each independently or collectively be as described in any of the aspects or embodiments disclosed in this application. Second-line or additional-line administration

[00289] It has been surprisingly found that the use of compound (1) after cancer therapy with at least one systemic anticancer therapy agent has the potential to improve or stabilize clinical outcome.

[00290] In a preferred embodiment, at least one additional therapeutic agent is administered in a treatment line prior to compound (1) at the doses and dosing regimens described in this application. Alternatively, the method of treating a cancer patient, as described above, comprises administering compound (1) at the doses and dosing regimens described in this application in a treatment line following the administration of at least one additional therapeutic agent.

[00291] In a preferred embodiment, the additional therapeutic agent administered in a treatment line prior to administration of compound (1) is selected from the group consisting of chemotherapy agents and systemic anticancer therapy agents. The Petition 870250085375, dated 09 / 22 / 2025, page 80 / 198 69 / 141 an additional therapeutic agent may be used in cancer treatment in addition to administering compound (1).

[00292] In a preferred embodiment, a systemic anticancer therapy agent is administered in a treatment line prior to compound (1). In particular, one or more systemic anticancer therapy agents may be administered in a treatment line prior to compound (1). In other words, it is preferable that compound (1) be used to treat cancer in a treatment line following the administration of a treatment line comprising one or more systemic anticancer therapy agents. These systemic anticancer therapy agents may be administered as separate treatment lines or in combination with each other in the same line. Additionally or alternatively, the systemic anticancer agent(s) administered in a treatment line prior to compound (1) may be used in combination with any other anticancer therapy other than compound (1), whether systemic or not.This means that compound (1) can be administered as second-line (if only one line of treatment comprising at least one systemic anticancer therapy is administered before compound (1)) or add-on line treatment (if more than one line of treatment comprising at least one systemic anticancer therapy is administered before compound (1)). In this embodiment, compound (1) is preferably administered at the doses and dosing regimens described in this application.

[00293] In this context, the terms “after” and “following” mean that the additional therapeutic agent, especially the chemotherapy agent or the systemic anticancer therapy agent, is administered as a first-line or prior line of therapy for an initial period of time, for example, over a few hours, Petition 870250085375, dated 09 / 22 / 2025, page 81 / 198 70 / 141 days or one or more weeks, using one or more doses, and is followed by administration of compound (1) over a second time period, for example, over a few hours, days or one or more weeks, using one or more doses, provided there is no overlap between the first and second time periods. In particular, it is preferable that the systemic anticancer therapy agent or chemotherapy agent and compound (1) are not administered on the same day. Also in particular, administration of a single systemic anticancer therapy agent or chemotherapy agent is not restarted at the same dosage (of said single systemic anticancer therapy agent or chemotherapy agent) once compound (1) is administered. The terms “after” and “following” do not require that compound (1) be administered directly after the line of therapy with the systemic anticancer therapy agent(s).Therefore, it may be possible that another line of therapy be administered between the systemic anticancer therapy agent or chemotherapy and compound (1), provided that the systemic anticancer therapy or chemotherapy is administered in a line of treatment prior to compound (1). Preferably, the systemically detectable doses of the anticancer therapy agent in the previously administered anticancer therapy are below a therapeutically effective amount established before administration of compound (1). In another preferred embodiment, the selected daily dose and daily administration schedule of compound (1) may also be chosen based on one or all pretreatments with a systemic anticancer therapy agent.

[00294] Those skilled in the art will recognize that the terms “before,” “prior,” “after,” and “following” are used in this application to refer to different and / or separate lines of therapy. In other words, any reference to the administration of compound (1) after systemic anticancer therapy or chemotherapy corresponds to a reference to Petition 870250085375, dated 09 / 22 / 2025, page 82 / 198 71 / 141 administration of compound (1) as second-line or subsequent-line therapy after administration of systemic anticancer therapy or chemotherapy, even when this is not explicitly stated.

[00295] As used in this application, “second line or additional line” and grammatical variants thereof have the meaning known in the art. In particular, “second line or additional line” and grammatical variants thereof may refer to the administration of compound (1) after a first line or prior line of therapy that has failed, ceased to function, decreased in effectiveness, had intolerable side effects, or was only partially successful, according to the attending physician’s judgment, especially when the first line or prior line of therapy is never again administered to the patient. The expression “second-line or subsequent-line administration” may be read as second-line administration or subsequent-line administration.

[00296] As used in this application, the “systemic anticancer therapy agent” may be present and administered as a single pharmaceutical compound or single active ingredient. The agent may also be present and administered as a combination of two or more pharmaceutical compounds or active ingredients. Pharmaceutical compounds may include small or large molecules, chemical elements, metal complexes, for example, containing platinum (Pt), biological products, and combinations thereof.

[00297] As used in this application, the term “systemic anticancer therapy” includes the administration of at least one systemic anticancer therapy agent, alone or in combination with another pharmaceutical compound or active ingredient.

[00298] As used in this application, the term “systemic” has the meaning commonly attributed to it in the technique and, therefore, may be Petition 870250085375, dated 09 / 22 / 2025, page 83 / 198 72 / 141 refers to a route of administration that affects the whole body, as opposed to local administration, where the effect is generally local. Systemic administration can be enteral (e.g., through the gastrointestinal tract) or parenteral (e.g., through injection, infusion, implant, etc.). Preferably, systemic anticancer therapy is parenteral anticancer therapy.

[00299] As used in this application, the “chemotherapeutic agent” or “chemotherapeutic agent” may be present and may be administered in the form of only a single pharmaceutical compound or single active ingredient. The agent may also be present and administered in the form of a combination of two or more pharmaceutical compounds or active ingredients.

[00300] As used in this application, the term “chemotherapy” includes the administration of at least one chemotherapeutic agent, alone or in combination with another pharmaceutical compound or active ingredient.

[00301] As used in this application, the term “chemotherapy” has the meaning commonly attributed to it in the art and, therefore, may refer to a chemical agent or a combination of chemical agents useful in the prevention and / or treatment of cancer, especially when the agent or combination is or comprises a cytotoxic and / or cytostatic agent.

[00302] Preferably, chemotherapy is administered systemically, that is, it is systemic chemotherapy.

[00303] In a preferred embodiment, the systemic anticancer therapy agent is selected from the group consisting of platinum-based chemotherapy, antiHER2 drug-antibody conjugates, taxanes, antimetabolites, immunotherapeutic agents, and combinations thereof. Preferably, the term "combinations thereof" may include the separate administration of two or more members of this list at different time intervals or at different times. Petition 870250085375, dated 09 / 22 / 2025, page 84 / 198 73 / 141 points in time, such as different lines of therapy or the administration of two or more members of this list in combination in the same line of therapy. The combination may, for example, include a first-line treatment including a platinum-based chemotherapy agent and subsequently a second-line treatment based on an ADC, preferably an anti-HER2-ADC, or vice versa, before a treatment based on compound (1). The combination may be a planned sequence or may be performed based on the outcome of the treatment.

[00304] As used in this application, the expression “platinum-based chemotherapy” and grammatical variants thereof have the meaning commonly attributed to them in the art and, therefore, may refer to one or more chemotherapeutic agents comprising platinum (Pt). Preferred platinum-based chemotherapeutic agents include oxaliplatin, carboplatin, and / or cisplatin. Even more preferred platinum-based chemotherapeutic agents include carboplatin and / or cisplatin.

[00305] Drug-antibody-anti-HER2 conjugates may be as defined above. Preferred drug-antibody-anti-HER2 conjugates include: trastuzumab deruxtecan and / or trastuzumab emtansine.

[00306] As used in this application, the term “taxane” and grammatical variants thereof have the meaning commonly ascribed to them in the art and therefore may refer to a diterpene with a taxadiene core. Taxanes generally function as mitotic inhibitors, specifically as disruptors of microtubule function. Preferred taxanes include cabazitaxel, larotaxel, tesetaxel, docetaxel, and / or paclitaxel. Even more preferred taxanes include docetaxel and / or paclitaxel.

[00307] As used in this application, the term “antimetabolite” and Petition 870250085375, dated 09 / 22 / 2025, page 85 / 198 74 / 141 grammatical variants of the same have the meaning commonly attributed to them in the art and therefore may refer to one or more agents that interfere with metabolic processes within cells. Specifically, antimetabolites may inhibit a metabolite. Preferred antimetabolites include: 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, hydroxycarbamide, methotrexate, phototrexate, gemcitabine, pemetrexed and / or tegafur. Even more preferred antimetabolites include: gemcitabine, pemetrexed and / or tegafur.

[00308] As used in this application, the terms “immunotherapy,” “immunotherapeutic agent,” and grammatical variants thereof have the meaning commonly attributed to them in the art and, therefore, may refer to one or more agents that interfere with (e.g., activate or suppress) the immune system and thus contribute to the prevention and / or treatment of cancer. Preferred immunotherapeutic agents include: cemiplimab, dostarlimab, trastuzumab, pertuzumab, margetuximab, pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab, and / or ramucirumab. Even more preferred immunotherapeutic agents include: pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab, and / or ramucirumab.

[00309] 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.

[00310] In a preferred embodiment, the systemic anticancer therapy agent is selected from the group consisting of: Petition 870250085375, dated 09 / 22 / 2025, page 86 / 198 75 / 141 carboplatin, cisplatin, trastuzumab deruxtecan, trastuzumab emtansine, pemetrexed, docetaxel, paclitaxel, gemcitabine, pembrolizumab, durvalumab, tremelimumab, ramucirumab, atezolizumab, tegafur, nivolumab and ipilimumab.

[00311] In a preferred embodiment, the systemic anticancer therapy agent comprises or consists of an anti-HER2 drug-antibody conjugate.

[00312] In a preferred embodiment, the systemic anticancer therapy agent is trastuzumab deruxtecan and / or trastuzumab emtansine.

[00313] In a preferred embodiment, the systemic anticancer therapy agent comprises platinum-based chemotherapy.

[00314] In a preferred embodiment, the systemic anticancer therapy agent comprises pembrolizumab, pemetrexed and / or platinum-based chemotherapy.

[00315] In a preferred embodiment, the systemic anticancer therapy agent comprises pembrolizumab, pemetrexed, and platinum-based chemotherapy.

[00316] In a preferred embodiment, the systemic anticancer therapy agent comprises pembrolizumab, pemetrexed, and cisplatin.

[00317] In a preferred embodiment, the systemic anticancer therapy agent comprises pembrolizumab, pemetrexed, and carboplatin.

[00318] In a preferred embodiment, the systemic anticancer therapy agent comprises pembrolizumab and / or pemetrexed.

[00319] In a preferred embodiment, the systemic anticancer therapy agent comprises a standard treatment therapy, optionally followed by maintenance therapy. Said standard treatment therapy may comprise a combination of Petition 870250085375, dated 09 / 22 / 2025, page 87 / 198 76 / 141 pembrolizumab, pemetrexed and platinum-based chemotherapy, wherein said combination is optionally administered once every 3 weeks for one or more administrations, preferably for 1, 2, 3 or 4 administrations, most preferably for 4 administrations. Maintenance therapy may comprise a combination of pembrolizumab and pemetrexed, optionally administered once every 3 weeks for one or more administrations.

[00320] In another preferred embodiment, compound (1) as defined below (1) is for use in the treatment of cancer, wherein compound (1) is administered in a treatment line following the administration of chemotherapy or a systemic anticancer therapy agent. Alternatively, in a preferred embodiment, a method of treating a cancer patient comprises administering compound (1), wherein compound (1) is administered in a treatment line following the administration of chemotherapy or a systemic anticancer therapy agent. Preferably, in these embodiments, compound (1) is administered according to the doses and dosing regimens described above. In addition, or alternatively, in these embodiments, the anticancer and / or systemic therapy agent may be as defined in this application. Preferably, the systemic cancer therapy agent is an anti-HER2 systemic cancer therapy agent, for example, an anti-HER2 drug-antibody conjugate.

[00321] In a preferred embodiment, compound (1) is used in the treatment of cancer at least 21 days after the last day of administration of the chemotherapy agent or anticancer therapy. Petition 870250085375, dated 09 / 22 / 2025, page 88 / 198 77 / 141 systemic. Alternatively, in a preferred embodiment, the method of treatment of a cancer patient comprises administering compound (1), wherein compound (1) is administered at least 21 days after the last day of administration of the chemotherapy agent or systemic anticancer therapy. In these embodiments, preferably, compound (1) is administered for at least 21 consecutive days or for 21 days multiplied by X, wherein X is a natural number equal to or greater than 1. Pharmaceutical composition

[00322] This application provides a pharmaceutical composition comprising compound (1) as defined below. (1) and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein compound (1) is administered at a daily dose of at least 30 mg. Alternatively, a method is disclosed for treating a cancer patient comprising administering a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered at a daily dose of at least 30 mg. Preferably, in these embodiments, compound (1) is administered in accordance with the doses and dosage regimens described above. Also preferably, in these embodiments, the cancer is as defined in this application (in any aspect or embodiment). All embodiments described above relating to compound (1) for use in the treatment of cancer or to the method of treating a cancer patient with compound (1) are applicable to the pharmaceutical composition for use in the treatment Petition 870250085375, dated 09 / 22 / 2025, page 89 / 198 78 / 141 of cancer or the method of treating a cancer patient with the pharmaceutical composition.

[00323] The term “pharmaceutically acceptable excipient” refers to a non-toxic component that does not destroy the pharmacological activity of the compound with which it is formulated. The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that may be used in the compositions of this invention include fillers, disintegrants, glidants, lubricants, and coating agents. The compositions may comprise other pharmaceutically acceptable excipients selected from buffers, dispersing agents, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, processing aids, colorants, sweeteners, fragrance agents, flavoring agents, diluents, and other known additives usable in the manufacture of a pharmaceutical product.

[00324] In a preferred embodiment, the compound (1) or pharmaceutical composition is administered orally. The compound (1) or pharmaceutical composition may be administered as a tablet, hard or soft gelatin capsule, pill, granules or a suspension. In preferred embodiments, the compound (1) or pharmaceutical composition is in the form of a tablet.

[00325] Unless defined otherwise, the technical and scientific terms used in this application have the same meaning commonly understood by one skilled in the art to which this invention pertains.

[00326] The following examples serve to illustrate the invention in more detail, but do not constitute a limitation thereof. Example 1 - An open-label, dose-escalation, Phase I clinical trial, with confirmation and dose expansion, of compound (1) as monotherapy in patients with unresectable solid tumors, Petition 870250085375, dated 09 / 22 / 2025, pp. 90 / 198 79 / 141 advanced and / or metastatic cases with HER2 aberrations 1.1 Protocol:

[00327] This is a first dose escalation and expansion study in humans to determine the Maximum Tolerated Dose (MTD) and explore the safety, pharmacokinetics, pharmacodynamics and early signs of efficacy of compound (1) as monotherapy in patients with advanced, metastatic and / or unresectable, HER2 aberration-positive solid tumors.

[00328] The dose escalation portion of the trial (also known as Phase Ia) includes consecutive cohorts of patients treated with increasing doses of the compound (1). 1.1.1 Objectives:

[00329] The main objectives of the dose escalation portion of the study are: - To investigate the safety, tolerability, and pharmacokinetics (PK) of increasing doses of compound (1) as orally administered monotherapy bis in die (BID, twice-daily dosing) or quaque die (QD, once-daily) in patients with advanced and / or metastatic solid tumors exhibiting HER2 aberrations; - Determine the MTD and / or the Recommended Dose for Phase II (RP2D, corresponding to the recommended dose for dose expansion in Phase Ib, see Example 3) of monotherapy with compound (1) administered orally for each regimen studied. 1.1.2 Final points:

[00330] The primary endpoints of the dose escalation portion of the study are: - MTD, defined as the highest dose with less than a 25% risk of the true Dose-Limiting Toxicity (DLT) rate being equal to or greater than 33% during the MTD evaluation period in any regimen studied; Petition 870250085375, dated 09 / 22 / 2025, page 91 / 198 80 / 141 - Number of patients with DLTs during the MTD evaluation period.

[00331] The MTD evaluation period is defined as the first 21 days of treatment (first cycle).

[00332] The secondary endpoints of the dose escalation portion of the study are: - Number of patients who experienced DLTs throughout the treatment period; - The following pharmacokinetic parameters of compound (1) after the first and multiple doses of the compound on Day 1 and 15 (if possible): Cmax: maximum measured concentration of compound (1) in plasma; AUC0-t2: area under the concentration-time curve of compound (1) in plasma.

[00333] If assessable and applicable, the following additional endpoints are evaluated: - Number of patients who experienced adverse events (AEs) during the treatment period; - Objective response (OR), defined as the best overall response of complete response (CR) or partial response (PR), where best overall response is determined in accordance with RECIST version 1.1, as assessed by the investigator, from the first administration of treatment until the earliest disease progression, death, or last evaluable tumor assessment before initiation of subsequent anticancer therapy, loss to follow-up, or withdrawal of consent; - Disease control (DC), defined as best overall response of complete response (CR) or partial response (PR) or stable disease (SD), where best overall response is defined according to RECIST version 1.1, as assessed by the investigator, from the onset of disease progression, death, or last evaluable tumor assessment before initiation of subsequent anticancer therapy, loss of Petition 870250085375, dated 09 / 22 / 2025, page 92 / 198 81 / 141 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 onset of disease progression or death among objectively responsive patients; - Duration of disease control (DoDC), defined as the time from the first administration of treatment until the onset of disease progression or death, among patients with disease control; - Tumor reduction according to RECIST 1.1, defined as the best (smallest) percent change from baseline of the sum of the largest diameter of the target lesions assessed by the investigator across all tumor assessments under treatment; - If data permit, the pharmacokinetic parameters to be calculated for compound (1) as monotherapy include: • AUCo-~: area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity; • AUC0-tz: area under the plasma concentration-time curve during the time interval from 0 to the last measured time point (tz); • Cmin: minimum plasma concentration measured in plasma; • t1 / 2: terminal half-life of the analyte in plasma; • tmax: time from dosage to Cmax in plasma. 1.1.3 Dose Escalation

[00334] Dose escalation is performed according to an open-label study. Data obtained in the study determine the MTD estimate based on a Bayesian logistic regression model (BLRM) with overdose control (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 estimates of the probability of observing a DLT during the period of Petition 870250085375, dated 09 / 22 / 2025, page 93 / 198 82 / 141 MTD assessment for each dose level in the study, as patient information becomes available, taking into account updated DLT information from both timelines. At no point in the study is dose escalation permitted to a dose that does not meet the principle of escalation with overdose control (EWOC). Dose escalation is restricted to a maximum increment of 100% of the previous dose. Dose escalation and cohort size are based on decisions of the Dose Escalation Committee (DEC), guided by the BLRM.

[00335] The dose escalation portion of the trial tests BID and QD dosing regimens for compound (1) within a BLRM with one covariate (which discriminates between BID and QD). In the BID regimen, cycles last 3 weeks (i.e., 21 days) and compound (1) is administered twice daily (BID), while in the QD regimen, cycles last 3 weeks (i.e., 21 days) and compound (1) is administered once daily. The trial begins with the BID schedule; after a dose level above the predicted human therapeutic dose is determined to be safe by the DEC, the QD schedule is initiated. When this QD cohort is deemed safe, the next BID dose level will be opened.

[00336] After this point, all dose-level cohorts are opened, alternating between the BID and QD regimens (see Figures 1A and 1B). The BID dose cohort is filled first, and then it descends to the equivalent QD cohort.

[00337] Successive cohorts of patients receive increasing doses of compound (1) until the MTD is reached. After all patients in a cohort have experienced a DLT or have been observed for 21 days without experiencing DLTs, the BLRM is updated with the newly accumulated data from both timelines. The overdose risk is then calculated for each dose and Petition 870250085375, dated 09 / 22 / 2025, pp. 94 / 198 83 / 141 Dose escalation is permitted for all doses that meet the EWOC criteria. For each dosing regimen, based on the model and additional information (HR, pharmacodynamics, patient profiles, information from the other dosing regimen), the DEC members arrive at a joint decision on the next dose level to be investigated and the size of the next cohort. The pre-specified dose levels are provisional, and intermediate levels may be explored as deemed necessary by the DEC.

[00338] All cohorts include at least 3 patients. In the case of only two patients in a cohort being evaluable (i.e., one patient not being evaluable) and neither of them having experienced a DLT within the MTD evaluation period, dose escalation may occur based on those two patients.

[00339] If DLTs are observed in the first two consecutive patients at a previously untested dose level, subsequent enrollment in that cohort will be stopped. The BLRM is updated to confirm that the dose level still meets the EWOC principle. Based on this information, the DEC assesses whether subsequent patients will be enrolled at the same dose level or at a lower dose level.

[00340] No further dose escalation is allowed after the MTD criterion is met. More patients may be included to confirm this MTD estimate, i.e., to confirm that the EWOC criterion is still met. The DEC may declare any dose that meets the EWOC criterion as RP2D, regardless of the MTD estimate. RP2D does not exceed MTD. Any DLTs that occur after the MTD assessment period are considered for the RP2D assessment for compound (1). If no DLTs are observed, the DEC may decide to declare RP2D based on pharmacokinetic / pharmacodynamic outcomes and the overall safety profile. Petition 870250085375, dated 09 / 22 / 2025, pages 95 / 198 84 / 141 MTDs and RP2Ds are defined separately for both schemes.

[00341] At the end of dose escalation, when the dose(s) selected for dose expansion are declared, dose escalation may remain open for inclusion of patients ineligible for dose expansion, at selected doses, at participating dose escalation sites, if agreed with the DEC.

[00342] The RP2D(s) of compound (1) as monotherapy administered BID and QD is / are defined based on the DLT / MTD (if achieved), all safety data and, if data permit, pharmacokinetics, pharmacokinetics / pharmacodynamics collected during the study. If DLT or MTD is not achieved, the RP2D(s) is / are determined based on safety data (i.e., overall tolerability and incidence of serious toxicity) as well as, if data permit, pharmacokinetics, pharmacokinetics / pharmacodynamics. The RP2D does not need to be the same in both regimens (BID, QD). The BLRM is performed based on extended data, including all DLT-like events throughout the treatment period, as well as by treatment schedule alone, to further guide the selection of the RP2D(s).

[00343] RP2D can be defined and the dose expansion portion initiated before the MTD is reached / dose escalation is completed.

[00344] Patients may continue to receive treatment with compound (1) until disease progression (DP) according to RECIST or until another reason that requires treatment interruption. 1.1.4 Dose:

[00345] The initial doses for the dose escalation portion of the study are: Petition 870250085375, dated 09 / 22 / 2025, pp. 96 / 198 85 / 141 - BID schedule: 15 mg twice daily (i.e., total daily dose of 30 mg) - QD schedule: 60 mg once daily (unless otherwise directed by the DEC).

[00346] The dose escalation steps are determined by the DEC.

[00347] The predicted human dose for compound (1) was 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. Unbound in vitro cell potency, plasma exposure, and tumor growth inhibition data in mice were used to train the model. A comprehensive pharmacokinetic profile of compound (1) in vitro and in vivo, using mice, rats, dogs, and minipigs, allowed the prediction of FC parameters in humans. The predicted human pharmacokinetic parameters were used to simulate the human plasma profile, which was incorporated into the preclinical PK / TGI model. In this setting, the PK / TGI model was used to predict and identify the dose required in humans to achieve a TGI >100%.This was predicted at 40 mg BID as well as 80 mg QD (predicted effective human doses). In other words, it was estimated that exposure to a human dose of 40 mg BID as well as 80 mg QD would be sufficient to achieve >100% inhibition of tumor growth in patients. 1.1.5 Patients

[00348] The dose-escalation portion includes patients with advanced, unresectable, and / or metastatic solid tumors that are refractory to standard therapy for the disease or for whom standard therapy is not appropriate. Patients must also have exhausted treatment options known to prolong the disease. Petition 870250085375, dated 09 / 22 / 2025, pp. 97 / 198 86 / 141 survival in the context of the disease. These patients must also have a confirmed positive diagnosis of a HER2 aberration (described as overexpression according to standard diagnostic criteria OR gene amplification according to standard diagnostic criteria OR non-synonymous somatic mutation OR a genetic rearrangement involving HER2 or NRG1).

[00349] Based on the provisional dose levels and escalation schedule, it was originally planned to enroll approximately 66 patients (about 36 patients for the BID dosing regimen and about 30 patients for the QD dosing regimen) in the dose-escalation portion of the study. This number was increased to approximately 96 patients (about 36 patients for the BID dosing regimen and about 60 patients for the QD dosing regimen). The total number of patients depends on the number of dose escalations required.

[00350] All patients, including those who are eligible for the study based on local testing, must provide a tumor sample for confirmation of their HER2 status.

[00351] Main inclusion criteria: - Patients with a confirmed diagnosis of an advanced, unresectable, and / or metastatic non-hematologic malignancy with at least one measurable or assessable lesion. The patient must present with at least one measurable lesion according to RECIST 1.1. - Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. - Availability and willingness to provide a sample of archived, formalin-fixed, paraffin-embedded (FFPE) tumor tissue for confirmation of the patient's HER2 status. Patients must be willing and able to Petition 870250085375, dated 09 / 22 / 2025, pages 98 / 198 87 / 141 meet the requirements for blood collection and tumor biopsy for pharmacokinetic, pharmacodynamic, and biomarker analyses. - Proper organ function, as routinely measured in the field. - Recovered from any prior therapy-related toxicity to < Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at treatment initiation (except for alopecia, stable sensory neuropathy, and hypothyroidism (patients on thyroid replacement therapy), which must be < CTCAE Grade 2). - Life expectancy of at least 12 weeks at the start of treatment, according to the researcher. - Be at least 18 years of age at the time of consent or be older than the legal age of consent in countries where this is higher than 18 years. - Written informed consent, signed and dated, in accordance with the International Council for Harmonisation of Good Clinical Practice (ICH-GCP) and local legislation, prior to admission to the study. - Male or female patients. Women of childbearing potential (WOCBP) and men who could be fathers should be prepared and able to use highly effective methods of birth control, as per ICH M3 (R2), that result in a low failure rate of less than 1% per year when used consistently and correctly. - Patients with documented HER2 gene aberration comprising: EITHER overexpression by immunohistochemistry (IHC), increased gene copy number by in situ hybridization (ISH), non-synonymous genetic mutation OR genetic fusion of HER2 or NRG-1 genes. - A patient who has not responded to conventional treatment or for whom there is no proven effective therapy. Petition 870250085375, dated 09 / 22 / 2025, pages 99 / 198 88 / 141 or who is not eligible for established treatment options. The patient must have exhausted, or not be a suitable candidate for, available treatment options that prolong survival in the context of the disease.

[00352] Main exclusion criteria: - Major surgery (major according to the researcher's assessment) performed within 4 weeks prior to the first experimental treatment or planned within 6 months after screening. - Previous or concurrent malignant neoplasms, in addition to the one treated in this study, within the last 2 years, except; Non-melanoma skin cancers treated effectively, cervical carcinoma in situ treated effectively, ductal carcinoma in situ treated effectively, and other malignancies treated effectively and considered cured by local treatment. - Treatment with systemic anticancer therapy or investigational drug within 21 days or 5 half-lives (whichever is shorter) of the first treatment with compound (1). Patients who must or wish to continue taking restricted medications or any drug considered likely to interfere with the safe conduct of the study.

[00353] As those skilled in the art will recognize, other inclusion and exclusion criteria may apply.

[00354] Patients may discontinue experimental treatment or withdraw consent to participate in the study as a whole. 1.1.6 Compound:

[00355] Compound (1) is administered as film-coated tablets. This formulation was developed in three dosages: 5 mg (approximately 10 mm round), 20 mg (approximately 10 mm Petition 870250085375, dated 09 / 22 / 2025, pp. 100 / 198 89 / 141 round) and 100 mg (oval, approximately 16 x 7 mm). In addition to the pharmaceutical substance, the tablets contain standard pharmaceutical excipients in common amounts. 1.1.7 Effectiveness assessment:

[00356] Tumor assessments should include computed tomography (CT) scans of the chest, abdomen / pelvis (or PET / CT) and a magnetic resonance imaging (MRI) scan of the brain at screening. If clinically indicated, imaging of any other known or suspected sites of disease (e.g., bone) should be performed using an appropriate method (CT, MRI, PET / CT, or bone scan). The same radiographic procedure should be used throughout the trial. Assessments are performed by the investigator at screening (<28 days before treatment initiation), every 2 cycles (6 weeks ±5 days), at the end-of-treatment visit (EOT) (if not performed in the previous 3 weeks), and at the investigator's discretion, and copies may be collected by the sponsor or designated individual.Whenever possible, the assessment schedule should not be altered, but if there is an interruption or delay in treatment, altering the tumor assessment schedule to align it with clinical assessments is permitted. Additional unscheduled tumor assessments may be performed at the investigator's discretion. If the patient discontinues the study medication for a reason other than progression, tumor assessment according to RECIST v1.1 continues until progression (or until one of the following occurs: death, loss to follow-up, end of study).

[00357] The patient's clinical status is assessed locally by each researcher. Decline in clinical status should be attributed to progression of the underlying tumor and not to comorbidity or concomitant medication. In case of clinical deterioration related to the tumor, every effort should be made to confirm progression of the Petition 870250085375, dated 09 / 22 / 2025, page 101 / 198 90 / 141 disease diagnosed by imaging tests.

[00358] 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) whole-body assessment (classic RECIST 1.1) and b) assessment of tumors in areas unrelated to the CNS. Assessment according to classic RECIST 1.1 by the investigator and / or local radiologist is the basis for continuation or discontinuation of the study in an individual patient (in addition to safety). No whole-body RECIST assessment is performed during the dose escalation phase.

[00359] Baseline imaging should include imaging of all known or suspected disease sites using an appropriate method. The investigator (or designated investigator) records target and non-target lesions on the Case Report Form (CRF or eCRF). Lesions in previously irradiated areas may not be considered measurable at baseline unless they occurred after irradiation. The same assessment method and imaging technique should be used at each subsequent time point to characterize each lesion reported during treatment and during follow-up. 1.1.8 Safety assessment:

[00360] Physical examinations, including height (screening only) and weight measurements, are performed at screening, on day 1 of each treatment cycle, at the EOT visit, and at the 30-day safety follow-up visit. However, patients undergo an abbreviated physical examination (focused on the specific disease, at the investigator's discretion) on Cycle 1, Day 1 (if the previous physical examination was performed within 72 hours of treatment initiation) and on Cycle 1, Day 15.

[00361] A complete physical examination is used to assess the general condition. Petition 870250085375, dated 09 / 22 / 2025, page 102 / 198 91 / 141 health assessment and also as a clinical evaluation of the tumor and may include, but is not limited to, a cardiopulmonary examination, examination of regional lymph nodes, abdomen, and an assessment of mental and neurological status. Additional symptoms not reported during a previous examination should be clarified. Whenever possible, the same investigator should perform this examination.

[00362] A limited physical examination should include a cardiopulmonary examination, a clinical assessment of the tumor, an examination of the regional lymph nodes, and an examination of the abdomen. 1.1.9 Assessment of adverse events:

[00363] An adverse event (AE) is defined as any adverse medical occurrence in a patient or clinical investigation individual who has received a medication and does not necessarily have to have a causal relationship with that treatment.

[00364] An adverse event (AE) can therefore be any unintended adverse sign (including an abnormal laboratory finding), symptom or illness temporarily associated with the use of a medication, regardless of whether or not it is considered related to the medication.

[00365] A serious adverse event (SAE) is defined as any AE that meets at least one of the following criteria: - results in death, - It is a life-threatening event, which refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically could have caused death if it had been more severe. - requires hospitalization or extension of existing hospitalization, - results in persistent or significant disability or impairment, - It is a congenital anomaly / birth defect. - It is considered serious for any other reason if it is an event Petition 870250085375, dated 09 / 22 / 2025, page 103 / 198 92 / 141 Important medical event when based on appropriate medical judgment that may place the patient at risk and may require medical or surgical intervention to prevent one of the other outcomes listed in the definitions above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or seizures that do not result in hospitalization or the development of dependence or abuse.

[00366] Medical judgment should be used to determine whether there is a reasonable possibility of a causal relationship between the adverse event and the compound (1), considering all relevant factors, including reaction pattern, temporal relationship, discontinuation or reintroduction, confounding factors such as concomitant medication, concomitant diseases and relevant history.

[00367] Arguments that may suggest there is a reasonable possibility of a causal relationship could be: The event is consistent with the known pharmacology of the drug. The event is known to be caused by, or attributed to, a class of drugs. - A plausible time for the event to begin in relation to the timing of exposure to the medication. Evidence that the event is reproducible when the drug is reintroduced. - No clinically sound alternative etiology that could explain the event (e.g., pre-existing or concomitant diseases, or comedications). The event is usually related to the medication and is uncommon in the general population not exposed to the medication (e.g., Stevens-Johnson syndrome). - An indication of dose-response (i.e., larger size of Petition 870250085375, dated 09 / 22 / 2025, p. 104 / 198 93 / 141 effect if the dose is increased, smaller effect size if the dose is reduced).

[00368] Arguments that may suggest that there is no reasonable possibility of a causal relationship may include: - There is no evidence of a plausible time frame for the onset of the event in relation to the time of exposure to the drug (e.g., cases of pre-treatment, diagnosis of cancer or chronic disease within days / weeks of drug administration; an allergic reaction weeks after discontinuation of the drug in question). - Continuation of the event despite withdrawal of the medication, taking into account the pharmacological properties of the compound (e.g., after 5 half-lives). It is worth noting that this criterion may not be applicable to events whose temporal course is prolonged despite the removal of the original trigger. - Additional arguments beyond those mentioned previously, such as alternative explanations (for example, situations where other drugs or underlying diseases seem to provide a more likely explanation for the observed event than the drug in question). - Disappearance of the event even if the pharmacological treatment under study continues or remains unchanged.

[00369] The researcher maintains and keeps detailed records of all AEs in the patient's files. 1.1.10 Pharmacokinetic assessment:

[00370] The pharmacokinetic (PK) profiles of compound (1) are investigated after the first and after repeated doses. Standard pharmacokinetic parameters are calculated if the data permit and if they are scientifically reasonable.

[00371] Individual concentration data and calculated pharmacokinetic parameters are tabulated and displayed graphically. Statistical analyses are performed. The pharmacokinetic data of Petition 870250085375, dated 09 / 22 / 2025, page 105 / 198 94 / 141 a patient is flagged and excluded from statistical analyses in case of protocol violations relevant to pharmacokinetic assessment (to be decided by the Report Planning Meeting) or in case of non-evaluability of pharmacokinetics (as revealed during data analysis, based on the criteria specified below). The reasons for excluding a patient's data are documented in the Clinical Trial Report (CTR).

[00372] If data permit, the pharmacokinetic parameters Cmax (,ss), AUCc-t2 (,ss), of compound (1) are evaluated in terms of dose proportionality, to reach steady state. If necessary, additional pharmacokinetic parameters may be used for these evaluations.

[00373] Preliminary pharmacokinetic analyses may be performed as needed for DEC decisions. 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 pharmacokinetic analysis, preliminary analyses are based on planned sampling times and not actual times; no supplemental patient information, e.g., on AEs or concomitant medication, is used in these analyses, and the results are not validated. Therefore, minor discrepancies may occur between preliminary and final results. 1.1.11 Compliance:

[00374] Patients should bring all remaining study medications with them, including empty packaging, when attending their appointments.

[00375] Based on tablet count, treatment adherence is calculated as shown in the formula below. Doses missed according to protocol (e.g., dose interruption due to adverse events) are not included in the calculation. A Petition 870250085375, dated 09 / 22 / 2025, pp. 106 / 198 95 / 141 compliance is verified by the Clinical Research Associate (CRA) authorized by the sponsor or delegate. Number of tablets actually taken χ² / 100 Treatment adherence (%) = _____________________________________________________ Number of tablets that should have been taken according to the investigator's instructions.

[00376] Treatment adherence of 80 to 120% is considered good. 1.1.12 Statistical methods:

[00377] Dose escalation is guided by a BLRM with overdose control (EWOC) that is adjusted to binary toxicity results (DLTs). The parameter estimates are updated as data are accumulated using the BLRM. At the end of the dose escalation phase, the probability of toxicity at each dose level is calculated to determine an estimate of the MTD. 1.1.13 Investigation plan

[00378] All patients must adhere to the appointment schedule. If treatment administration is delayed at any time, the schedule for all subsequent visits / cycles will be recalculated based on the actual treatment date. Visits may occur over more than one day for logistical reasons, provided that all assessments take place within the period defined by the sponsor, i.e., within ±1 or ±2 days of the scheduled assessment.

[00379] Each visit and assessment is conducted within permitted windows. Additional flexibility (e.g., to accommodate holidays and patient unavailability) may be allowed if agreed upon between the researcher and the sponsor.

[00380] If a patient misses an appointment, it should be rescheduled as soon as possible, and the delay should be documented with the actual date and reason for the delay. Subsequent appointments should not be rescheduled, therefore, if this is not possible... Petition 870250085375, dated 09 / 22 / 2025, page 107 / 198 96 / 141 reschedule before the next planned visit, the missed visit should be ignored.

[00381] If a patient is hospitalized for administrative reasons to allow for PK treatment and sampling, this will not be considered an EAG unless any other criteria for an EAG are met.

[00382] In addition to scheduled assessments, unscheduled consultations and assessments not scheduled for safety reasons may be carried out at any time, according to clinical need.

[00383] In case of force majeure or other disruptive circumstances (e.g., pandemic, war), sites should adhere to necessary protocol procedures to the extent possible. However, when a patient is unable or unwilling to attend a clinical appointment (due to force majeure or other disruptive circumstances such as pandemic, war), the researcher should assess the risk-benefit for the individual patient and may decide to conduct a remote appointment if this is in the patient's best interest and agreed upon with the sponsor. All deviations from the original schedule of visits and procedures will be documented and the implications will be considered for the analysis of the study data.

[00384] After informed consent, the patient undergoes screening assessments. Assessments should occur within the acceptable screening consultation period, but do not need to be performed on the same day. Screening assessments may be repeated, provided they are within the screening consultation period. If more than one screening assessment is available, the most recent assessment prior to the start of treatment should be used to assess eligibility.

[00385] If the patient meets the eligibility criteria during screening, the first treatment appointment will be scheduled. Any underlying conditions present at the screening appointment should be Petition 870250085375, dated 09 / 22 / 2025, pp. 108 / 198 97 / 141 reported in eCRF.

[00386] Eligible patients receive compound (1) daily until the criteria for discontinuation of treatment are met.

[00387] Patients may continue treatment for unlimited cycles, until the criteria for discontinuing treatment are met, for example, as long as the patient has clinical benefit or until there is undue drug toxicity or withdrawal of consent, whichever occurs first.

[00388] After the decision to permanently discontinue treatment within the study, no further administration of the study drug should occur and the EOT visit should be performed within 7 days of the decision. If the decision to permanently discontinue experimental treatment is made during a scheduled appointment, the EOT visit should be performed instead of the scheduled appointment.

[00389] In the dose escalation portion of the study, the follow-up visit (FV) is conducted at least 30 days after permanent discontinuation of the compound (1) and has the primary purpose of collecting follow-up safety information. An individual patient who completes the follow-up visit will be considered to have completed the study. 1.2. Results:

[00390] The study design is shown in Figure 1. The study data are summarized in general terms and grouped for the QD and BID regimens and for the dose selected for the dose expansion portion of the study. In the following paragraphs, in 1.2.1, 1.2.2, 1.2.3, 1.2.4, 1.2.5, 1.2.6 and 1.2.7, including in Tables 1 to 7, the data lock-up point is March 2023. 1.2.1 Security

[00391] At the data lock point, the security data Petition 870250085375, dated 09 / 22 / 2025, pp. 109 / 198 98 / 141 were available for 43 patients (Tables 1 to 3). Patients were treated with increasing doses of compound (1) monotherapy, administered twice daily (BID, 17 patients) or once daily (QD, 26 patients). The initial dose was 15 mg twice daily in the BID regimen (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 investigated. The initial dose was 60 mg once daily in the QD regimen (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 investigated.

[00392] At the time of data locking, 17 of the 43 (39.5%) treated patients had discontinued experimental treatment, 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. Twenty-six patients (60.5%) were ongoing. 1.2.2 Exposure and Demographics

[00393] In total, 43 patients were treated with the compound (1). Overall, the mean duration of treatment at the data cutoff date was 126.0 days; exposure ranged from 9 to 417 days. The mean number of treatment cycles initiated was 4.0 (range: 1 to 15).

[00394] Twenty-six patients (60.5%) were Asian and 17 patients (39.5%) were white. The mean age of the patients was 58 years (range 32 to 79); 23 (53.5%) patients were male. The main primary diagnosis was NSCLC (27 patients; 62.8%). The mean time since the first histological diagnosis was 34.46 months (range 7.2 to 137.7 months). All patients had metastatic disease at screening, with the predominant metastasis locations being lung, lymph node, and bone.

[00395] Among patients who were tested for HER2 (or NRG1 mutations), 10 of 42 (23.8%) patients showed HER2 overexpression; 25 of 42 (59.5%) patients showed Petition 870250085375, dated 09 / 22 / 2025, page 110 / 198 99 / 141 non-synonymous somatic mutations, and 9 of 42 (21.4%) patients presented with HER2 or NRG1 genetic rearrangements. 1.2.3 Security Overview

[00396] In all doses and regimens, up to the data cutoff, no serious unexpected safety findings were observed and the reported adverse events (AEs) were manageable. The observed AEs and considerations regarding DLTs are summarized below.

[00397] A total of 38 of the 43 patients (88.4%) experienced one or more AEs. For 28 patients (65.1%), at least 1 AE was considered treatment-related by the investigator. Two patients (4.7%) experienced side effects that led to a reduction in the dose of the compound (1).

[00398] The most common adverse events were diarrhea (15 patients, 34.9%), followed by increased ALT (8 patients, 18.6%), anemia (8 patients, 18.6%), and increased blood creatinine (7 patients, 16.3%).

[00399] In total, 11 patients (25.6%) presented with Grade 1 CTCAE maximum aortic aneurysms, 11 patients (25.6%) with Grade 2, 10 patients (23.2%) with Grade 3, 1 patient (2.3%) with Grade 4 and 5 patients (11.6%) with Grade 5.

[00400] Based on the preferred term (PT) defined in the “Medical Dictionary for Regulatory Activities” (MedDRA), Grade 3 events were elevated ALT (5 patients, 11.6%), elevated AST (2 patients, 4.7%), anemia (2 patients, 4.7%), diarrhea, pneumonia, elevated GGT, hypertriglyceridemia, hypocalcemia, extremity pain, pleural effusion, atrial flutter, basal cell carcinoma, decreased lymphocyte count, pericardial effusion, and sepsis (1 patient each, 2.3%). One patient (2.3%) experienced a Grade 4 event (COVID-19). All coded Grade 5 events (1 not yet coded) (i.e., fatal) were disease-related events. Petition 870250085375, dated 09 / 22 / 2025, page 111 / 198 100 / 141 underlying cancer (progression of malignant neoplasm: 3 patients, 7.0%; malignant lung neoplasm: 1 patient, 2.3%).

[00401] In total, 18 patients (41.9%) experienced a maximum Grade 1 drug-related adverse event, 6 patients (14.0%) experienced a Grade 2 adverse event, 4 patients (9.3%) experienced a Grade 3 adverse event, 0 patients experienced a Grade 4 adverse event, and 0 patients experienced a Grade 5 adverse event. Patients with Grade 3 drug-related AEs at the time of data lockout were: one patient with Grade 3 drug-related elevated AST and ALT, two patients with Grade 3 drug-related elevated ALT, and one patient with Grade 3 hypocalcemia.

[00402] Overall, 14 patients (32.6%) experienced a serious adverse event (SAE). One patient (2.3%) experienced SAEs that were considered drug-related by the investigator: grade 3 ALT elevation and grade 3 AST elevation.

[00403] Eleven of the 14 patients presented with EAGs that were considered related to the underlying disease or an external cause: progression of malignancy in 1 patient, progression of malignancy and basal cell carcinoma in 1 patient, progression of malignancy and pleural effusion in 1 patient, malignant lung neoplasm and metastases in the central nervous system in 1 patient, pericardial effusion, pneumonia and pleural effusion in 1 patient, anemia and “not yet coded” (reported as “death”; clarification of the cause was ongoing at the time of data locking) in 1 patient, sepsis in 1 patient, elevated ALT in 1 patient, diarrhea in 1 patient, peritumoral edema in 1 patient and cerebral edema in 1 patient.

[00404] In addition, 3 patients presented with AEs, in which the researcher reported no relationship with the underlying disease or extraneous cause. These AEs were: Grade 2 / 3 atrial flutter in 1 patient, Grade 2 pneumonia in 1 patient, and Grade 4 COVID-19 (with risk). Petition 870250085375, dated 09 / 22 / 2025, page 112 / 198 101 / 141 deaths) in 1 patient. All three patients recovered from the EAG.

[00405] At the time of data lockout, four patients experienced dose-limiting toxicity: one of these patients (QD 60 mg) had an AE that was erroneously reported as a DLT by the investigator (grade 3 anemia unrelated to the drug on day 213); the error has not yet been corrected at the time of data lockout. One patient (60 mg BID cohort) experienced grade 2 edema on day 58 (drug-related, not severe). One patient (150 mg BID cohort) experienced grade 2 diarrhea on day 155 (drug-related, not severe). One patient (180 mg QD cohort) had a grade 3 ALT elevation (drug-related, not severe) and a grade 2 ALT elevation on Day 84 (drug-related, not severe).

[00406] No DLT was reported in cohorts of 240 mg QD and 300 mg QD doses in Cycle 1 or later.

[00407] None of the patients in the dose-escalation portion of the study experienced DLT during the MTD assessment period (first cycle; 21 days), with doses administered up to 150 mg twice daily and 300 mg once daily. Thus, MTD was not achieved in either regimen, totaling 43 patients served. Table 1 - General summary of adverse events during the treatment period, BID cohort escalation, treated group in the March 2023 data lock. Compound (1), Dose in mg 15 30 60 100 150 Total BID N % N % N % N % N % N % Number of patients 3 100.0 3 100.0 4 100.0 4 100.0 3 100.0 1 7 100.0 Petition 870250085375, dated 09 / 22 / 2025, page 113 / 198 102 / 141 Compound (1), Dose in mg 15 30 60 100 150 Total Patients with any AE 2 66.7 3 100.0 4 100.0 4 100.0 3 100.0 1 6 94.1 Patients with investigator-defined drug-related adverse events 2 66.7 2 66.7 4 100.0 3 75.0 2 66.7 1 3 76.5 Patients with protocol-specified adverse events of special interest (AESI) 0 0.0 0 0.0 1 25.0 0 0.0 1 33.3 2 11.8 Patients with AEs that led to dose reduction of Compound (1) 0 0.0 0 0.0 1 25.0 0 0.0 0 0.0 1 5.9 Patients with AS that 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Petition 870250085375, dated 09 / 22 / 2025, page 114 / 198 103 / 141 Compound (1), Dose in mg 15 30 60 100 150 Total led to discontinuation of Compound (1) Patients with AEs that led to discontinuation of Compound (1) 0 0.0 1 33.3 2 50.0 0 0.0 2 66.7 5 29.4 Patients with DLTs 0 0.0 0 0.0 1 25.0 0 0.0 1 33.3 2 11.8 Patients with severe AEs 1 33.3 2 66.7 2 50.0 0 0.0 2 66.7 7 41.2 Death 1 33.3 1 33.3 0 0.0 0 0.0 1 33.3 3 17.6 risk of death 0 0.0 0 0.0 1 25.0 0 0.0 0 0.0 1 5.9 Disability or permanent damage 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Hospitalization (initial or prolonged) 0 0.0 2 66.7 1 25.0 0 0.0 1 33.3 4 23.5 Congenital anomaly or detection at birth 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Petition 870250085375, dated 09 / 22 / 2025, pp. 115 / 198 104 / 141 Compound (1), Dose in mg 15 30 60 100 150 Total Other serious (important) medical events 1 33.3 0 0.0 0 0.0 0 0.0 1 33.3 2 11.8 Worst CTCAE grade Grade 1 0 0.0 0 0.0 1 25.0 3 75.0 0 0.0 4 23.5 Grade 2 1 33.3 1 33.3 1 25.0 1 25.0 1 33.3 5 29.4 Grade 3 0 0.0 1 33.3 1 25.0 0 0.0 1 33.3 3 17.6 Grade 4 0 0.0 0 0.0 1 25.0 0 0.0 0 0.0 1 5.9 Degree 5 1 33.3 1 33.3 0 0.0 0 0.0 1 33.3 3 17.6 Table 2 - Overall summary of adverse events during the treatment period, QD escalation of the cohort, treated group in the March 2023 data lock. Compound (1), Dose in mg 60 120 180 240 300 Total QD N % N % N % N % N % N % Number of patients 5 100.0 4 100.0 6 100.0 6 100.0 5 100.0 2 6 100.0 Patients with any AE 5 100.0 4 100.0 5 83.3 5 83.3 3 60.0 2 2 84.6 Patients with drug-related adverse events 3 60.0 2 50.0 4 66.7 4 66.7 2 40.0 1 5 57.7 Petition 870250085375, dated 09 / 22 / 2025, pp. 116 / 198 105 / 141 Compound (1), Dose in mg 60 120 180 240 300 Total defined by the investigator Patients with adverse events of special interest specified by the protocol (AESI) 1 20.0 0 0.0 1 16.7 1 16.7 0 0.0 3 11.5 Patients with AEs that led to dose reduction of Compound (1) 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 1 3.8 Patients with AEs that led to discontinuation of Compound (1) 1 20.0 0 0.0 1 16.7 0 0.0 0 0.0 2 7.7 Patients with AEs that led to 0 0.0 2 50.0 1 16.7 0 0.0 0 0.0 3 11.5 Petition 870250085375, dated 09 / 22 / 2025, pp. 117 / 198 106 / 141 Compound (1), Dose in mg 60 120 180 240 300 Total interruption of Compound (1) Patients with DLTs 1 20.0 0 0.0 1 16.7 0 0.0 0 0.0 2 7.7 Patients with severe AEs 2 40.0 2 50.0 0 0.0 2 33.3 1 20.0 7 26.9 Death 2 40.0 0 0.0 0 0.0 0 0.0 0 0.0 2 7.7 Risk of death 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Disability or permanent damage 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Hospitalization (initial or prolonged) 2 40.0 2 50.0 0 0.0 0 0.0 1 20.0 5 19.2 Congenital anomaly or detection at birth 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Other serious (important) medical events 0 0.0 1 25.0 0 0.0 2 33.3 0 0.0 3 11.5 Worst CTCAE grade Grade 1 2 40.0 0 0.0 0 0.0 3 50.0 2 40.0 7 26.9 Grade 2 0 0.0 2 50.0 3 50.0 1 16.7 0 0.0 6 23.1 Petition 870250085375, dated 09 / 22 / 2025, pages 118 / 198 107 / 141 Compound (1), Dose in mg 60 120 180 240 300 Total Grade 3 1 20.0 2 50.0 2 33.3 1 16.7 1 20.0 7 26.9 Grade 4 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Grade 5 2 40.0 0 0.0 0 0.0 0 0.0 0 0.0 2 7.7 Table 3 - General summary of adverse events during the treatment period, escalation, treated group in the March 2023 data lock. BID QD Total N % N % N % Number of patients 17 100.0 26 100.0 43 100.0 Patients with any AE 16 94.1 22 84.6 38 88.4 Patients with investigator-defined drug-related adverse events 13 76.5 15 57.7 28 65.1 Patients with protocol-specified adverse events of special interest (AESI) 2 11.8 3 11.5 5 11.6 Patients with AEs leading to dose reduction of Compound (1) 1 5.9 1 3.8 2 4.7 Patients with AEs leading to discontinuation of Compound (1) 0 0.0 2 7.7 2 4.7 Patients with AEs leading to discontinuation of Compound (1) 5 29.4 3 11.5 8 18.6 Patients with DLTs 2 11.8 2 7.7 4 9.3 Patients with severe ASs 7 41.2 7 26.9 14 32.6 Death 3 17.6 2 7.7 5 11.6 Risk of death 1 5.9 0 0.0 1 2.3 Disability or permanent damage 0 0.0 0 0.0 0 0.0 Hospitalization (initial or prolonged) 4 23.5 5 19.2 9 20.9 Congenital anomaly or detection at birth 0 0.0 0 0.0 0 0.0 Petition 870250085375, dated 09 / 22 / 2025, pp. 119 / 198 108 / 141 BID QD Total births Other serious (important) medical events 2 11.8 3 11.5 5 11.6 Worst grade CTCAE Grade 1 4 23.5 7 26.9 11 25.6 Grade 2 5 29.4 6 23.1 11 25.6 Grade 3 3 17.6 7 26.9 10 23.3 Grade 4 1 5.9 0 0.0 1 2.3 Grade 5 3 17.6 2 7.7 5 11.6 1.2.4 Overview of effectiveness

[00408] Among all treated patients, tumor response assessments were available for 34 of 43 patients, 16 treated BID and 18 treated QD. Overall, the best overall response of partial response (PR), regardless of confirmation, was reported for 13 of 34 evaluable patients (38.2%). Stable disease was achieved in 18 patients (52.9%); 3 patients (8.8%) had PD; a complete response (CR) was not reported for any patients. Among NSCLC patients, tumor response assessments were available for 24 of 32 patients. Among evaluable NSCLC patients, 11 reported a best overall response of PR (45.8% of 24 evaluable patients, regardless of confirmation), while for 12 patients (50%) the best overall response was PD, and for one patient (4.2%) the best response was PD.For this assessment, patients are considered to have NSCLC if the primary diagnosis for study entry was entered as NSCLC or lung cancer in general that was not classified as small cell lung cancer. Table 4 - Best overall response according to RECIST v1.1 (investigator assessment), regardless of confirmation in the March 2023 data lock - dose escalation, Petition 870250085375, dated 09 / 22 / 2025, pp. 120 / 198 109 / 141 BID scheme, treated set. Compound (1) in mg 15 30 60 100 150 BID Total N % N % N % N % N % N % Number of patients 3 100.0 3 100.0 4 100.0 4 100.0 3 100.0 1 7 100.0 Best overall response (RECIST 1.1) Complete response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Partial response 0 0.0 2 66.7 2 50.0 1 25.0 1 33.3 6 35.3 Stable disease 3 100.0 1 33.3 2 50.0 3 75.0 1 33.3 1 0 58.8 No CR / No PD 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0 Progressive disease 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Not assessable 0 0.0 0 0.0 0 0.0 0 0.0 1 33.3 1 5.9 Table 5 - Best overall response according to RECIST v1.1 (investigator assessment), regardless of confirmation in March 2023 data lock - dose escalation, QD schedule, treated set. Compound (1) in mg 60 120 180 240 300 QD Total N % N % N % N % N % N % Number 5 100, 4 100, 6 100, 6 100, 5 100, 2 100, Petition 870250085375, dated 09 / 22 / 2025, pp. 121 / 198 110 / 141 Compound (1) in mg 60 120 180 240 300 of patients 0 0 0 0 0 6 0 Best overall response (RECIST 1.1) Complete response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Partial response 2 40.0 2 50.0 1 16.7 2 33.3 0 0.0 7 26.9 Stable disease 2 40.0 1 25.0 4 66.7 0 0.0 1 20.0 8 30.8 Non-CR / Non-PD 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Progressive disease 1 20.0 1 25.0 0 0.0 1 16.7 0 0.0 3 11.5 Not available 0 0.0 0 0.0 1 16.7 3 50.0 4 80.0 8 30.8 Table 6 - Best overall response according to RECIST v1.1 (investigator assessment), regardless of confirmation for NSCLC patients in the March 2023 data block, dose escalation, BID regimen, treated set. Compound (1) in mg 15 30 60 100 150 BID Total N % N % N % N % N % N % Number of patients 1 100.0 2 100.0 3 100.0 3 100.0 2 100.0 1 1 100.0 Best overall response (RECIST 1.1) Petition 870250085375, dated 09 / 22 / 2025, page 122 / 198 111 / 141 Compound (1) in mg 15 30 60 100 150 Complete response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Partial response 0 0.0 1 50.0 2 66.7 1 33.3 1 50.0 5 45.5 Stable disease 1 100.0 1 50.0 1 33.3 2 66.7 1 50.0 6 54.5 Non-CR / Non-PD 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Progressive disease 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Not evaluable 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Table 7 - Best overall response according to RECIST v1.1 (investigator assessment), regardless of confirmation for NSCLC patients in the March 2023 data block, dose escalation, QD regimen, treated set. Compound (1) in mg 60 120 180 240 300 QD Total N % N % N % N % N % N % Number of patients 2 100.0 4 100.0 5 100.0 5 100.0 5 100.0 2 1 100.0 Best overall response (RECIST 1.1) Complete response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Partial response 1 50.0 2 50.0 1 20.0 2 40.0 0 0.0 6 28.6 Petition 870250085375, dated 09 / 22 / 2025, page 123 / 198 112 / 141 Compound (1) in mg 60 120 180 240 300 Stable disease 1 50.0 1 25.0 3 60.0 0 0.0 1 20.0 6 28.6 Non-CR / Non-PD 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Progressive disease 0 0.0 1 25.0 0 0.0 0 0.0 0 0.0 1 4.8 Not evaluable 0 0.0 0 0.0 1 20.0 3 60.0 4 80.0 8 38.1

[00409] Other preliminary evidence of efficacy is provided in Figures 2 to 9. According to Figure 2(A), 13 out of 35 patients (37.14%) who were treated for at least one 21-day cycle have at least one PR assessment. This increases to 7 out of 18 patients (38.89%) when considering the QD scheme, as shown in Figures 2A and 4A. In Figures 2 to 9 and 12, each bar represents a different patient. The bars represent patients whose index is ranked by maximum reduction in %. The change from baseline was calculated as the difference between lesion size at screening and at the end of 2 cycles (Day 42). Negative values ​​indicate a reduction in the sum of target lesion diameters and positive values ​​an increase. 1.2.5 Exposure

[00410] Plasma exposure increased with increasing doses, with no apparent deviation from dose-proportional pharmacokinetics. However, there was substantial intra- and inter-patient variability in pharmacokinetics observed with overlapping exposure between dose groups, for example, at 180 mg QD, 240 mg QD, and 300 mg QD.

[00411] The relationship between the dose level (total daily dose) and the rate of Petition 870250085375, dated 09 / 22 / 2025, pp. 124 / 198 The objective response of 113 / 141 was assessed using a logistic regression model (regular / non-Bayesian), based on the set of patients who have at least one post-baseline tumor assessment. The estimated relationship and 95% confidence range are reported in Figure 10. The relationship between dose level (total daily dose) and the best percent change in the sum of the largest diameters of the target tumor lesions relative to baseline (tumor reduction) was assessed using a linear regression model (regular / non-Bayesian) based on the set of patients who have at least one post-baseline tumor assessment. The estimated relationship and 95% confidence range are reported (Figure 11).

[00412] Flat exposure-response / safety relationships were observed, especially flattened exposure-response curves for tumor reduction and ORR, indicating no trend toward substantial efficacy improvements in the higher dose range (180 mg to 300 mg).

[00413] Exposure-toxicity analyses were also performed. In terms of toxicity endpoints, the occurrence of Grade 2 or higher AEs and Grade 3 or higher AEs was considered. For all exposure endpoints considered, the overall relationship between exposure and toxicity, considering all adverse events, is relatively stable, with no indication of a higher incidence of overall Grade 2 / 3 (and higher) adverse events for patients with higher exposure. However, for specific AEs, for example, diarrhea AEs, a trend towards a potentially higher incidence was observed for higher exposure. 1.2.6 Duration of Treatment

[00414] Twenty-four patients were on treatment in the higher dose cohorts (100 mg twice daily and above and 180 mg once daily and above) for relatively long periods up to the cutoff date. Petition 870250085375, dated 09 / 22 / 2025, page 125 / 198 114 / 141 For these patients, the median total duration of treatment was > 6 months at the time of data lock-up for the 150 mg BID cohort and almost 5 months for the 100 mg BID and 180 mg QD cohorts, as shown below. Most of these patients were still on treatment at the time of data lock-up. 100 mg BID for 147 days (2 / 4 pts still on treatment at the time of data lock) 150 mg BID for 185 days (2 / 3 patients still on treatment at the time of data blocking) 180 mg QD 146 days (6 / 6 pts still on treatment at the time of data lock) 240 mg QD for 72 days (5 / 6 patients still on treatment at the time of data lock) 300 mg QD 57 days (5 / 5 pts still on treatment at the time of data lock)

[00415] Overall, the mean duration of treatment at the data cutoff date was 126.0 days. The mean number of treatment cycles initiated was 4.0 (range: 1 to 15). 1.2.7 Response duration

[00416] Based on all patients treated, the median duration of response (Kaplan-Meier estimates) was 7 months.

[00417] Based on all patients treated with NSCLC, the median duration of response (Kaplan-Meier estimates) was 6.9 months (95% CI: 1.4 to 7.0). 1.2.8 Patients pre-treated with trastuzumab deruxtecan

[00418] At the July 2023 data cutoff, 50 patients had been treated. 5 (10.0%) patients received trastuzumab deruxtecan prior to compound (1). These patients had NSCLC. Tumor reduction of up to -53% (mean -22.5%, median -16.1%) was observed in these patients. Petition 870250085375, dated 09 / 22 / 2025, pp. 126 / 198 115 / 141

[00419] The results presented in this application are only preliminary, because many patients are still undergoing treatment at the time of filing this application. Example 2 - Updating the results from Example 1 (section 1.2 and subsections)

[00420] This example shows an update of the results from Example 1, where data are reported up to the January 2024 cutoff. The study design and protocol are identical to Example 1 (see paragraph 1.1 and subsections), except that the 360 ​​mg QD dose level has been added. Note that in April 2023, the dose expansion portion of the trial was opened. After this period, NSCLC patients with HER2 tyrosine kinase domain mutations were no longer eligible to be included in Phase Ia of the study, but were included in Phase Ib (dose expansion, see Example 3) of the study. NSCLC patients ineligible for Phase Ib were still eligible to participate in Phase Ia, provided they met the remaining criteria for Phase Ia enrollment.Furthermore, after the dose expansion was opened, researchers were authorized to enroll patients in Phase Ia at a dose of their choice from among the dose levels that were explored and considered safe by the DEC in the QD regimen, i.e., doses up to 360 mg QD. 2.1 Exposure and Demographics

[00421] In total, 83 patients were treated with compound (1) in the dose escalation portion up to the data cutoff date of this Example 2. Overall, the mean duration of treatment at the data cutoff date was 4.2 months, and exposure ranged from 0 to 24 months.

[00422] Thirty-nine patients (47%) were Asian and 35 patients (42.2%) were white. The mean age of the patients was 59 years (range 31 to 81); 38 (45.8%) patients were male. The main primary diagnoses were NSCLC (33 patients; Petition 870250085375, dated 09 / 22 / 2025, pp. 127 / 198 116 / 141 39.8%) and unspecified lung cancers (10 patients, 12%). The median time since the first histological diagnosis was 36.2 months (range 6 to 237.5 months). All patients who provided data on this had metastatic disease at screening (76 patients), with the predominant metastasis locations being lung, lymph node, bone, and liver. For the remaining 7 patients, information on the presence of metastasis was missing.

[00423] Among the patients for whom data were available on the results of tests for HER2 aberrations, 28 of 75 (37.3%) patients had HER2 overexpression; 42 of 75 (56%) patients had non-synonymous somatic mutation, and 12 of 75 (16%) patients had genetic rearrangements involving HER2 or NRG1. 2.2 Security Overview

[00424] At the time of data locking for this Example, 7 of 83 patients (8.4%) experienced dose-limiting toxicity (DLT) at some point during the entire treatment period (from the start of treatment to the end of the residual effect period). The following DLTs were observed, in addition to those reported in Example 1 (see subsection 1.2.3). Among patients in the 240 mg QD cohort, one patient experienced Grade 4 thrombocytopenia and another patient experienced Grade 3 diarrhea. One patient (300 mg QD cohort) experienced Grade 4 hypokalemia and Grade 4 neutropenia, considered as DLTs. One patient (360 mg QD) had Grade 3 decreased platelet count.

[00425] No DLT was reported in cohorts of 120 mg QD and 60 mg QD doses in Cycle 1 or beyond in the dose escalation portion of the study.

[00426] Three of the patients mentioned above presented DLTs during the MTD evaluation period (first cycle, 21 days): one with Petition 870250085375, dated 09 / 22 / 2025, pages 128 / 198 117 / 141 One group received a 360 mg QD dose, another a 300 mg QD dose, and one a 240 mg QD dose. Thus, the DLT rates within the MTD evaluation period were 5.9% at the 240 mg QD dose, 5% at the 300 mg QD dose, and 16.7% at the 360 ​​mg QD dose. For all other doses, no DLTs occurred during the MTD evaluation period. Based on this and the BLRM analysis, the MTD was not achieved in either regimen, with a total of 83 patients treated at the data cutoff.

[00427] Notably, at all doses, there were very low rates of adverse events leading to dose reduction (9.6%) of compound (1) and a limited rate of patients with adverse events leading to temporary dose interruptions (26.5%) of compound (1). In addition, only 2 patients (2.4%) experienced serious adverse events that the investigator considered related to compound (1). Overall, the tested dosing regimens of compound (1) surprisingly showed a very tolerable and manageable safety profile.While other tyrosine kinase inhibitors that inhibit HER2 are typically associated with high rates of toxicities resulting from off-target inhibition of wild-type EGFR, the dosing regimen of compound (1) has been surprisingly found to lead to relatively low rates of these EGFR-associated AEs (e.g., rash, stomatitis, paronychia, AEs that are common to HER2 tyrosine kinase inhibitors such as pirotinib and pozoitinib, as reported, for example, 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). Table 1-A - Overall summary of adverse events during the treatment period, BID cohort escalation, treated group at the January 2024 data lock. Values ​​in bold are updated compared to Table 1. Petition 870250085375, dated 09 / 22 / 2025, pp. 129 / 198 118 / 141 Compound (1), Dose in mg 15 30 60 100 150 Total BID N % N % N % N % N % N % Number of patients 3 100.0 3 100.0 4 100.0 4 100.0 3 100.0 1 7 100.0 Patients with any AE 2 66.7 3 100.0 4 100.0 4 100.0 3 100.0 1 6 94.1 Patients with investigator-defined drug-related adverse events 2 66.7 2 66.7 4 100.0 3 75.0 2 66.7 1 3 76.5 Patients with protocol-specified adverse events of special interest (AESI) 0 0.0 0 0.0 1 25.0 0 0.0 1 33.3 2 11.8 Patients with adverse events that led to dose reduction of 0 0.0 0 0.0 1 25.0 0 0.0 1 33.3 2 11.8 Petition 870250085375, dated 09 / 22 / 2025, pp. 130 / 198 119 / 141 Compound (1), Dose in mg 15 30 60 100 150 Total Compound (1) Patients with AEs leading to discontinuation of Compound (1) 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Patients with AEs leading to discontinuation of Compound (1) 0 0.0 0 0.0 3 75.0 0 0.0 3 100.0 6 35.3 Patients with DLTs 0 0.0 0 0.0 1 25.0 0 0.0 1 33.3 2 11.8 Patients with severe AEs 1 33.3 2 66.7 2 50.0 1 25.0 2 66.7 8 47.1 Death 1 33.3 1 33.3 0 0.0 1 25.0 1 33.3 4 23.5 Risk of death 0 0.0 0 0.0 1 25.0 0 0.0 0 0.0 1 5.9 Disability or permanent damage 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Hospitalization (initial or prolonged) 0 0.0 2 66.7 1 25.0 0 0.0 2 66.7 5 29.4 Petition 870250085375, dated 09 / 22 / 2025, page 131 / 198 120 / 141 Compound (1), Dose in mg 15 30 60 100 150 Total Congenital anomaly or detection at birth 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Other serious (important) medical events 1 33.3 0 0.0 0 0.0 0 0.0 1 33.3 2 11.8 Worst CTCAE grade Grade 1 0 0.0 0 0.0 1 25.0 2 50.0 0 0.0 3 17.6 Grade 2 1 33.3 1 33.3 1 25.0 1 25.0 1 33.3 5 29.4 Grade 3 0 0.0 1 33.3 1 25.0 0 0.0 1 33.3 3 17.6 Grade 4 0 0.0 0 0.0 1 25.0 0 0.0 0 0.0 1 5.9 Grade 5 1 33.3 1 33.3 0 0.0 1 25.0 1 33.3 4 23.5 Table 2-A - Overall summary of adverse events during the treatment period, QD escalation of the cohort, treated group at the January 2024 data lock-up. Values ​​in bold are updated compared to Table 2. Compound (1), Dose in mg 60 120 180 240 300 360 Total QD N % N % N % N % N % N % N % Number of patients 5 10 0.0 5 10 0.0 1 3 10 0.0 1 7 10 0.0 2 0 10 0.0 6 10 0.0 6 6 10 0.0 Patients with 5 10 0.0 4 80.0 1 2 92.3 1 4 82.4 1 9 95.0 6 10 0.0 6 0 90.9 Petition 870250085375, dated 09 / 22 / 2025, page 132 / 198 121 / 141 Compound (1), Dose in mg 60 120 180 240 300 360 Total any AE Patients with adverse events related to the drug defined by the investigator 3 60.0 3 60.0 9 69.2 1 3 76.5 1 6 80.0 6 10 0.0 5 0 75.8 Patients with adverse events of special interest specified by the protocol (AESI) 0 0.0 0 0.0 1 7.7 2 11.8 1 5.0 1 16.7 5 7.6 Patients with AEs that led to reduction 0 0.0 0 0.0 1 7.7 2 11.8 2 10.0 1 16.7 6 9.1 Petition 870250085375, dated 09 / 22 / 2025, page 133 / 198 122 / 141 Compound (1), Dose in mg 60 120 180 240 300 360 Total dose of Compound (1) Patients with AEs that led to discontinuation of Compound (1) 1 20.0 1 20.0 2 15.4 2 11.8 0 0.0 0 0.0 6 9.1 Patients with AEs that led to discontinuation of Compound (1) 1 20.0 3 60.0 5 38.5 2 11.8 4 20.0 1 16.7 1 6 24.2 Patients with DLTs 0 0.0 0 0.0 1 7.7 2 11.8 1 5.0 1 16.7 5 7.6 Patients with severe AEs 2 40, 0 4 80, 0 7 53, 8 6 35, 3 7 35, 0 0 0,0 2 6 39, 4 Death 2 40, 0 1 20, 0 0 0,0 3 17, 6 0 0,0 0 0,0 6 9,1 risk of death 1 20, 0 0 0,0 0 0,0 1 5,9 0 0,0 0 0,0 2 3,0 Petition 870250085375, dated 09 / 22 / 2025, page 134 / 198 123 / 141 Compound (1), Dose in mg 60 120 180 240 300 360 Total Permanent disability or damage 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Hospitalization (initial or prolonged) 2 40.0 3 60.0 7 53.8 5 29.4 7 35.0 0 0.0 2 4 36.4 Congenital anomaly or detection at birth 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Other serious (important) medical events 0 0.0 2 40.0 0 0.0 3 17, 6 1 5.0 0 0.0 6 9.1 Worst CTCAE Grade Grade 1 2 40.0 0 0.0 0 0.0 4 23.5 2 10.0 2 33.3 1 0 15.2 Grade 2 0 0.0 2 40.0 4 30.8 4 23.5 9 45.0 3 50.0 2 2 33.3 Grade 3 1 20.1 20.8 61.3 17.7 35.1 16.2 31. Petition 870250085375, dated 09 / 22 / 2025, p. 135 / 198 124 / 141 Compound (1), Dose in mg 60 120 180 240 300 360 Total 0 0 5 6 0 7 1 8 Grade 4 0 0.0 0 0.0 0 0.0 0 0.0 1 5.0 0 0.0 1 1.5 Grade 5 2 40.0 1 20.0 0 0.0 3 17.6 0 0.0 0 0.0 6 9.1 Table 3-A - General summary of adverse events during the treatment period, escalation, treated set in the January 2024 data lock. Values ​​in bold are updated compared to Table 3. BID QD Total N % N % N % Number of patients 17 100.0 66 100.0 83 100.0 Patients with any AE 16 94.1 60 90.9 76 91.6 Patients with investigator-defined drug-related adverse events 13 76.5 50 75.8 63 75.9 Patients with protocol-specified adverse events of special interest (AESI) 2 11.8 5 7.6 7 8.4 Patients with AEs leading to dose reduction of Compound (1) 2 11.8 6 9.1 8 9.6 Patients with AEs leading to discontinuation of Compound (1) 0 0.0 6 9.1 6 7.2 Patients with AEs leading to discontinuation of Compound (1) 6 35.3 16 24.2 22 26.5 Patients with DLTs 2 11.8 5 7.6 7 8.4 Patients with severe AS 8 47.1 26 39.4 34 41.0 Death 4 23.5 6 9.1 10 12.0 Risk of death 1 5.9 2 3.0 3 3.6 Disability or permanent damage 0 0.0 0 0.0 0 0.0 Petition 870250085375, dated 09 / 22 / 2025, pp. 136 / 198 125 / 141 BID QD Total Hospitalization (initial or prolonged) 5 29.4 24 36.4 29 34.9 Congenital anomaly or detection at birth 0 0.0 0 0.0 0 0.0 Other serious (important) medical events 2 11.8 6 9.1 8 9.6 Worst CTCAE grade Grade 1 3 17.6 10 15.2 13 15.7 Grade 2 5 29.4 22 33.3 27 32.5 Grade 3 3 17.6 21 31.8 24 28.9 Grade 4 1 5.9 1 1.5 2 2.4 Grade 5 4 23.5 6 9.1 10 12.0 2.3 Overview of effectiveness

[00428] For the updated analyses of accumulated data in the dose escalation portion of the study, the longer follow-up allowed for analysis of the best confirmed overall response rather than the objective response, regardless of confirmation of the previous data cutoff presented in Example 1. That is, in contrast to Example 1, patients are only considered to have a partial response if a partial response assessment is made in two subsequent tumor assessments for a patient, i.e., if a second tumor assessment confirms the initial partial response at a later time point.

[00429] Among all treated patients, 74 of 83 patients were evaluated for tumor response assessment, 17 treated BID and 57 treated QD. Patients were considered not evaluable (NE) for response in this analysis if they were in ongoing and too recently started treatment to be evaluated, i.e., not NE due to a PD assessment before day 36 of treatment and did not have a post-baseline tumor assessment that would allow them to be assigned a confirmed overall response. Overall, the best Petition 870250085375, dated 09 / 22 / 2025, page 137 / 198 126 / 141 partial tumor response (PR), requiring confirmation, was reported for 26 of 74 patients (35.1%) evaluable for analysis. Stable disease was achieved in 37 patients (50%); 5 patients (6.7%) had PD; a complete response (CR) was not reported for any of the patients.

[00430] Among NSCLC patients, 41 of 43 patients were evaluated for confirmed best overall response, as defined above. Among evaluable NSCLC patients, 18 reported a best overall response of PR (43.9% of 41 evaluable patients), while for 20 patients (48.8%) the best overall response was DS, and for one patient (2.4%) the best response was PD. Two other patients had a best overall response of “not evaluable,” despite not being ongoing and having been on treatment for too short a time to be evaluated, which can happen, for example, if a patient discontinues treatment before a tumor image is taken (these patients should be included in the analyses as non-responders). Table 4-A - Best overall response according to RECIST v1.1 (investigator assessment), with confirmation requirement in January 2024 data lock - dose escalation, BID regimen, treated set. Values ​​in bold are updated compared to Table 4. Compound (1) in mg 15 30 60 100 150 BID Total N % N % N % N % N % N % Number of patients 3 100.0 3 100.0 4 100.0 4 100.0 3 100.0 1 7 100.0 Best overall response (RECIST 1.1) Response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Petition 870250085375, dated 09 / 22 / 2025, pp. 138 / 198 127 / 141 Compound (1) in mg 15 30 60 100 150 Complete Partial Response 0 0.0 0 0.0 1 25.0 1 25.0 1 33.3 3 17.6 Stable Disease 3 100.0 3 100.0 3 75.0 2 50.0 1 33.3 1 2 70.6 Non-CR / Non-PD 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Progressive Disease 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Not Evaluable 0 0.0 0 0.0 0 0.0 1 25.0 1 33.3 2 11.8 Table 5-A - Best overall response according to RECIST v1.1 (investigator assessment), with confirmation requirement in January 2024 data lock - dose escalation, QD regimen, treated set. Values ​​in bold are updated compared to Table 5. Compound (1) in mg 60 120 180 240 300 360 QD Total N % N % N % N % N % N % N % Number of patients 5 100.0 5 100.0 1 3 100.0 1 7 100.0 2 0 100.0 6 100.0 6 6 100.0 Best overall response (RECIST 1.1) Response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Petition 870250085375, dated 09 / 22 / 2025, pp. 139 / 198 128 / 141 Compound (1) in mg 60 120 180 240 300 360 Complete response Partial response 1 20.0 3 60.0 2 15.4 7 41.2 6 30.0 4 66.7 2 3 34.8 Stable disease 3 60.0 0 0.0 7 53.8 5 29.4 8 40.0 2 33.3 2 5 37.9 Non-CR / Non-PD 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Progressive disease 1 20.0 1 20.0 1 7.7 1 5.9 1 5.0 0 0.0 5 7.6 Not available 0 0.0 1 20.0 3 23.1 4 23.5 5 25.0 0 0.0 1 3 19.7 Table 6-A - Best overall response according to RECIST v1.1 (investigator assessment), with confirmation requirement for NSCLC patients in the January 2024 data lock-in, dose escalation, BID regimen, treated set. Values ​​in bold are updated compared to Table 6. Compound (1) in mg 15 30 60 100 150 BID Total N % N % N % N % N % N % Number of patients 1 100.0 2 100.0 3 100.0 3 100.0 2 100.0 1 1 100.0 Petition 870250085375, dated 09 / 22 / 2025, pp. 140 / 198 129 / 141 Compound (1) in mg 15 30 60 100 150 Best overall response (RECIST 1.1) Complete response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Partial response 0 0.0 0 0.0 1 33.3 1 33.3 1 50.0 3 27.3 Stable disease 1 100.0 2 100.0 2 66.7 2 66.7 1 50.0 8 72.7 Non-CR / Non-PD 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Progressive disease 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 No available 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Table 7-A - Best overall response according to RECIST v1.1 (investigator assessment), with confirmation requirement for NSCLC patients on dose escalation data lock-in January 2024, QD schedule, treated set. Values ​​in bold are updated compared to Table 7. Compound (1) in mg 60 120 180 240 300 360 QD Total N % N % N % N % N % N % N % Number of patients 2 100 .0 5 100 .0 6 100 .0 7 100 .0 1 1 100 .0 1 100 .0 3 2 100 .0 Best overall response (RECIST 1.1) Petition 870250085375, dated 09 / 22 / 2025, p. 141 / 198 130 / 141 Compound (1) in mg 60 120 180 240 300 360 Complete response 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Partial response 0 0.0 3 60.0 2 33.3 5 71.4 5 45.5 0 0.0 1 5 46.9 Stable disease 2 100.0 0 0.0 4 66.7 2 28.6 3 27.3 1 100.0 0 0.0 0 0.0 Progressive disease 0 0.0 1 20.0 0 0.0 0 0.0 0 0.0 0 0.0 1 3.1 Not available 0 0.0 1 20.0 0 0.0 0 0.0 3 27.3 0 0.0 4 12.5 2.4 Duration of Treatment

[00431] Among the 83 patients treated in this Example, 38 (45.8%) are still ongoing and continuing treatment at the time of data lock-up. Among patients in the QD cohorts, the majority (34 of 66 patients, 51.5%) are still ongoing. At the time of data lock-up, the median treatment duration (time to discontinuation) based on a Kaplan-Meier estimate is 8.3 months, while the third quartile (time at which 75% of patients are expected to discontinue) is 20.3 months. Thus, based on the Kaplan-Meier estimate of treatment duration / time to discontinuation, 25% of patients are expected to remain on treatment for more than 20 months before discontinuing treatment. Petition 870250085375, dated 09 / 22 / 2025, page 142 / 198 131 / 141 with the tested dosage regimens of compound (1), indicating generally tolerable treatment over long periods of time. Up to the data cutoff, the longest treatment duration for an individual patient was approximately 2 years (24 months, patient on 30 mg twice daily). Due to the study design, patients on higher doses were recruited later than patients on lower doses, so patients on higher doses were on treatment for shorter periods compared to those on lower doses. Still, with 120 mg QD, the maximum treatment duration is 18 months, and for 240 mg QD, the maximum treatment duration is 13 months at the cutoff date, where many patients on these higher dose levels are still ongoing, indicating that the higher dose levels are well tolerated by patients. 2.5 Response time

[00432] Based on all patients treated, the median duration of confirmed response (Kaplan-Meier estimates) was 12.7 months (95% confidence interval: 5.6 months to 15.8 months). Overall, this indicates strong durability of responses across the entire range of doses and regimens studied, even starting at very low dose levels. For example, with 60 mg twice daily, one patient had a confirmed response lasting 12.7 months, and with 120 mg four times daily, two patients with confirmed responses had durations exceeding 12 months (14.1 and 15.8 months at the time of data cutoff). At higher dose levels, longer durations of response were also observed, for example, one patient with a confirmed response duration of almost 12 months with 240 mg QD.Due to the study design, patients on higher doses were recruited later than patients on lower doses, meaning that patients on high doses had less time for follow-up regarding the durability of the treatment. Petition 870250085375, dated 09 / 22 / 2025, pp. 143 / 198 132 / 141 response at the time of data cutoff, on average. Even so, the results indicate an impressive durability of the response across the entire dose range studied.

[00433] Based on all patients treated with NSCLC, the median duration of response (Kaplan-Meier estimates) was 15.8 months (95% confidence interval: 5.6 to 15.8 months). 2.6 Duration of disease control

[00434] Among all treated patients, the median duration of disease control according to a Kaplan-Meier estimate was 8.7 months (95% confidence interval: 7.2 to 13.9 months). The median duration was 8.4 months in the BID cohorts and 10.3 months in the QD cohorts. Overall, long duration of disease control was observed across a wide range of doses, including lower dose levels. For example, with 120 mg QD, a median duration of disease control of 17.2 months was observed in 3 patients with disease control, and with 30 mg BID, one patient had a duration of disease control of 20.8 months at the time of data cutoff.

[00435] In patients with NSCLC, the median duration of disease control according to a Kaplan-Meier estimate was 12.3 months (95% confidence interval: 8.3 months NC, where NC refers to “cannot be calculated due to lack of events”). The median duration of disease control in the QD regimen was 12.3 months, and in the BID regimen, 13.8 months. Overall, greater durability of disease control was observed in patients with NSCLC compared to the population of all treated patients. 2.7 Patients pre-treated with trastuzumab deruxtecan

[00436] 19 of the 83 patients treated (22.9%) received trastuzumab deruxtecan prior to the compound (1). Of these, 15 patients already had post-baseline tumor assessments at the time of data cutoff and are considered evaluable for objective response, Petition 870250085375, dated 09 / 22 / 2025, pp. 144 / 198 133 / 141 regardless of the confirmation that follows.

[00437] Among the 15 evaluable patients who had received prior treatment with trastuzumab deruxtecan, 5 had a partial response as the best overall response (33.3%, regardless of confirmation), 8 (53.3%) had stable disease, and 2 (12.3%) had progressive disease. Therefore, a disease control rate of 86.7% was observed in these patients. Tumor reduction of up to -90.6% was observed in this group of patients, with a mean tumor reduction of -19.1% and a median of -12.5%. 2.8 Progression-free survival

[00438] At the data cutoff, 36 of the 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 considered 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 for not having post-baseline assessments (yet), and 26 patients (31.3%) are ongoing in the data lock and considered censored at the last tumor assessment available at the time.Based on Kaplan-Meier analysis, as illustrated in Figure 12, the median PFS in the BID regimen was 8.0 months (95% confidence interval: 2.8 months for NC, where NC means that the value could not be calculated due to a lack of events) and in the QD schedule 8.3 months (95% confidence interval: 5.6 to 13.9 months). Overall, similar PFS was observed at different dose levels. However, in low-dose groups, patients showed very low PFS results. Petition 870250085375, dated 09 / 22 / 2025, pages 145 / 198 134 / 141 promising (e.g., 30 mg twice daily in a patient with more than 20 months of PFS).

[00439] Among the 43 patients treated for 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); the remaining patients were considered censored for analysis. 16 (37.2%) of the lung cancer patients are data locked and considered censored at the last available tumor assessment, and 4 patients (9.3%) are censored at Day 1 as they have not yet had a post-baseline tumor assessment. For lung cancer patients, PFS was estimated to be greater than in the entire group of treated patients based on a Kaplan-Meier analysis, as shown in Figure 13: for the BID regimen, the estimate is a median PFS of 13.8 months (confidence interval: 2.3 months for NC), and for the QD schedule, it was 12.3 months (confidence interval: 7.6 to 17.2 months).Similar SPF was observed across the entire dose range explored in patients with lung cancer.

[00440] Other preliminary evidence of efficacy is provided in Figures 2 to 9. The results presented in this application are only preliminary, because many patients are still undergoing treatment at the time of filing this application. Example 3 - Dose expansion portion (Phase Ib) of the clinical trial from Examples 1 and 2

[00441] 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 advanced or metastatic refractory NSCLC, carrying mutations in the HER2 gene, were enrolled. Specific elements of Phase Ib are reported in the protocol below. For other unspecified elements, the Petition 870250085375, dated 09 / 22 / 2025, pp. 146 / 198 Protocol 135 / 141 remains as in Example 1. Patients are divided into 5 cohorts according to the main inclusion criteria listed below. 3.1 Protocol

[00442] The objectives of the Phase Ib trial include: - For cohort 1, cohort 2, and cohort 5, assess the objective tumor response rate by independent central review; - For cohort 3, assess the objective tumor response rate using investigator evaluation; - For all cohorts, further investigate the safety, tolerability, and pharmacokinetics of the investigated doses of compound (1) in patients with advanced / metastatic NSCLC with a positive HER2 mutation; - For all cohorts, continue evaluating safety and patient-reported outcomes.

[00443] The main endpoints of Phase Ib include: - For cohorts 1, 2, and 5: OR assessed by independent central review, according to RECIST version 1.1; - For cohort 3: OR determined by the investigator.

[00444] Secondary endpoints include:

[00445] For Cohorts 1, 2 and 5: - Objective duration of response (DoR) according to RECIST 1.1 by independent central review; - Disease control (DC) according to RECIST 1.1 by independent central review; - SLP in accordance with RECIST 1.1 by independent central review;

[00446] For Cohort 3 only: - Duration of OR as per RECIST 1.1 based on investigator assessment; - DC in accordance with RECIST 1.1 as assessed by the investigator; - SLP in accordance with RECIST 1.1 as assessed by the investigator; Petition 870250085375, dated 09 / 22 / 2025, pp. 147 / 198 136 / 141

[00447] For all cohorts: - Number of patients who experienced DLTs throughout the treatment period; - Change of baseline to C5D1 (cycle 5, day 1) in the scoring of the physical functioning domain of the EORTC QLQ-C30; - Change of baseline to C5D1 in the total CPNPCSAQ score; - Change of baseline to C5D1 in the scoring of the EORTC IL46 item.

[00448] EORTC QLQ-C30, NSCLC-SAQ, and EORTC IL46 are patient-reported outcome measures (PROMs). Specifically, the EORTC QLQ-C30 physical functioning domain score (IL19) is a 5-item functional scale of the EORTC QLQ-C30, which is a questionnaire specifically for assessing health-related quality of life (QoL) in cancer patients. NSCLC-SAQ is a 7-item PROM for use in adults to assess symptoms of advanced NSCLC. It contains five domains and accompanying items that have been identified as NSCLC symptoms: 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 impact of side effects. Another PROM may be measured during the course of the study.

[00449] The main inclusion criteria include: - Patients with a confirmed diagnosis of advanced, unresectable and / or metastatic non-hematologic malignancy with at least one measurable lesion (similar to Example 1); - Availability and willingness to provide a sample of archived, formalin-fixed, paraffin-embedded (FFPE) tumor tissue material (similar to Example 1); Patients must be willing to comply with the collection requirements. Petition 870250085375, dated 09 / 22 / 2025, pages 148 / 198 137 / 141 of blood and tumor biopsy for pharmacokinetic, pharmacodynamic and biomarker analyses (similar to Example 1); - For cohort 1: Patients with documented HER2 tyrosine kinase domain (TKD) positive mutation in non-squamous NSCLC who, in the advanced / metastatic setting, received at least one line of systemic therapy that includes platinum-based combination chemotherapy; - For cohort 2: Patients with documented HER2 tyrosine kinase domain (TKD) positive mutation in non-squamous NSCLC who have not received any prior line of therapy (neoadjuvant chemotherapy or adjuvant chemotherapy, chemoradiotherapy or radiotherapy are permitted if at least 6 months have elapsed before disease progression); - For cohort 3: Patients with HER2-positive non-TKD NSCLC and HER2-positive TKD squamous cell carcinoma who have received, in the advanced / metastatic setting, at least one line of systemic therapy that includes platinum-based combination chemotherapy; Patients in cohorts 1 to 3 should not have received prior therapy with antibody-drug conjugates (ADCs) targeting HER2; - For cohort 5: Patients with HER2 TKD mutation-positive non-squamous NSCLC who have received prior HER2-targeted ADC therapy in the advanced / metastatic setting and who experienced disease progression during or after completion of that therapy.

[00450] As those skilled in the art will recognize, other inclusion and exclusion criteria may apply.

[00451] Compound (1) is administered orally at a dose of 120 mg or 240 mg QD. Petition 870250085375, dated 09 / 22 / 2025, pp. 149 / 198 138 / 141

[00452] Treatment consists of repeated 3-week cycles, as long as the patient experiences clinical benefit or until undue drug toxicity occurs or consent is withdrawn, whichever comes first (similar to Example 1).

[00453] For Cohort 1, the primary endpoint OR analysis by independent central review is performed with a one-sided z-test at a one-sided alpha level of 0.0125 (to account for the two doses investigated).

[00454] For Cohorts 2 and 5, the analysis of the primary outcome OR by independent central review is performed with a one-tailed z-test at the one-tailed alpha level of 0.025.

[00455] For Cohort 3, no confirmatory tests are performed. Only descriptive analyses are carried out, in terms of observed ORR and 95% CIs by Wilson's method. In addition, the primary OR endpoint by investigator assessment is analyzed using a Bayesian Hierarchical Model (BHM) for ORR, thus leveraging the available coding data from Cohorts 1, 2 and 3 in a meta-analytic Bayesian approach. 3.2 Results

[00456] In July 2023, 42 patients were treated in Phase Ib Cohort 1 (randomized to 120 / 240 mg QD). Treatment-related adverse events (TREs) (all / grade >3) were observed in 67% / 10% of patients. The most common TREs were diarrhea (29% / 0%), rash (21% / 0%), elevated aspartate aminotransferase (10% / 2%), loss of appetite (10% / 0%), and dysgeusia (10% / 0%). No adverse events led to treatment discontinuation. RRO / RCD in 23 evaluable patients (who received 2 to 5 cycles at cutoff) was 74% / 91%. The best mean percent change from baseline in target lesions was -41.2%. The best change from baseline in target lesions is shown in Petition 870250085375, dated 09 / 22 / 2025, pp. 150 / 198 139 / 141 Figure 14. All patients who responded remained on treatment at the time of data cutoff. Example 4 - Efficacy of compound (1) (zongertinib) in T-DXd-resistant NSCLC cells

[00457] Zongertinib (i.e., compound (1)) consistently inhibits downstream HER2 signaling and proliferation of cancer cells dependent on high HER2WT expression, and its mechanism of action differs from that of antibody-based therapeutics, offering the opportunity to address resistance. Therefore, this Example investigates whether zongertinib is effective against human cancer cells that are dependent on high HER2WT expression but resistant to HER2-targeted ADCs. First, a trastuzumab deruxtecan (T-DXd) resistant tumor model was generated. 4.1. MATERIALS AND METHODS 4.1.1. Derivation of T-DXd-resistant tumors in vivo

[00458] To generate T-DXd-resistant models, the NCIN87 model is used and tumor-bearing mice are treated with three cycles of T-DXd, tumors that regrow are collected and then the tumor cells are cultured in vitro, as shown in Figure 15. Parental and T-DXd-resistant NCI-N87 cells are treated with deruxtecan, T-DXd or zongertinib.

[00459] NCI-N87 cells are suspended in 2.5*10⁷ cells in PBS (Gibco, #14190-094) with 5% FBS (Gibco, #26140-079). The cell suspension is then injected subcutaneously into the right flank of BomTac:NMRI-Foxn1nu mice with a volume of 100 µl (2.5*10⁶ cells per mouse). After 15 days, the mice are randomized based on the volume of the tumor with an average size of 120 mm³. On this day, treatment is initiated with 3 mg / kg of T-DXd iv. From then on, the tumor size is measured three times a week using a caliper. On day 22 after the first treatment, a Petition 870250085375, dated 09 / 22 / 2025, pp. 151 / 198 On days 140 / 141, the second treatment is injected at 10 mg / kg of T-DXd. Follow-up treatments are conducted on days 43, 64, 85, and 106 with 7 mg / kg IV. After this, growth is observed. Tumors are collected on day 174 (#18 at 514.09 mm3) and day 209 (#17 at 626.21 mm3) and cultured in PBS on ice. 4.1.2. In vitro tumor expansion

[00460] Tumors are sectioned into 1 mm3 fragments and homogenized using the Tumor Dissociation Kit, mouse (Miltenyi Biotec, No. 130-096-730), in combination with the gentleMACS™ Octo Dissociator (Miltenyi). Cells are resuspended in 3 ml of RPMI medium (PAN-Biotech, #P04-18047) supplemented with 10% FBS (Gibco, #26140-079), 1x GlutaMAX™ (Gibco, #35050-038), 1x Pen Strep (Gibco, #15140-122) and the cell count is measured. 6.8 χ¹⁰⁶ cells are plated in 3 ml of medium per well in a TC-treated 6-well cell culture plate (Corning, No. 3506) and cultured in a humidified incubator at +37°C and 5% CO₂. Over the next 2 days, the cells are washed daily with 3 ml of PBS (Gibco, #14190-094) to remove loose cells, and the medium is replaced. The cells are passed to 60-80% confluence by washing with 1 ml of PBS, subsequently dissociated with 500 µL of trypsin (PANBiotech, #P10-0210300) and incubated at 37°C until the cells detach.Trypsin is blocked with 1 mL of medium, and 500 µL of cell suspension are placed back into a 6-well plate with 3 mL of medium or into a T25 cell culture flask with 7 mL of medium (Corning, #353109). The cells are cultured for 5 passages until no more residual fibroblasts are visible before performing the proliferation assay after drug treatment. 4.1.3. Proliferation assay

[00461] Per well, 1000 cells are seeded in 40 pL of medium in sterile 384-well white culture plates (treated with TC; Petition 870250085375, dated 09 / 22 / 2025, pp. 152 / 198 141 / 141 PerkinElmer #6007680) and incubated overnight in a humidified incubator at 37°C and 5% CO2. A 0.1% DMSO control or serial dilution of the compound in triplicate is added. T-DXd is diluted in 0.3% Tween solution and added to the cells. After 5 days of incubation with the test compounds, the cell plates are measured by adding the luminescent cell viability reagent CellTiter Glo (Promega, #G9243) to assess cell viability. The plates are placed on a shaker for five minutes and additionally incubated for 10 minutes at room temperature to induce cell lysis and stabilize the luminescent signal. The luminescent signal of each well is measured on an EnSpire Multilabel 658 plate reader (PerkinElmer). Dose-response curves are fitted and visualized using Boehringer Ingelheim's proprietary MegaLab software and PRISM (GraphPad Inc.). 4.2. RESULTS

[00462] Using a cell lineage model, in this Example, it was demonstrated that zongertinib potently inhibits the proliferation of HER2-dependent cells that have 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, with a difference of at least 100-fold in their IC50 (Figures 16A and 16B). Conversely, both parental and resistant NCI-N87 cells were sensitive to zongertinib, with a difference of less than 10-fold in their IC50 (Figure 16C). Therefore, zongertinib inhibits the growth of trastuzumab deruxtecan-resistant human HER2-dependent NSCLC cells.

[00463] The data presented in this Example raise the exciting possibility that zongertinib may be effective in treating HER2-dependent tumors that are resistant to ADCs. Petition 870250085375, dated 09 / 22 / 2025, pp. 153 / 198

Claims

1 / 5 CLAIMS 1. Compound (1) as defined below (1), characterized in that it is for use in the treatment of cancer, wherein the Compound (1) is administered at a daily dose of at least 30 mg.

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

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

4. Compound (1) for use according to any one of claims 1 to 3, characterized in that it is 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, characterized in that it 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.

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

7. Compound (1) for use according to any one of claims 1 to 6, characterized in that it is administered at a daily dose of 120 mg or 240 mg. Petition 870250085375, dated 22 / 09 / 2025, page 154 / 198 2 / 5 8. Compound (1) for use according to any one of claims 1 to 7, characterized in that it is administered at a daily dose of 120 mg.

9. Compound (1) for use according to any one of claims 1 to 7, characterized in that it is administered at a daily dose of 240 mg.

10. Compound (1) for use according to any one of claims 1 to 9, characterized in that it is administered once or twice daily.

11. Compound (1) for use according to any one of claims 1 to 10, characterized in that it is administered once daily.

12. Compound (1) for use according to any one of claims 1 to 11, characterized in that it 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.

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

14. Compound (1) for use according to any one of claims 1 to 13, characterized in that it is administered once daily at a daily dose of 120 mg or 240 mg.

15. Compound (1) for use according to any one of claims 1 to 14, characterized in that it is administered once daily at a daily dose of 120 mg. Petition 870250085375, dated 22 / 09 / 2025, page 155 / 198 3 / 5 16. Compound (1) for use according to any one of claims 1 to 14, characterized in that it is administered once daily at a daily dose of 240 mg.

17. Compound (1) for use according to any one of claims 1 to 16, characterized in that it is administered orally.

18. Compound (1) for use according to any one of claims 1 to 17, characterized in that it is administered as a tablet.

19. Compound (1) for use according to any one of claims 1 to 18, characterized in that it is administered after the administration of a systemic anticancer therapy agent.

20. Compound (1) as defined below (1) characterized in that it is for use in the treatment of cancer, wherein Compound (1) is administered after the administration of a systemic anticancer therapy agent.

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

22. Compound (1) for use, according to any of claims 19 to 21, characterized in that the systemic anticancer therapy agent is or comprises trastuzumab Petition 870250085375, dated 09 / 22 / 2025, page 156 / 198 4 / 5 deruxtecan and / or trastuzumab emtansine.

23. Compound (1) for use according to any one of claims 19 to 21, characterized in that 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, characterized in that the cancer is selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric 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. Compound (1) for use according to any one of claims 1 to 24, characterized in that the cancer is non-small cell lung cancer.

26. Compound (1) for use according to any one of claims 1 to 25, characterized in that said cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant.

27. Compound (1) for use according to any one of claims 1 to 26, characterized in that said cancer comprises a mutation in the tyrosine kinase domain of HER2.

28. Compound (1) for use according to any one of claims 1 to 27, characterized in that said cancer is an unresectable, advanced and / or metastatic cancer.

29. Compound (1) for use according to any one of claims 1 to 28, characterized in that said cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 drug-antibody conjugate. Petition 870250085375, dated 22 / 09 / 2025, p. 157 / 198 5 / 5 30. Compound (1) as defined below (1), characterized in that it is for use in the treatment and / or prevention of cancer, wherein the cancer is resistant to treatment with an anti-HER2 antibody and / or an anti-HER2 drug-antibody conjugate.

31. Compound (1) for use according to claim 30, characterized in that the cancer is as defined in any one of claims 24 to 28.

32. Compound (1) for use according to any one of claims 29 to 31, characterized in that the cancer is resistant to treatment with trastuzumab deruxtecan.

33. Pharmaceutical composition, characterized in that it comprises Compound (1) as defined below (1), and at least one excipient that is pharmaceutically acceptable for use in the treatment of cancer, wherein Compound (1) is administered at a daily dose of at least 30 mg.

34. Pharmaceutical composition for use according to claim 33, characterized in that Compound (1) is administered as defined in any one of claims 2 to 23.

35. Pharmaceutical composition for use, according to claim 33 or 34, characterized in that cancer is as defined in any of claims 24 to 29. Petition 870250085375, dated 09 / 22 / 2025, pp. 158 / 198

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