WO2024200637A2 - Schéma posologique d'un inhibiteur d'her2 - Google Patents

Schéma posologique d'un inhibiteur d'her2 Download PDF

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Publication number
WO2024200637A2
WO2024200637A2 PCT/EP2024/058464 EP2024058464W WO2024200637A2 WO 2024200637 A2 WO2024200637 A2 WO 2024200637A2 EP 2024058464 W EP2024058464 W EP 2024058464W WO 2024200637 A2 WO2024200637 A2 WO 2024200637A2
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Prior art keywords
compound
cancer
administered
daily dose
daily
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2024/058464
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English (en)
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WO2024200637A3 (fr
Inventor
Anke Baum
Krzysztof CHYLINSKI
Neil Gibson
Ralph NEUMUELLER
Behbood SADROLHEFAZI
Dirk Scharn
Lukas SCHROETER
Josep Serra
Ute VON WANGENHEIM
Sven WIND
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Priority to AU2024247020A priority Critical patent/AU2024247020A1/en
Priority to CN202480032966.5A priority patent/CN121263188A/zh
Priority to KR1020257036057A priority patent/KR20260004349A/ko
Priority to EP24717127.5A priority patent/EP4687907A2/fr
Publication of WO2024200637A2 publication Critical patent/WO2024200637A2/fr
Publication of WO2024200637A3 publication Critical patent/WO2024200637A3/fr
Priority to MX2025011417A priority patent/MX2025011417A/es
Priority to IL323596A priority patent/IL323596A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a dosing schedule of the HER2 inhibitor 7V- ⁇ l-[8-( ⁇ 3-methyl- 4-[(l-methyl-U7-l,3-benzodiazol-5-yl)oxy]phenyl ⁇ amino)-[l,3]diazino[5,4-J]pyrimidin-2- yl]piperidin-4-yl ⁇ prop-2-enamide, which is useful in the prevention and/or treatment of cancer.
  • the dosing schedule can be defined by doses and/or second or further line administration of the HER2 inhibitor.
  • Zongertinib is a potent and selective tyrosine kinase inhibitor of wild type and mutant HER2 that spares wild type epithelial growth factor receptor (EGFR). Therefore, it is useful for the treatment and/or prevention of diseases and/or conditions wherein the inhibition of wild type and/or mutant HER2 is of therapeutic benefit, especially oncological and/or hyperproliferative diseases, such as cancer.
  • FIG. 1 (A) Design of the dose escalation part of a clinical trial testing different doses and schedules of compound (1) in pre-treated patients with unresectable, advanced and/or metastatic solid tumors with an aberration of the HER2 gene, as described in Examples 1 and 2. (B) Alternative representation of the dose escalation part of the clinical trial of Example 1.
  • FIG. 1 Swimmer plot of response assessments and duration of treatment by patient and dose (A) as of March 2023 and (B) as of January 2024.
  • the bars represent progression-free survival durations, not treatment durations.
  • Each bar represents a patient in Phase la (see Examples 1 and 2).
  • BID bis in die, twice daily;
  • QD quaque die, once a day;
  • PR partial response;
  • SD stable disease;
  • FIG. 3 Swimmer plot of response assessments and duration of treatment by patient and dose in the BID schedule (A) as of March 2023 and (B) as of January 2024.
  • the bars represent progression-free survival durations, not treatment durations.
  • Each bar represents a patient in Phase la (see Examples 1 and 2).
  • Abbreviations are defined as in figure 2.
  • FIG. 4 Swimmer plot of response assessments and duration of treatment by patient and dose in the QD schedule (A) as of March 2023 and (B) as of January 2024.
  • the bars represent progression-free survival durations, not treatment durations.
  • Each bar represents a patient in Phase la (see Examples 1 and 2).
  • Abbreviations are defined as in figure 2.
  • FIG. 5 Waterfall plot of BID vs QD schedules showing best change from baseline in target lesions (RECIST vl.l) expressed as a percentage. Each bar represents a patient in Phase la (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 interval between 20% and -30% corresponds to stable disease (SD). Data are from January 2023 in panel (A) and from January 2024 in panel (B).
  • FIG. 6 Waterfall plot of BID dose levels showing best change from baseline in target lesions (RECIST vl. l) expressed as a percentage. Each bar represents a patient in Phase la (see Examples 1 and 2). The dashed lines have the same meaning as in Figure 5. Data are from March 2023 in panel (A) and from January 2024 in panel (B).
  • FIG. 7 Waterfall plot of QD dose levels showing best change from baseline in target lesions (RECIST vl. l) expressed as a percentage. Each bar represents a patient in Phase la (see Examples 1 and 2). The dashed lines have the same meaning as in Figure 5. Data are from March 2023 in panel (A) and from January 2024 in panel (B).
  • Figure 8 Waterfall plot of BID dose levels showing best change from baseline in target lesions (RECIST vl.l) expressed as a percentage in (A) non-small cell lung cancer patients and (B) patients with other tumors as of March 2023.
  • Panel (C) corresponds to panel (A) but with a cut-off date of January 2024.
  • Each bar represents a patient in Phase la (see Examples 1 and 2).
  • the dashed lines have the same meaning as in Figure 5.
  • Figure 9 Waterfall plot of QD dose levels showing best change from baseline in target lesions (RECIST vl.l) expressed as a percentage in (A) non-small cell lung cancer patients and (B) patients with other tumors as of March 2023.
  • Panel (C) corresponds to panel (A) but with a cut-off date of January 2024.
  • Each bar represents a patient in Phase la (see Examples 1 and 2).
  • the dashed lines have the same meaning as in Figure 5.
  • Figure 10 Analysis on the correlation between objective response rate and total daily dose with logistic regression, based on the dose levels and schedules of Phase la 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 on the correlation between best percentage change from baseline in sum of longest diameters of target lesion (i.e., tumor shrinkage) and total daily dose with linear regression, based on the dose levels and schedules of Phase la shown in Figure 1(A) and (B).
  • the dashed line with longer dashes (higher at the start) represents the estimated relationship
  • the dashed line with shorter dashes (lower at the start) indicates -30% tumor shrinkage (defining partial response)
  • the dotted area shows the 95% confidence interval.
  • Data are from March 2023.
  • FIG. 12 Kaplan-Meier plot of progression-free survival (RECIST v.1.1) by dosing schedule (BID, QD) in the set of all treated patients of Phase la (see Examples 1 and 2), median progression-free survival (Med), and lower and upper confidence limit (LCL, UCL) of the 95% confidence interval for the estimate of median progression-free survival. Crosses on the line indicate timepoints where a BID patient was censored, and circles indicate timepoints where a QD patient was censored. Data are from January 2024.
  • FIG. 13 Kaplan-Meier plot of progression-free survival (RECIST v.1.1) by dosing schedule (BID, QD) in the set of lung cancer patients of Phase la (see Examples 1 and 2), median progression-free survival (Med), and lower and upper confidence limit (LCL, UCL) of the 95% confidence interval for the estimate of median progression-free survival. Crosses on the line indicate timepoints where a BID patient was censored, and circles indicate timepoints where a QD patient was censored. Data are from January 2024.
  • Figure 14 Waterfall plot showing best change from baseline in target lesions (RECIST vl. l) expressed as a percentage. Each bar represents a patient in Cohort 1 of Phase lb that started treatment at least 7 weeks prior to the snapshot date with baseline and post-baseline tumor assessments (see Example 3). Patients were treated with 120 mg QD or 240 mg QD. Data cut-off is July 2023.
  • FIG. 15 Schematic representation of the experiment for data in Figure 16.
  • T-DXd resistant tumors are generated in vivo, harvested and cultured in vitro, then tested for sensitivities to T-DXd, the T-DXd payload deruxtecan and compound (1).
  • compound (1) as defined below for use in the treatment of cancer, wherein compound (1) is administered in a daily dose of at least 30 mg.
  • a method of treating a patient suffering from cancer comprising administering compound (1) in a daily dose of at least 30 mg.
  • compound (1) is administered in a daily dose of 30 mg to 600 mg.
  • compound (1) is administered in a daily dose of at least 60 mg.
  • compound (1) is administered in a daily dose of 60 mg to 300 mg.
  • compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg. In embodiments, compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg or 360 mg.
  • compound (1) is administered in a daily dose of 120 mg or 240 mg.
  • compound (1) is administered in a daily dose of 120 mg.
  • compound (1) is administered in a daily dose of 240 mg.
  • compound (1) is administered once or twice daily.
  • compound (1) is administered once daily.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg or 360 mg, or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg or 360 mg.
  • compound (1) is administered once daily in a daily dose of 120 mg or 240 mg.
  • compound (1) is administered once daily in a daily dose of 120 mg.
  • compound (1) is administered once daily in a daily dose of 240 mg.
  • compound (1) is administered orally.
  • compound (1) is administered as a tablet.
  • compound (1) is administered following administration of a systemic anticancer therapy agent.
  • Another aspect relates to a compound (1) as defined below for use in the treatment of cancer, wherein compound (1) is administered following administration of a systemic anti-cancer therapy agent.
  • a method of treating a patient suffering from cancer comprising administering compound (1) following administration of a systemic anti-cancer therapy agent.
  • compound (1) is preferably administered as defined above, especially with respect to daily dose, once/twice daily administration and/or oral (particularly tablet) administration.
  • the systemic anti-cancer therapy agent is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, taxanes, antimetabolites, immunotherapeutic agents and combinations thereof.
  • systemic anti-cancer therapy agent is or comprises trastuzumab deruxtecan and/or trastuzumab emtansine.
  • the systemic anti -cancer therapy agent comprises pembrolizumab, pemetrexed and/or platinum-based chemotherapy.
  • 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, esophagus tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
  • said cancer is non-small cell lung cancer.
  • said cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant.
  • said cancer comprises a mutation in the tyrosine kinase domain of HER2.
  • said cancer is unresectable, advanced and/or metastatic.
  • said cancer is resistant to treatment with an anti-HER2 antibody and/or an anti-HER2 antibody-drug conjugate.
  • Another aspect relates to compound (1) as defined below 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.
  • a method of treating and/or preventing cancer in a subject in need thereof comprising administering compound (1), wherein the cancer is resistant to treatment with an anti-HER2 antibody and/or an anti-HER2 antibody-drug conjugate.
  • the cancer is preferably as defined in any one or more of the above embodiments.
  • the cancer is resistant to treatment with trastuzumab deruxtecan.
  • a pharmaceutical composition comprising compound (1) as defined below and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein compound (1) is administered in a daily dose of at least 30 mg.
  • a method of treating a patient suffering from cancer comprises administering a pharmaceutical composition comprising compound (1) and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in a daily dose of at least 30 mg.
  • compound (1) is preferably administered as defined in any of the above embodiments referring to compound (1) for use, especially with respect to daily dose, once/twice daily administration and/or oral (particularly tablet) administration.
  • the cancer may be as defined above in any embodiment.
  • any of the embodiments or aspects disclosed herein referring to compatible features may be combined with each other to provide further embodiments of the invention.
  • efficacy can be evidenced by 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 that have a best overall response of “non-evaluable” at the time of data cut-off) as of the earlier cut-off date.
  • ORR overall response rate
  • DCR disease control rate
  • Further preliminary evidence of efficacy is provided in Examples 1 and 2 (see in particular 1.2.4 and 2.3 and Figures 2-9 and 12-13) and in Example 3 (see in particular 3.2 and Figure 14).
  • the side effects brought by the dose regime according to the invention are surprisingly few and mild, as demonstrated by the facts that only 3 dose limiting toxicities (DLT) have been observed, all of them occurring outside the maximum tolerated dose (MTD) observation period, and the MTD has not been reached yet at the first cut-off date (see 1.2.3 in Example 1).
  • DLT dose limiting toxicities
  • MTD maximum tolerated dose
  • the second cut-off date 4 patients had experienced a DLT at one point during the complete on-treatment period and the MTD has not been reached yet (see 2.2 in Example 2).
  • the dose regime according to the invention seems also to be suitable for a variety of patients who have already received other cancer related treatments.
  • the positive safety profile observed with the dosing schedules of the invention allows for relatively high amounts of compound (1) to be administered at the same time. This in turn can have several advantageous effects, for instance on patient compliance.
  • the dosing regimen of the invention was comparably efficacious in the patient population pre-treated with the anti-HER2 antibody drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) (see 1.2.8 in Example 1 and 2.7 in Example 2).
  • ADC anti-HER2 antibody drug conjugate
  • T-DXd trastuzumab deruxtecan
  • compound (1) refers to the compound as defined below or a pharmaceutically acceptable salt thereof:
  • the IUPAC name of compound (1) is A- ⁇ l-[8-( ⁇ 3-methyl-4-[(l-methyl-lJ7-l,3-benzodiazol- 5-yl)oxy]phenyl ⁇ amino)-[l,3]diazino[5,4-t ]pyrimidin-2-yl]piperidin-4-yl ⁇ prop-2-enamide. In case of discrepancy between IUPAC name and depicted formula, the formula shall prevail.
  • Compound (1) is also known as zongertinib.
  • Compound (1) is disclosed in WO 2021/213800 as example compound 1-01.
  • WO 2021/213800 describes [l,3]diazino[5,4-t ]pyrimidines such as compound (1) as HER2 inhibitors and provides a synthesis procedure for compound (1).
  • Properties of compound (1) and evidence for inhibitory effect on HER2 wild-type and YVMA kinase activity, while sparing EGFR, are also disclosed in WO 2021/213800, which is herein incorporated by reference.
  • compound (1) as used herein also encompasses any tautomers and pharmaceutically acceptable salts and all solid-state forms of the compound, as well as solvates, including hydrates and solvates of pharmaceutically acceptable salts thereof.
  • compound (1) is used as a free base.
  • pharmaceutically acceptable salts of compound (1) are used.
  • pharmaceutically acceptable used herein refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts of compound (1) refers to compound (1) wherein the compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts as used herein generally includes both acid and base addition salts.
  • Pharmaceutically acceptable acid addition salts refer to those salts which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable, formed with inorganic acids or organic acids.
  • Pharmaceutically acceptable base addition salts include salts derived from inorganic bases or organic nontoxic bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethane sulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.
  • pharmaceutically acceptable salts are selected from chloride and fumarate salts.
  • 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 like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • solvate refers to an association or complex of one or more solvent molecules and compound (1).
  • solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, tert-butyl methyl ether, tetrahydrofuran, methylethyl ketone, N-methylpyrrolidone and ethanolamine.
  • hydrate refers to a complex where the solvent molecule is water.
  • This dose regime is especially helpful for use in the treatment of cancer.
  • this dose regime of compound (1) or a pharmaceutical composition comprising compound (1) is especially helpful in a method of treating a patient suffering from cancer.
  • the dose regime seems also to be suitable as a second or further line treatment, wherein the patient already received in the past one or more kinds of cancer treatments.
  • dose regime or “dose schedule” refers to the administration of compound (1) according to any one or more features, including but not limited to: daily dose, once/twice daily administration, oral administration, administration for a certain duration, administration following a systemic anti-cancer therapy, etc.
  • daily dose or “total daily dose” refers to the amount of active substance, i.e. compound (1), which is administered to the patient within a 24 h timeframe.
  • the 24 h timeframe does not necessarily start at noon or midnight.
  • compound (1) is administered in a daily dose of at least 60 mg.
  • the method of treating a patient suffering from cancer described above comprises administering compound (1) in a daily dose of at least 60 mg.
  • compound (1) is administered in a daily dose of at least 80 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of at least 80 mg.
  • compound (1) is administered in a daily dose of at least 120 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of at least 120 mg.
  • compound (1) is administered in a daily dose of at least 180 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of at least 180 mg.
  • compound (1) is administered in a daily dose of at least 200 mg.
  • the method of treating a patient suffering from cancer comprising administering compound (1) in a daily dose of at least 200 mg.
  • compound (1) is administered in a daily dose of at least 240 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of at least 240 mg.
  • compound (1) is administered in a daily dose of at least 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of at least 300 mg.
  • compound (1) is administered in a daily dose of 30 mg to 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 30 mg to 600 mg.
  • compound (1) is administered in a daily dose of 60 mg to 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 60 mg to 600 mg.
  • compound (1) is administered in a daily dose of 80 mg to 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 80 mg to 600 mg.
  • compound (1) is administered in a daily dose of 120 mg to 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 120 mg to 600 mg.
  • compound (1) is administered in a daily dose of 30 mg to 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 30 mg to 300 mg.
  • compound (1) is administered in a daily dose of 60 mg to 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 60 mg to 300 mg.
  • compound (1) is administered in a daily dose of 80 mg to 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 80 mg to 300 mg.
  • compound (1) is administered in a daily dose of 120 mg to 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 120 mg to 300 mg.
  • compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg or 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg or 360 mg.
  • compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg or 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg or 300 mg.
  • compound (1) is administered in a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg or 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg or 360 mg.
  • compound (1) is administered in a daily dose of 120 mg or 240 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 120 mg or 240 mg.
  • compound (1) is administered in a daily dose of 30 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 30 mg.
  • compound (1) is administered in a daily dose of 60 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 60 mg.
  • compound (1) is administered in a daily dose of 80 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 80 mg.
  • compound (1) is administered in a daily dose of 120 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 120 mg.
  • compound (1) is administered in a daily dose of 180 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 180 mg.
  • compound (1) is administered in a daily dose of 200 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 200 mg.
  • compound (1) is administered in a daily dose of 240 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 240 mg.
  • compound (1) is administered in a daily dose of 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 300 mg.
  • compound (1) is administered in a daily dose of 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 360 mg.
  • compound (1) is administered in a daily dose of 400 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 400 mg.
  • compound (1) is administered in a daily dose of 420 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 420 mg.
  • compound (1) is administered in a daily dose of 480 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 480 mg.
  • compound (1) is administered in a daily dose of 500 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 500 mg.
  • compound (1) is administered in a daily dose of 540 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 540 mg.
  • compound (1) is administered in a daily dose of 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) in a daily dose of 600 mg.
  • compound (1) is administered once or twice daily. This means, that the daily dose is either administered on a daily basis as a single dose or the daily dose is divided in two separate administrations, each administered at a different time point of each day, i.e. within 24 h.
  • 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 of 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours, still preferably of 8, 9, 10, 11 or 12 hours, also preferably of approximately 12 hours.
  • compound (1) is administered once daily. In a preferred embodiment, compound (1) is administered as a single dose every 24 h.
  • compound (1) is administered twice daily. In a preferred embodiment, compound (1) is administered twice every 24 h. 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 amount.
  • compound (1) is administered at least for 21 consecutive days. In further preferred embodiments, compound (1) is administered for 21 days multiplied by X, wherein X is a natural number equal or larger than 1. As used herein, “21 days” and “3 weeks” are intended as synonyms. It is also possible, that in the overall cancer treatment between the treatment times including administering compound (1) a dose-free time-interval is included.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg or administering compound (1) twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg or administering compound (1) twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg or 360 mg, or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg or 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg or 360 mg or administering compound (1) twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg or 360 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg or administering compound (1) twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg.
  • compound (1) is administered once daily in a daily dose of 120 mg or 240 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 120 mg or 240 mg.
  • compound (1) is administered once daily in a daily dose of 60 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 60 mg.
  • compound (1) is administered once daily in a daily dose of 120 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 120 mg.
  • compound (1) is administered once daily in a daily dose of 180 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 180 mg.
  • compound (1) is administered once daily in a daily dose of 240 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 240 mg.
  • compound (1) is administered once daily in a daily dose of 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 300 mg.
  • compound (1) is administered once daily in a daily dose of 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 360 mg.
  • compound (1) is administered once daily in a daily dose of 400 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 400 mg.
  • compound (1) is administered once daily in a daily dose of 420 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 420 mg.
  • compound (1) is administered once daily in a daily dose of 480 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 480 mg.
  • compound (1) is administered once daily in a daily dose of 500 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 500 mg.
  • compound (1) is administered once daily in a daily dose of 540 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 540 mg.
  • compound (1) is administered once daily in a daily dose of 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) once daily in a daily dose of 600 mg.
  • compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.
  • compound (1) is administered twice daily in a daily dose of 30 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 30 mg.
  • each of the two daily administrations is of 15 mg.
  • compound (1) is administered twice daily in a daily dose of 60 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 60 mg.
  • each of the two daily administrations is of 30 mg.
  • compound (1) is administered twice daily in a daily dose of 120 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 120 mg.
  • each of the two daily administrations is of 60 mg.
  • compound (1) is administered twice daily in a daily dose of 200 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 200 mg.
  • each of the two daily administrations is of 100 mg.
  • compound (1) is administered twice daily in a daily dose of 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 300 mg.
  • each of the two daily administrations is of 150 mg.
  • compound (1) is administered twice daily in a daily dose of 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 360 mg.
  • each of the two daily administrations is of 180 mg.
  • compound (1) is administered twice daily in a daily dose of 400 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 400 mg.
  • each of the two daily administrations is of 200 mg.
  • compound (1) is administered twice daily in a daily dose of 420 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 420 mg.
  • each of the two daily administrations is of 210 mg.
  • compound (1) is administered twice daily in a daily dose of 480 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 480 mg.
  • each of the two daily administrations is of 240 mg.
  • compound (1) is administered twice daily in a daily dose of 500 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 500 mg.
  • each of the two daily administrations is of 250 mg.
  • compound (1) is administered twice daily in a daily dose of 540 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 540 mg.
  • each of the two daily administrations is of 270 mg.
  • compound (1) is administered twice daily in a daily dose of 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) twice daily in a daily dose of 600 mg.
  • each of the two daily administrations is of 300 mg.
  • compound (1) is administered orally.
  • compound (1) is administered as a tablet.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 120 mg or 240 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 120 mg or 240 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 60 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 60 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 120 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 120 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 180 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 180 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 240 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 240 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 300 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 360 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 400 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 400 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 420 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 420 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 480 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 480 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 500 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 500 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 540 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 540 mg.
  • compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once daily in a daily dose of 600 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 30 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 30 mg.
  • each of the two daily administrations is of 15 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 60 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 60 mg.
  • each of the two daily administrations is of 30 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 120 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 120 mg.
  • each of the two daily administrations is of 60 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 200 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 200 mg.
  • each of the two daily administrations is of 100 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 300 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 300 mg.
  • each of the two daily administrations is of 150 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 360 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 360 mg.
  • each of the two daily administrations is of 180 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 400 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 400 mg.
  • each of the two daily administrations is of 200 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 420 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 420 mg.
  • each of the two daily administrations is of 210 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 480 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 480 mg.
  • each of the two daily administrations is of 240 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 500 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 500 mg.
  • each of the two daily administrations is of 250 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 540 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 540 mg.
  • each of the two daily administrations is of 270 mg.
  • compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 600 mg.
  • the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, twice daily in a daily dose of 600 mg.
  • each of the two daily administrations is of 300 mg.
  • dose regimes described in this paragraph are also applicable in cases, wherein the patient already received one or more systemic anti-cancer treatments or therapies.
  • One aspect relates to compound (1) and the dose regime described herein for use in the treatment and/or prevention of cancer.
  • a further aspect relates to compound (1) and the dose regime described herein for use in the treatment and/or prevention of cancer, wherein the patient already received in the past one or more anti-cancer treatments or therapies, in particular a systemic anti-cancer therapy agent.
  • compound (1) is provided for use as an anti -cancer medicament, in the dose regime as described herein.
  • cancer is in certain cases a “hyperproliferative disease” and refers to conditions wherein cell growth is increased over normal levels.
  • Hyperproliferative diseases include malignant diseases, such as cancers, and non-malignant diseases.
  • cancer is in certain cases also referred to as “oncological disease”.
  • An oncological disease refers to a disease or medical condition associated with cancer or cancer indication. Cancers can be classified by the type of tissue in which the cancer originates (histological type) and by primary site, or the location in the body, where the cancer first developed.
  • compound (1) is provided in the dose regime as described herein for use in the treatment and/or prevention of cancer.
  • a further embodiment provides the pharmaceutical composition as described herein in the dose regime as described herein for use in the treatment and/or prevention of cancer.
  • a further embodiment provides compound (1) or the pharmaceutical composition as described herein for use in the treatment and/or prevention of cancer, wherein the patient already received a different first, second or further line treatment.
  • a different treatment comprises administration of an anti-cancer therapy, drug or agent different from and not comprising compound (1).
  • the previously performed first, second or further line treatment is not correlated with administration of compound (1) and the previously performed first, second or further line treatment is finished or has ended before a treatment comprising the administration of compound (1) is performed.
  • a further aspect relates to a method of treating and/or preventing cancer, wherein the method comprises the step of administering compound (1) in the dose regime described herein or the pharmaceutical composition as described herein in the dose regime described herein to a patient.
  • such method comprises administering to a human in need of such treatment the disclosed therapeutically effective amount of compound (1) or pharmaceutical composition comprising compound (1) as described herein.
  • a further aspect relates to a method of treating and/or preventing cancer, wherein the method comprises the step of administering compound (1) in the dose regime described herein or the pharmaceutical composition as described herein in the dose regime described herein to a patient, wherein the patient already received a different first, second or further line treatment.
  • such method comprises administering to a human in need of such treatment a therapeutically effective amount of compound (1) or pharmaceutical composition comprising compound (1) as described herein, wherein the patient already received a different first, second or further line treatment.
  • An embodiment relates to the use of compound (1) in the dose regime described herein or the pharmaceutical composition in the dose regime described herein in the manufacture of a medicament for the treatment and/or prevention of cancer.
  • the cancer or tumor comprises a HER2 aberration.
  • HER2 aberration means that the cells of the cancer or tumor harbor an aberration of HER2.
  • the expressions “HER2 aberration”, “aberration of HER2” and grammatical variants thereof have the meaning commonly attributed 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 in the HER2 protein (in particular non-synonymous mutations, somatic mutations, mutations in specific regions, e.g.
  • the cancer comprises a HER2 aberration, it can be referred to as HER2 aberrant.
  • the cancer comprises an overexpression of the HER2 protein, it can be referred to as HER2 overexpressed.
  • the cancer comprises an amplification of the HER2-encoding gene, it can be referred to as HER2 amplified.
  • the cancer comprises a mutation in the HER2- encoding gene and/or in the HER2 protein, it can be referred to as HER2 mutant.
  • the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant.
  • the cancer comprises a mutation in the tyrosine kinase domain of HER2. In embodiments, the cancer is HER2 exon 20 mutant cancer.
  • the cancer comprises a gene rearrangement of HER2 and/or NRG1.
  • HER2 overexpressed refers to a cancer, where the cells of the cancer or tumor express HER2 at levels detectable by immunohistochemistry (e.g. IHC 2+ and IHC 3+) and/or methods assaying ERBB2 messenger RNA.
  • immunohistochemistry e.g. IHC 2+ and IHC 3+
  • methods assaying ERBB2 messenger RNA e.g. IHC 2+ and IHC 3+
  • HER2 amplified refers to a cancer where the cancer 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 HER.2 gene ERBB2.
  • HER2 expression, gene copy number and amplification can be measured, for example, by determining nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof.
  • HER2 testing methods include immunohistochemistry (IHC), 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 or on the cancer sample cells can be compared to a reference cell.
  • the reference cell can be a non-cancer cell obtained from the same subject as the sample cell.
  • the reference cell can be a non-cancer cell obtained from a different subject or a population of subjects.
  • the cancer When the cancer is HER2 overexpressed and/or HER2 amplified in or on a cell, the cancer can be referred to as being “HER2 positive”.
  • HER2 mutant refers to a cancer harboring at least one mutation, i.e. an alteration in the nucleic acid sequence of the HER2-encoding gene and/or an alteration in the amino acid sequence of the HER2 protein, including but not limited to those listed below. Mutations can be found with any method known to the skilled person, 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.
  • PCR Polymerase Chain Reaction
  • SSCP Single Strand Conformational Polymorphism
  • DGGE Denaturing Gradient Gel Electrophoresis
  • RFLP Restriction fragment length polymorphism
  • NGS Next Generation Sequencing
  • the mutation is a non-synonymous mutation.
  • non-synonymous has the meaning commonly attributed to it in the art and in particular refers to a mutation in the nucleic acid sequence of the HER2-encoding gene that alters the amino acid sequence of the HER2 protein.
  • the mutation is a somatic mutation.
  • the term “somatic” has the meaning commonly attributed to it in the art and in particular refers to a mutation in the nucleic acid sequence of the HER2-encoding gene occurring in a cell other than a gamete, a germ cell or a gametocyte.
  • the mutation is a non-synonymous somatic mutation.
  • the mutation is a non-synonymous somatic mutation in the tyrosine kinase domain of HER2.
  • the mutation is in the tyrosine kinase domain of HER2, in particular in the exon 20 of HER2.
  • the cancer can be referred to as HER2 exon 20 mutant.
  • HER2 mutant may also refer to a rearrangement involving the HER2 gene ERBB2 and/or the NRG J gene.
  • a cancer comprising a mutation in the tyrosine kinase domain of HER2 is a cancer where the cancer or tumor cells harbour at least one mutation in the tyrosine kinase domain of HER2, which ranges from amino acids 694 to 883 and/or exons 18 to 21.
  • Cancer with HER2 exon 20 mutation” or “HER2 exon 20 mutant cancer” as used herein refers to a cancer where the cancer or tumor cells harbour at least one HER2 exon 20 mutation including but not limited to the mutations listed below.
  • ERBB2 (HER2) exon 20 encodes for a part of the kinase domain and ranges from amino acids 769 to 835. Every mutation, insertion, duplication or deletion within this region is defined as an exon 20 mutation including the following mutations: p.A772_G773insMMAY; p.Y772_A775_dup (YVMA); p.A775_G776insYVMA; p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insSVMA; p.A775_G776insVVMA; p.A775_G776insYVMS; p.A775_G776insC; p.A776_delinsVC; p.A776_delinsLC; p.A776_delinsVV; p.A776_delinsAVGC; p.A776_
  • HER2 mutations exist outside of 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.” is referring to the HER2 protein).
  • the cancer is one of the following cancers, tumors or other proliferative diseases, without being restricted thereto:
  • Cancers/tumors/carcinomas of the head and neck e.g. tumors/carcinomas/cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); cancers/tumors/carcinomas of the lung: e.g.
  • non-small cell lung cancer SCCLC
  • SCLC small cell lung cancer
  • neoplasms of the mediastinum e.g.
  • neurogenic tumors including neurofibroma, neurilemoma, 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, hemangio
  • renal pelvis renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor; ureter; urinary bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g. distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis); cancers/tumors/carcinomas of the testis: e.g. seminomas, non-seminomas;
  • Gynecologic cancers/tumors/carcinomas e.g. tumors/carcinomas/cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus); cancers/tumors/carcinomas of the breast: e.g.
  • mammary carcinoma infiltrating ductal, colloid, lobular invasive, 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
  • cancers/tumors/carcinomas of the endocrine system e.g.
  • tumors/carcinomas/cancers of the endocrine glands thyroid gland (thyroid carcinomas/tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma/tumor), adrenal cortex (adrenal cortical carcinoma/tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; nonfluorineunctional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors; sarcomas of the soft tissues: e.g.
  • fibrosarcoma fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma
  • myeloma myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma; mesothelioma: e.g.
  • pleural mesothelioma peritoneal mesothelioma
  • cancers of the skin e.g. basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer
  • neoplasms of the central nervous system and brain e.g.
  • astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g.
  • B-cell non-Hodgkin lymphomas (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leuk
  • NDL small lymphocytic lymphoma
  • LPL lymphoplasmacytoid lymphoma
  • MCL mantle
  • cancers/tumors/carcinomas mentioned above which are characterized by their specific location/origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom.
  • the cancer as defined herein (including in any embodiment referring to e.g. cancer types) is metastatic, advanced, and/or unresectable.
  • All cancers/tumors/carcinomas mentioned above may be further differentiated by their hi stopathol ogi cal cl assifi cati on :
  • Epithelial cancers e.g. 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, 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;
  • SCC squamous cell carcinoma
  • AC adenocarcinoma
  • AC well-differentiated, mucinous, papillary, pleomorphic
  • Nonepithilial cancers e.g. sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.
  • sarcomas fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibros
  • the cancer is a solid tumor. In some embodiments, the cancer is manifested by at least one solid tumor.
  • the cancer is selected from the group consisting of brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecologic cancer, head and neck tumor, lung cancer, nervous system cancer, and skin cancer.
  • said brain cancer is a glioblastoma or a glioma.
  • said breast cancer is lobular breast cancer.
  • said breast cancer is preferably metastatic.
  • said endocrine cancer is nerve sheath tumor, more preferably HER2 mutant nerve sheath tumor.
  • 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, esophagus tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer and small bowel cancer.
  • said gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably HER2 mutant.
  • 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.
  • said gynecologic cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer and ovarian cancer.
  • head and neck tumor preferably refers to a head and neck cancer.
  • said head and neck tumor is a salivary gland cancer or tumor.
  • said lung cancer is non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • said nervous system cancer is peripheral nervous system cancer, more preferably HER2 amplified peripheral nervous system cancer.
  • said skin cancer is not a melanoma, i.e. non-melanoma skin cancer.
  • 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, esophagus tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancer and non-melanoma skin cancer.
  • NSCLC non-small cell lung cancer
  • the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer 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, esophagus tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non- small cell lung cancer (NS)
  • 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, esophagus tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
  • the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer 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, esophagus tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
  • HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer 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, esophagus tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallblad
  • 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, skin cancer, gastric cancer, esophagus tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
  • the cancer is HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer 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, esophagus tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
  • HER2 overexpressed, HER2 amplified and/or HER2 mutant (in particular HER2 exon 20 mutant) cancer 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, esophagus tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.
  • the cancer is selected from the group consisting of breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer or lung cancer.
  • the cancer is selected from cancers/tumors/carcinomas of the lung: e.g. nonsmall cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer).
  • NSCLC nonsmall cell lung cancer
  • SCLC small cell lung cancer
  • the cancer is NSCLC.
  • the cancer is HER2 exon 20 mutant NSCLC.
  • the cancer is unresectable. In still further embodiments, the cancer is unresectable HER2 exon 20 mutant NSCLC.
  • said cancer is advanced or metastatic. In a further preferred embodiment, said cancer is advanced and metastatic. In a further preferred embodiment, when said cancer is metastatic, the metastases are located in the lung, lymph node, bone or liver. In a further preferred embodiment, the cancer is advanced cancer including metastases and the metastases are located in the lung, lymph node, bone or liver. In addition or in alternative, said cancer can be unresectable.
  • the cancer is unresectable advanced cancer comprising solid tumors and solid metastases and the metastases are located in the lung, liver, lymph node-tissue or bone.
  • the cancer is advanced NSCLC comprising solid, unresectable tumors and metastases and the metastases are located in the lung, liver lymph node-tissue or bone.
  • the cancer is HER2 exon 20 mutant advanced NSCLC comprising solid, unresectable tumors and metastases and the metastases are located in the lung- or lymph node-tissue or bone.
  • the cancer is advanced, unresectable or metastatic NSCLC harbouring a HER2 mutation, wherein said HER2 mutation is in the tyrosine kinase domain.
  • compound (1) is administered as first line of therapy.
  • compound (1) as described herein is administered as second or further line of therapy.
  • the cancer is HER2 positive metastatic breast cancer.
  • compound (1) as described herein is administered as first line of therapy.
  • compound (1) as described herein is administered as second or further line of therapy.
  • the cancer is HER2 positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma or metastatic esophageal adenocarcinoma.
  • compound (1) as described herein is administered as first line of therapy.
  • compound (1) as described herein is administered as second or further line of therapy.
  • the cancer is resistant to treatment with an anti-HER2 antibody or an anti- HER2 antibody-drug-conjugate as defined herein.
  • the cancer is resistant to single-agent treatment with said anti-HER2 antibody or anti-HER2 antibody-drug-conjugate.
  • the resistance may be advantageously overcome by treatment with compound (1), in particular when administered according to the doses/dosing regimes described herein.
  • antibody which may be used interchangeably with “antibody molecule” encompasses various antibody structures, including but not limited to poly- or monoclonal, chimeric, humanized, human, mono-, bi- or multispecific antibodies, single chain antibodies, single domain antibodies, and fragmented antibodies (also referred to as antibody fragments), such as Fab, F(ab)2, F(ab’)2, Fab’, single chain variable-fragments (scFv) or antigen binding domains of an antibody, so long as they exhibit the desired antigen-binding activity.
  • antibody shall encompass complete immunoglobulins as they are produced by lymphocytes and for example present in blood sera, monoclonal antibodies secreted by hybridoma cell lines, polypeptides produced by recombinant expression in host cells, which have the binding specificity of immunoglobulins or monoclonal antibodies, and molecules which have been derived from such immunoglobulins, monoclonal antibodies, or polypeptides by further processing while retaining their binding specificity.
  • the term “antibody” includes complete immunoglobulins comprising two heavy chains and two light chains. The term further encompasses a fragment of an immunoglobulin, like Fab fragments and polypeptides having one or more variable domains derived from an immunoglobulin, like single chain antibodies (scFv), single domain antibodies, and the like.
  • antibody “fragment” shall refer to fragments of such an antibody retaining antigen binding capacities.
  • the antibody may have an effector function, such as ADCC or CDC, that is usually mediated by the Fc part (antibody constant region) of the antibody, or it may have no effector function, e.g. by lacking a Fc part or having a blocked, masked Fc part, in essence a Fc part that is not or insufficiently recognized by immune cells or immune system components, like the complement system.
  • the antibody or its fragment may be of any type, e.g. IgA, IgD, IgE, IgG, IgM. Preferred is IgG.
  • monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of a single amino acid composition or of a homogenous antibody population, i.e., 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, IgG, IgM, or a fragment thereof.
  • a “recombinant antibody” is an antibody which has been produced by a recombinantly engineered host cell. It is optionally isolated or purified.
  • a “human antibody” is one which possesses an amino acid sequence which 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-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigenbinding residues.
  • recombinant human antibody 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 a NSO 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.
  • a host cell such as a NSO or CHO cell
  • an animal e.g. a mouse
  • Such recombinant human antibodies have variable and constant regions in a rearranged form.
  • the recombinant human antibodies may have been subjected to in vivo somatic hypermutation.
  • amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germ line VH and VL sequences, may not naturally exist within the human antibody germ line repertoire in vivo.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human hypervariable regions (HVRs) and amino acid residues from human framework regions (FRs).
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g. complementary determining regions (CDRs)) correspond to those of a non-human antibody, and all or substantially the entire FRs correspond to those of a human antibody.
  • a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
  • a “humanized form” of an antibody, e.g. a non-human antibody refers to an antibody that has undergone humanization.
  • Binding of a polypeptide means “having affinity for” or “having specificity for” a certain epitope, antigen or protein (or for at least one part, fragment or epitope thereof).
  • binding and specific binding referring to the binding of the antibody or antigen binding moiety to an epitope of the antigen may be determined in an in vitro assay, preferably in a plasmon resonance assay (BIAcore®, GE Healthcare Uppsala, Sweden) with purified wildtype antigen.
  • the term “specificity” refers to the number of different types of antigens or epitopes to which a particular antigen-binding molecule (such as an antibody described herein) can bind.
  • the specificity of an antigen-binding molecule can be determined based on its affinity and/or avidity.
  • the affinity represented by the equilibrium constant for the dissociation of an antigen with an antigen-binding protein (KD), is a measure for the binding strength between an epitope and an antigen-binding site on the antigen-binding protein: the lesser the value of the KD, the stronger the binding strength between an epitope and the antigen-binding molecule (alternatively, the affinity can also be expressed as the affinity constant (KA), which is 1/KD).
  • affinity can be determined in a manner known in the art, depending on the specific antigen of interest.
  • Avidity is the measure of the strength of binding 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 pertinent antigen.
  • Avidity is related to both the affinity between an epitope and its antigen binding site on the antigen-binding molecule and the number of pertinent binding sites present on the antigenbinding molecule.
  • epitope is a region of an antigen that is bound by an antigen-binding molecule (such as an antibody described herein).
  • the term “epitope” includes any polypeptide determinant capable of specific binding to an antibody or antigen binding moiety.
  • epitope determinants include chemically active surface groupings of molecules such as amino acids, glycan side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
  • variable domain or “variable region” or Fv as used herein denotes each of the pair of light and heavy chains which is involved directly in binding the antibody to the 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 variable light and heavy chain domains have the same general structure and each domain comprises four framework (FR) regions whose sequences are widely conserved, connected by three HVRs (or CDRs).
  • the framework regions adopt a beta-sheet conformation and the CDRs may form loops connecting the beta-sheet structure.
  • the CDRs in each chain are held in their three-dimensional structure by the framework regions and form together with the CDRs from the other chain the antigen binding site.
  • the antibody’s heavy and light chain CDR regions play a particularly important role in the binding specificity/affinity of the antibodies.
  • CDR CDR
  • Chothia and Lesk J. Mol. Biol. 1987, 196: 901-917
  • Kabat E.A. Kabat, T.T. Wu, H. Bilofsky, M. Reid-Miller and H. Perry, Sequence of Proteins of Immunological Interest, National Institutes of Health, Bethesda (1983)).
  • constant domains or “constant region” as used within the current application denotes the sum of the domains of an antibody other than the variable region.
  • the constant region is not directly involved in binding of an antigen, but exhibits various effector functions.
  • the “constant domains” as used in the antibodies disclosed herein are preferably from human origin, which is from a constant heavy chain region of a human antibody of the subclass IgGl, IgG2, IgG3, or IgG4 and/or a constant light chain kappa or lambda region.
  • Such constant domains and regions are well known in the state of the art and e.g. described by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, MD, Publication No. 91).
  • the “Fc part” of an antibody is not involved directly in binding of an antibody to an antigen, but exhibits various effector functions.
  • a “Fc part of an antibody” is a term well known to the skilled artisan and defined on the basis of papain cleavage of antibodies.
  • antibodies or immunoglobulins are divided in the classes: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g. IgGl, IgG2, IgG3, and IgG4, IgAl, and IgA2.
  • the different classes of immunoglobulins are called a,5,e,y and p, respectively.
  • the Fc part of an antibody is directly involved in ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity) based on complement activation, Clq binding and Fc receptor binding.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • Complement activation (CDC) is initiated by binding of complement factor Clq to the Fc part of most IgG antibody subclasses. While the influence of an antibody on the complement system is dependent on certain conditions, binding to Clq is caused by defined binding sites in the Fc part. Such binding sites are known in the state of the art and described e.g.
  • binding sites are e.g. L234, L235, D270, N297, E318, K320, K322, P331 and P329 (numbering according to EU index of Kabat, E.A., see below).
  • Antibodies of subclass IgGl, IgG2 and IgG3 usually show complement activation and Clq and C3 binding, whereas IgG4 do not activate the complement system and do not bind Clq and C3.
  • domain (of a polypeptide or protein) as used herein refers to a folded protein structure which 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 may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain.
  • anti-HER2 antibody refers to an antibody that binds, in particular binds specifically, to the HER2 protein.
  • Anti-HER2 antibodies inhibit HER2 activation or downstream signaling by various mechanisms.
  • anti-HER2 antibodies can prevent ligand binding, receptor activation or receptor signal propagation, result in reduced HER2 expression or localization to the cell surface, inhibit HER2 cleavage, or induce antibody-mediated cytotoxicity.
  • the expression “anti-HER2 antibody” is thus intended as a synonym and is replaceable with “inhibitory antibody binding specifically to HER2”.
  • Anti-HER2 antibodies used for the treatment of cancer are typically monoclonal, although polyclonal antibodies are not excluded by the term.
  • the anti- HER2 antibody is selected from the group consisting of: trastuzumab, pertuzumab, margetuximab, and combinations thereof.
  • Trastuzumab also known as Herceptin, is a humanized IgGl monoclonal antibody that binds to HER2, in particular to its extracellular domain, especially to the HER2 domain that binds to another HER2 protein.
  • the mechanism of action underlying the antitumour effect of trastuzumab has not yet been fully determined, and may in fact involve several different mechanisms.
  • Trastuzumab may exert its effects by the activation of antibody-dependent cellular cytotoxicity, prevention of HER2 dimerization, the inhibition of the cleavage of the extracellular domain of HER2, interactions with signalling 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 in e.g., WO 92/22653, which is herein incorporated by reference.
  • Pertuzumab also known as Perjeta, is a humanized IgGl monoclonal antibody that binds to HER2, in particular to the extracellular domain of HER2, especially to the extracellular dimerization subdomain of HER2 receptor. Pertuzumab reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors, such as HER3. Pertuzumab is disclosed in e.g., US 6949245 and US 7862817 each of which is herein incorporated by reference.
  • Margetuximab also known as Margenza, is a mouse/human chimeric IgGl 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 in e.g., US 8802093 which is herein incorporated by reference.
  • the anti-HER.2 antibody is an inhibitory antibody.
  • the expression “inhibitory antibody” is intended as a synonym of and replaceable with “antagonistic antibody”.
  • An “inhibitory antibody” or “antagonistic antibody” within the meaning of this invention is an antibody that inhibits the interaction of HER2 with its ligand(s) or receptor(s).
  • the anti-HER2 antibody binds specifically to HER2.
  • the anti-HER2 antibody binds specifically to the extracellular domain of HER2.
  • the anti-HER2 antibody is an inhibitory antibody binding specifically to HER2.
  • the anti-HER2 antibody is an inhibitory antibody binding specifically to the extracellular domain of HER2.
  • the anti-HER2 antibody is selected from the group consisting of trastuzumab, pertuzumab, margetuximab and a combination thereof.
  • the anti-HER2 antibody is selected from the group consisting of trastuzumab and pertuzumab.
  • antibody drug conjugate also abbreviated herein as “ADC”
  • ADC antibody drug conjugate
  • ADC is well known in the art and describes a group of therapeutics that combine the specificity of tumortargeting binders, such as e.g. antibodies, with the potency of highly cytotoxic agents. Accordingly, such conjugates of cytotoxic and/or cytostatic agents to antibodies specific for tumor cells are powerful tools to specifically target cancer cells for their destruction.
  • ADCs are well known in the art and have been reviewed, for example, in Dumontet et al. 2023 (Dumontet, C., Reichert, J.M., Senter, P.D. et al. Antibody-drug conjugates come of age in oncology.
  • anti-HER2 antibody-drug conjugate refers to an ADC whose tumor-targeting binder is an antibody directed to, targeting and/or binding HER2, such as trastuzumab, pertuzumab and margetuximab.
  • anti-HER2 antibody-drug conjugate and “anti-HER2 ADC” thus refer to an anti-HER2 antibody conjugated to a cytotoxic drug, also called payload, optionally via a linker.
  • the anti-HER2 antibody in the ADC can deliver the payload to cells expressing HER2, especially to cells with high levels of HER2.
  • the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody that is an inhibitory antibody.
  • the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody binding specifically to HER2.
  • the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody binding specifically to the extracellular domain of HER2.
  • the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody that is an inhibitory antibody binding specifically to HER2.
  • the anti-HER2 antibody-drug conjugate comprises an anti-HER2 antibody binding specifically to an extracellular domain of HER2.
  • the anti-HER2 antibody-drug conjugate comprises trastuzumab.
  • trastuzumab can be as defined above in any of the aspects concerning the anti-HER2 antibody.
  • the anti-HER2 antibody-drug conjugate is selected from the group consisting of trastuzumab deruxtecan and trastuzumab emtansine.
  • trastuzumab can be as defined above in any of the aspects concerning the anti-HER2 antibody.
  • T-DM1 trastuzumab emtansine
  • ado-trastuzumab emtansine also known as T-DM1 or
  • Kadcyla refers to the antibody-drug conjugate comprising the anti-HER2 antibody trastuzumab, a thioether linker, and the microtubule inhibitor emtansine or DM1 - a derivative of maytansine - as cytotoxic payload.
  • the International Nonproprietary Name (INN) “trastuzumab emtansine” is published in the WHO’s INN Recommended List 65, which is herein incorporated by reference.
  • the INNs as used herein are meant to also encompass all biosimilar molecules with the same structure, in particular comprising the same, or substantially the same, amino acid sequences as the originator antibody, including but not limited to those biosimilar antibodies authorized under 42 USC ⁇ 262 subsection (k) in the US and equivalent regulations in other jurisdictions.
  • a “biosimilar” as used herein refers to an antibody (isolated or as part of and ADC) or antigenbinding fragment that has the same primary amino acid sequence as compared to a reference antibody (e.g., trastuzumab) and optionally, may have detectable differences in post-translation modifications (e.g., glycosylation and/or phosphorylation) as compared to the reference antibody (e.g., a different glycoform).
  • Cancer showing/developing “resistance” or being/becoming “resistant” to a therapy as used herein includes a cancer which is not responsive and/or exhibits reduced ability of producing a significant response, e.g., partial response and/or complete response, to treatment with the anti- HER2 antibody or the anti-HER2 antibody-drug-conjugate. Resistance may be de novo (primary) resistance or acquired resistance which arises in the course of a treatment method.
  • the term “acquired resistance” as used herein indicates that the cancer becomes resistant and/or substantially less responsive to the effects of the anti-HER2 antibody or the anti-HER2 antibody-drug-conjugate as defined herein after being exposed to it for a certain period of time.
  • Cancer may develop resistance to single-agent treatment with the anti-HER2 antibody or anti- HER2 antibody-drug conjugate.
  • the mechanisms of resistance may be attributed to the antibody or the payload, and may be receptor-related, referring to target accessibility, or intracellular, such as referring to the regulation of the intracellular signalling pathways.
  • the cancer is resistant to treatment with the payload of an anti-HER2 antibody-drug conjugate.
  • the cancer is resistant to treatment with deruxtecan or emtansine.
  • a cancer which initially responded to an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate can relapse and become resistant to the anti-HER2 antibody or anti-HER2 antibodydrug conjugate when the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is no longer effective in treating a subject with the cancer, for example despite the administration of increased dosages.
  • the cancer may be recurrent, relapsed, resistant or refractory to one or more anti-HER2 antibody or an anti-HER2 antibody-drug conjugate.
  • the patients may have received previous anti-cancer therapies with one or more anti-HER2 antibody or one or more anti-HER2 antibody-drug conjugate, which have not completely cured the disease.
  • Cancer with relapse and/or with resistance to anti-HER2 antibody or an anti-HER2 antibodydrug conjugate may be particularly amenable for single agent treatment with compound (1) in a second or further line of treatment as described herein.
  • an aspect refers 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.
  • compound (1), the dose schedule (e.g. the daily dose, the administration frequency, oral/tablet administration, the second or further line use, etc.) and the cancer can each independently or together be as described in any of the aspects or embodiments disclosed herein.
  • At least one additional therapeutic agent is administered in a line of treatment prior to or before compound (1) in the doses and dose regimes described herein.
  • the method of treating a patient suffering from cancer as described above comprises administering compound (1) in the doses and dose regimes described herein in a line of treatment after or following the administration of at least one additional therapeutic agent.
  • the additional therapeutic agent administered in a line of treatment prior to or before the administration of compound (1) is selected from the group consisting of chemotherapy and systemic anti-cancer therapy agents.
  • the additional therapeutic agent can be used in the treatment of cancer besides the administration of compound (1).
  • a systemic anti-cancer therapy agent is administered in a line of treatment prior to or before compound (1).
  • one or more systemic anti-cancer therapy agent(s) can be administered in a line of treatment prior to compound (1).
  • compound (1) is used to treat cancer in a line of treatment following or after administration of a line of treatment comprising one or more systemic anti-cancer therapy agent(s).
  • systemic anti-cancer therapy agents can be administered as separate lines of treatment or in combination with each other in the same line.
  • the systemic anti-cancer agent(s) administered in a line of treatment prior to compound (1) can be used in combination with any other anti-cancer therapy different from compound (1), whether systemic or not.
  • compound (1) can be administered as second (in case that only one line of treatment comprising at least one systemic anti-cancer therapy is administered prior to compound (1)) or further (in case that more than one line of treatment comprising at least one systemic anti-cancer therapy is administered prior to compound (1)) line treatment.
  • compound (1) is preferably administered in the doses and dosing regimes described herein.
  • the terms “after” and “following” mean that the additional therapeutic agent, especially the chemotherapy agent or the systemic anti-cancer therapy agent, is administered in a first or prior line of therapy during a first time period, for example over the course of a few hours, days or one or more weeks, using one or more doses, and is followed by administration of compound (1) during a second time period, for example over the course of 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.
  • the systemic anti-cancer therapy agent or chemotherapy agent and compound (1) are not administered on the same day.
  • a single systemic anti-cancer therapy agent or chemotherapy agent is not re-started with the same dosing (of said single systemic anti-cancer therapy agent or chemotherapy agent) once compound (1) is administered.
  • the terms “after” and “following” do not require that compound (1) is administered directly after or directly following the line of therapy with the systemic anti-cancer therapy agent(s). Therefore, it may be that another line of therapy is administered between the systemic anti-cancer therapy agent or chemotherapy and compound (1), so long as the systemic anti-cancer therapy or chemotherapy is administered in a line of treatment before compound (1).
  • the systemically detectable doses of the anti-cancer therapy agent in the previously performed anti-cancer therapy are below an established therapeutically effective amount before compound (1) is administered.
  • the selected daily dose and the daily application schedule of compound (1) can be chosen also as a function of one or all pre-treatments with a systemic anti-cancer therapy agent.
  • second or further line and grammatical variants thereof have the meaning known in the art.
  • second or further line and grammatical variants thereof can refer to the administration of compound (1) after or following a first or prior line of therapy that has failed, stopped working, decreased efficacy, intolerable side effects or been only partially successful, according to the judgment of the attending physician, especially wherein the first or prior line of therapy is never again administered to the patient.
  • the expression “second or further line administration” can be read as second line administration or further line administration.
  • systemic anti-cancer therapy agent can be present and can be administered in the form of only a single drug compound or single active ingredient.
  • the agent may also be present and administered in the form of a combination of two or more drug compounds or active ingredients.
  • Drug compounds may include small or large molecules, chemical elements, metal complexes for example comprising platinum (Pt), biologies and combinations thereof.
  • systemic anti-cancer therapy includes the administration of at least one systemic anti-cancer therapy agent, alone or in combination with another drug compound or active ingredient.
  • systemic has the meaning commonly attributed to it in the art and thus can refer to a route of administration affecting the entire body, as opposed to local administration where the effect is generally local.
  • Systemic administration can be enteral (e.g. via the gastrointestinal tract) or parenteral (e.g. via injection, infusion, implantation, etc.).
  • said systemic anti-cancer therapy is parenteral anti-cancer therapy.
  • chemotherapy agent or “chemotherapeutic agent” can be present and can be administered in the form of only a single drug compound or single active ingredient.
  • the agent may also be present and administered in the form of a combination of two or more drug compounds or active ingredients.
  • chemotherapy includes the administration of at least one chemotherapeutic agent, alone or in combination with another drug compound or active ingredient.
  • chemotherapy has the meaning commonly attributed to it in the art and thus can refer to a chemical agent or a combination of chemical agents useful in the prevention and/or treatment of cancer, especially where the agent or combination is or comprises a cytotoxic and/or cytostatic agent.
  • chemotherapy is administered systemically, i.e. it is systemic chemotherapy.
  • the systemic anti-cancer therapy agent is selected from the group consisting of platinum-based chemotherapy, anti-HER2 antibody-drug conjugates, taxanes, anti-metabolites, immunotherapeutic agents and combinations thereof.
  • the term “combinations thereof’ might include the separate administration of two or more members of that list in different time intervals or at different points in time, as different lines of therapy or the administration of two or more members of that list in combination in the same line of therapy.
  • the combination might for instance include a first line treatment including a platinum- based chemotherapy agent and, later on, a second line treatment based on an ADC, preferably an anti-HER2-ADC, or vice versa, prior to a treatment based on compound (1).
  • the combination can be a planned sequence or can be performed as a function of the treatment outcome.
  • platinum-based chemotherapy and grammatical variants thereof have the meaning commonly attributed to them in the art and thus can refer to one or more chemotherapy agents comprising platinum (Pt).
  • Preferred platinum-based chemotherapy agents include oxaliplatin, carboplatin and/or cisplatin.
  • Still preferred platinum-based chemotherapy agents include carboplatin and/or cisplatin.
  • anti-HER2 antibody-drug conjugates can be as defined above.
  • Preferred anti-HER2 antibody-drug conjugates include: trastuzumab deruxtecan and/or trastuzumab emtansine.
  • taxanes usually work as mitotic inhibitors, specifically as disruptors of the microtubule function.
  • Preferred taxanes include cabazitaxel, larotaxel, tesetaxel, docetaxel and/or paclitaxel.
  • Still preferred taxanes include docetaxel and/or paclitaxel.
  • anti-metabolite and grammatical variants thereof have the meaning commonly attributed to them in the art and thus can refer to one or more agents that interfere with metabolic processes within cells.
  • anti-metabolites can inhibit a metabolite.
  • Preferred anti-metabolites include: 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, hydroxycarbamide, methotrexate, phototrexate, gemcitabine, pemetrexed and/or tegafur.
  • Still preferred anti-metabolites include: gemcitabine, pemetrexed and/or tegafur.
  • immunotherapeutic agents include: cemiplimab, dostarlimab, trastuzumab, pertuzumab, margetuximab, pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab, and/or ramucirumab.
  • Still preferred immunotherapeutic agents include: pembrolizumab, durvalumab, atezolizumab, nivolumab, ipilimumab, tremelimumab, and/or ramucirumab.
  • the systemic anti-cancer 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.
  • the systemic anti-cancer therapy agent is selected from the group consisting of: carboplatin, cisplatin, trastuzumab deruxtecan, trastuzumab emtansine, pemetrexed, docetaxel, paclitaxel, gemcitabine, pembrolizumab, durvalumab, tremelimumab, ramucirumab, atezolizumab, tegafur, nivolumab and ipilimumab.
  • systemic anti-cancer therapy agent comprises or consists of an anti-HER2 antibody-drug conjugate.
  • the systemic anti-cancer therapy agent is trastuzumab deruxtecan and/or trastuzumab emtansine.
  • the systemic anti-cancer therapy agent comprises a platinum-based chemotherapy.
  • the systemic anti-cancer therapy agent comprises pembrolizumab, pemetrexed and/or platinum-based chemotherapy.
  • the systemic anti-cancer therapy agent comprises pembrolizumab, pemetrexed and platinum-based chemotherapy.
  • the systemic anti-cancer therapy agent comprises pembrolizumab, pemetrexed and cisplatin.
  • the systemic anti-cancer therapy agent comprises pembrolizumab, pemetrexed and carboplatin.
  • systemic anti-cancer therapy agent comprises pembrolizumab and/or pemetrexed.
  • the systemic anti-cancer therapy agent comprises a standard of care therapy, optionally followed by maintenance therapy.
  • Said standard of care therapy may comprise a combination of 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, more preferably for 4 administrations.
  • Said maintenance therapy may comprise a combination of pembrolizumab and pemetrexed, optionally administered once every 3 weeks for one or more administrations.
  • compound (1) as defined below is for use in the treatment of cancer, wherein compound (1) is administered in a line of treatment following administration of chemotherapy or a systemic anti-cancer therapy agent.
  • a method of treating a patient suffering from cancer comprises administering compound (1), wherein compound (1) is administered in a line of treatment following administration of chemotherapy or a systemic anti-cancer therapy agent.
  • compound (1) is administered according to the doses and dose regimes described hereinabove.
  • the cancer and/or the systemic anti-cancer therapy agent may be as herein defined.
  • the systemic anticancer therapy agent is a specific anti HER2 systemic anti-cancer therapy agent, e.g. an anti- HER2 antibody-drug conjugate, such as defined above.
  • compound (1) is used in the treatment of cancer at least 21 days after the last day of administering the chemotherapy or systemic anti-cancer therapy agent.
  • the method of treating a patient suffering from cancer comprises administering compound (1), wherein compound (1) is administered at least 21 days after the last day of administering the chemotherapy or systemic anti-cancer therapy agent.
  • compound (1) is administered at least for 21 consecutive days or for 21 days multiplied by X, wherein X is a natural number equal or larger than 1.
  • a pharmaceutical composition comprising compound (1) as defined below and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein compound (1) is administered in a daily dose of at least 30 mg.
  • a method of treating a patient suffering from cancer comprising administering a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in a daily dose of at least 30 mg.
  • compound (1) is administered according to the doses and dose regimes described hereinabove.
  • the cancer is as defined herein (in any aspect or embodiment). All embodiments described above relative to compound (1) for use in the treatment of cancer or to the method of treating a patient suffering from cancer with compound (1) are applicable to the pharmaceutical composition for use in the treatment of cancer or to the method of treating a patient suffering from cancer with the pharmaceutical composition.
  • 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.
  • compositions may comprise further pharmaceutically acceptable excipients selected from buffers, dispersion agents, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives usable in the manufacturing of a pharmaceutical product.
  • excipients selected from buffers, dispersion agents, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives usable in the manufacturing of a pharmaceutical product.
  • compound (1) or the pharmaceutical composition is administered orally.
  • Compound (1) or the pharmaceutical composition may be administered as a tablet, hard or soft gelatin capsule, pill, granules or a suspension.
  • compound (1) or the pharmaceutical composition is in the form of a tablet.
  • Example 1 An open label. Phase I dose escalation trial, with dose confirmation and expansion, of compound (1) as monotherapy in patients with unresectable, advanced and/or metastatic solid tumors with HER2 aberrations
  • MTD Maximum Tolerated Dose
  • the dose escalation part of the trial (also referred to as Phase la) includes consecutive cohorts of patients treated with escalating doses of compound (1).
  • the main objectives of the dose escalation part of the trial are to:
  • PK pharmacokinetics
  • the primary endpoints of the dose escalation part of the trial are:
  • DLT Dose Limiting Toxicity
  • the MTD evaluation period is defined as the first 21 days of treatment (first cycle).
  • the secondary endpoints of the dose escalation part of the trial are:
  • AUC0 2 area under the concentration-time curve of compound (1) in plasma.
  • Objective response defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to RECIST version 1.1 as assessed by the investigator, from the first treatment administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up or withdrawal of consent;
  • DC - Disease control
  • CR complete response
  • PR partial response
  • SD stable disease
  • DoR Duration of objective response
  • CR first documented complete response
  • PR partial response
  • DoDC Duration of disease control
  • Tumor shrinkage according to RECIST 1.1, defined as the best (smallest) percentage change from baseline of the sum of longest diameter of target lesions assessed by the investigator across all on-treatment tumor assessments;
  • PK parameters to be calculated for compound (1) as monotherapy include:
  • the dose escalation is performed according to an open-label design.
  • the data obtained from the trial determines 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 in the MTD evaluation period for each dose level in the trial as patient information becomes available, taking into account updated DLT information from both schedules.
  • EWOC overdose control
  • Dose escalation is restricted to a maximum increment of 100 % from the previous dose.
  • Dose escalation and cohort size are based on decisions of the Dose Escalation Committee (DEC), guided by the BLRM.
  • BID dose cohort is filled first, and then drop down to the equivalent QD cohort.
  • Successive cohorts of patients receive increasing doses of compound (1) until the MTD is reached.
  • the BLRM is updated with the newly accumulated data from both schedules.
  • the overdose risk is then calculated for each dose and dose escalation is permitted to all doses which fulfil the EWOC criterion.
  • the members of the DEC reach a joint decision on the next dose level to be investigated and the size of the next cohort. Pre-specified dose levels are provisional and intermediate levels may be explored as deemed necessary by the DEC.
  • DLTs are observed in the first two consecutive patients of a previously untested dose level, subsequent enrolment to that cohort is stopped.
  • the BLRM is updated to confirm that the dose level still fulfils the EWOC principle.
  • the DEC evaluates whether the next patients are enrolled at the same dose level, or if they are enrolled at a lower dose level. No further dose escalation takes place after the criterion for MTD is fulfilled. Further patients may be included to confirm this MTD estimate, i.e. to confirm that the EWOC criterion is still fulfilled.
  • the DEC can declare any dose fulfilling the EWOC criterion as the RP2D, independent of the MTD estimate. The RP2D does not exceed the MTD.
  • any DLTs occurring after the MTD evaluation period are considered for the evaluation of the RP2D for compound (1). If no DLT is observed, the DEC may decide to declare the RP2D based on PK/ Pharmacodynamic endpoints and overall safety profile. MTDs and RP2Ds are defined for both schedules separately.
  • dose escalation may remain open for inclusion of patients not eligible for dose expansion, at selected dose(s), in sites participating in dose escalation, if agreed with DEC.
  • the RP2D(s) of compound (1) as monotherapy administered BID and QD is/are defined based on DLT/MTD (if reached), all safety data, and, if data allows, PK, PK/pharmacodynamics collected during the study. Should DLT or MTD not be reached, the RP2D(s) is/are determined based on safety data (i.e. overall tolerance and incidence of severe toxicity) as well as if data allows, PK, PK/pharmacodynamics.
  • the RP2D does not need to be the same in the two schedules (BID, QD).
  • the BLRM is run based on extended data including all DLT-like events during the whole treatment period, as well as per treatment schedule alone, to further guide the selection of the RP2D(s).
  • the RP2D may be defined and the dose expansion part started before the MTD has been reached/dose escalation has concluded.
  • Patients may continue to receive treatment with compound (1) until disease progression (PD) according to RECIST or until another reason requiring termination of treatment.
  • PD disease progression
  • the starting doses of the dose escalation part of the trial are:
  • the predicted human dose for compound (1) was derived from a quantitative pharmacokinetic/tumor growth inhibition (PK/TGI) model. This preclinical mathematical model was built with input data from internal in vitro experiments and in vivo data from efficacy experiments in PC-9 YVMA xenograft. Unbound in vitro cellular potency, plasma exposure and tumor growth inhibition data from mice were used to train the model. A comprehensive pharmacokinetic profiling of compound (1) in vitro and in vivo, using mouse, rat, dog, and minipig, allowed the prediction of human PK parameters.
  • PK/TGI quantitative pharmacokinetic/tumor growth inhibition
  • Predicted human PK parameters were used to simulate the human plasma profile, which was incorporated in the preclinical PK/TGI model.
  • the PK/TGI model was used to predict and identify the required dose in human necessary to achieve a TGI >100%. This was predicted at 40 mg BID as well as 80 mg QD (predicted human efficacious doses). In other words, the exposure of a human dose of 40 mg BID as well as 80 mg QD were estimated to be sufficient to achieve tumor growth inhibition >100% in patients.
  • the dose escalation part enrols patients with advanced, unresectable and/or metastatic solid tumors who are either refractory after standard therapy for the disease or for whom standard therapy is not appropriate are eligible. Patients must also have exhausted treatment options known to prolong survival for their disease. These patients should show a confirmed positive diagnosis as well 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 gene rearrangement involving HER2 or NRG1).
  • FFPE formalin-fixed paraffin embedded
  • CTCAE Common Terminology Criteria for Adverse Events
  • HER2 Patients with a documented aberration of the HER2 gene comprising: EITHER overexpression by immunohistochemistry (IHC), gene copy-number increase by in-situ hybridization (ISH), non-synonymous gene mutation OR gene fusion of the HER2 or NRG-
  • Patients may discontinue trial treatment or withdraw consent to trial participation as a whole.
  • Compound (1) is administered as film-coated tablets. This formulation was developed in three dosage strengths: 5 mg (about 10 mm round), 20 mg (about 10 mm round) and 100 mg (oval, about 16 x 7 mm). In addition to the drug substance, the tablets contain standard pharmaceutical excipients in common amounts. 1.1.7 Assessment of efficacy:
  • Tumor assessments should include computed tomography (CT) scans of the chest, abdomen/pelvis (or PET/CT) and a brain MRI at screening. If clinically indicated, imaging of any other known or suspected sites of disease (e.g. bone) using an appropriate method (CT scan, MRI, PET/CT, or bone scan) should be performed. The same radiographic procedure must be used throughout the trial. Assessments are performed by the investigator at screening ( ⁇ 28 days prior to initiation of treatment), every 2 cycles (6 weeks ⁇ 5 days), at the end-of-treatment (EOT) visit (if not performed within the previous 3 weeks), and at the discretion of the investigator, and copies may be collected by the sponsor or designee.
  • CT computed tomography
  • the assessment schedule should not be changed, but if there is an interruption or delay to treatment, alteration of the tumor assessment schedule to align with clinical assessments is allowed. Additional unscheduled tumor assessments may be performed at the discretion of the investigator. If the patient stops trial medication for a reason other than progression, tumor assessment according to RECIST vl.l continues until progression (or until one of the following occurs; death, lost to follow-up, end of the trial).
  • Patient s clinical status is assessed locally by each investigator.
  • the clinical status decline must be attributed to the underlying tumor progression and not due to co-morbidity or concomitant medication.
  • every effort should be made to confirm the disease progression by imaging tests.
  • RECIST 1.1 Tumor response is evaluated 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 (classical RECIST 1.1) and b) the tumor assessment of non-CNS areas.
  • the assessment according to classical RECIST 1.1 by the investigator and/or the local radiologist is the basis for continuation or discontinuation of the trial in an individual patient (in addition to safety). No whole-body RECIST assessment is performed in the dose escalation part.
  • Baseline imaging should include imaging of all known or suspected sites of disease using an appropriate method.
  • the investigator or designee
  • CRF or eCRF Case Report Form
  • Lesions in previously irradiated areas may not be considered measurable at baseline unless the lesions occurred after irradiation.
  • the same method of assessment and the same imaging technique must be used at each subsequent timepoint to characterise each reported lesion throughout treatment and during follow-up.
  • Physical examinations including the measurements of height (screening only) and weight are done at screening, on Day 1 of each treatment cycle, at the EOT visit, and at the 30-day safety follow-up visit.
  • patients have an abbreviated physical examination (focused on the specific disease, at the investigator’s discretion) on Cycle 1 Day 1 (in case that previous physical examination is done within 72 hours of initiation of treatment), and Cycle 1 Day 15.
  • a full physical examination serves to assess general health status and also as a clinical tumor assessment and may include but not limited to a cardiopulmonary examination, examination of the regional lymph nodes, the abdomen and an assessment of the mental and neurological status. Additional symptoms which have not been reported during a previous examination should be clarified. Wherever possible the same investigator should perform this examination.
  • a limited physical examination should include a cardiopulmonary examination, a clinical tumor assessment, an examination of the regional lymph nodes and an examination of the abdomen.
  • An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment.
  • An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
  • a serious adverse event is defined as any AE, which fulfills at least one of the following criteria:
  • Medical judgement should be used to determine whether there is a reasonable possibility of a causal relationship between the adverse event and compound (1), considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history.
  • the event is known to be caused by or attributed to the drug class.
  • the event is typically drug-related and infrequent in the general population not exposed to drugs (e.g. Stevens-Johnson syndrome).
  • the investigator maintains and keeps detailed records of all AEs in the patient files.
  • PK profiles of compound (1) are investigated after the first and after repeated doses. Standard PK parameters are calculated, if data allows and if scientifically reasonable.
  • the pharmacokinetic parameters Cmax (,ss), AUCo-t2 (,ss), of compound (1) are assessed in terms of dose proportionality, for attainment of steady state. If deemed necessary, further PK parameters might be used for these assessments.
  • Preliminary PK analyses can be performed as necessary for DEC decisions. The final preliminary analysis are performed at the end of the dose escalation part prior to proceeding to the dose expansion part. In contrast to the final PK analysis, the preliminary analyses are based on planned sampling times rather than on actual times; no supplementary patient information, e.g. on AEs or concomitant medication, is used in these analyses, and the outputs are not validated. Minor discrepancies between preliminary and final results may therefore occur.
  • treatment compliance is calculated as shown in the formula below. Doses missed in accordance with the protocol (e.g. dose interruption for AEs) are not included in the calculation. Compliance is verified by the Clinical Research Associate (CRA) authorised by the sponsor or delegate.
  • CRA Clinical Research Associate
  • a treatment compliance of 80-120% is considered good.
  • Dose escalation is guided by a BLRM with overdose control (EWOC) that is fitted to binary toxicity outcomes (DLTs).
  • EWOC overdose control
  • DLTs binary toxicity outcomes
  • the estimate of parameters is updated as data are accumulated using the BLRM.
  • the toxicity probability at each dose level are calculated to determine an estimate of the MTD.
  • Visits may take place over more than one day for logistical reasons, as long as all assessments fall within the window defined by the sponsor, i.e. within ⁇ 1 or ⁇ 2 days of the scheduled assessment.
  • Each visit and assessment are conducted in allowed windows. Additional flexibility (e.g. to allow for public holidays and patient unavailability) may be allowed if agreed between the investigator and the sponsor.
  • the visit should be rescheduled as soon as possible, and the delayed visit documented with the actual date and the reason for the delay.
  • the scheduling of subsequent visits must not be altered, so if it is not possible to reschedule prior to the next planned visit, the missed visit should be skipped.
  • unscheduled visits and unscheduled assessments for safety reasons may be performed at any time according to clinical need.
  • screening assessments Following informed consent, the patient undergoes screening assessments. The assessments must fall within the acceptable screening visit window but do not need to be performed on the same day. Screening assessments may be repeated as long as they fall within the screening visit window. If more than one screening assessment is available, the latest assessment prior to the start of treatment must be used to assess eligibility.
  • the first treatment visit is scheduled. Any baseline conditions which are present at the screening visit should be reported in the eCRF. Eligible patients are administered compound (1) daily until criteria for treatment discontinuation are met.
  • Patients may continue on treatment for unlimited cycles, until criteria for stopping treatment are met, e.g. as long as the patient has clinical benefit or until undue drug toxicity or withdrawal of consent, whichever occurs first.
  • the follow-up visit (FU) is performed no less than 30 days after permanent discontinuation of compound (1) and is primarily to collect follow-up safety information. An individual patient who completes the follow up visit will be considered to have completed the trial.
  • Grade 3 events were ALT increased (5 patients, 11.6%), AST increased (2 patients, 4.7%), anaemia (2 patients, 4.7%), diarrhoea, pneumonia, GGT increased, hypertriglyceridaemia, hypocalcaemia, pain in extremity, pleural effusion, atrial flutter, basal cell carcinoma, lymphocyte count decreased, pericardial effusion, and sepsis (1 patient each, 2.3%).
  • PT Medical Dictionary for Regulatory Activities
  • SAE serious adverse event
  • Table 1 Overall summary of adverse events during on-treatment period, cohort BID escalation, treated set at the data lock of March 2023.
  • Table 2 Overall summary of adverse events during on-treatment period, cohort QD escalation, treated set at the data lock of March 2023.
  • tumor response assessments were available for 34 of 43 patients, 16 treated BID and 18 treated QD. Overall, the best tumor response of partial response (PR), regardless of confirmation, was reported for 13 patients of 34 patients (38.2%) evaluable for analysis. Stable disease was obtained in 18 patients (52.9%); 3 patients (8.8%) had PD; for none of the patients a complete response (CR) was reported.
  • tumor response assessments were available for 24 of 32 patients. Within the 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 SD, and for one patient (4.2%) the best response was PD. For this evaluation, patients are considered to have NSCLC if the primary diagnosis for trial entry was entered as either NSCLC or general cancer of the lung which was not classified as small-cell lung cancer.
  • Table 4 Best overall response according to RECIST vl.l (investigator assessment), regardless of confirmation at the data lock of March 2023 - dose escalation, BID schedule, treated set.
  • Table 5 Best overall response according to RECIST vl.l (investigator assessment), regardless of confirmation at the data lock of March 2023 - dose escalation, QD schedule, treated set.
  • Table 6 Best overall response according to RECIST vl.l (investigator assessment), regardless of confirmation for NSCLC patients at the data lock of March 2023 - dose escalation, BID schedule, treated set.
  • the relationship of the dose level (total daily dose) and objective response rate was assessed using a (regular/non-Bayesian) logistic regression model, based on the set of patients that have at least one post-baseline tumor assessment.
  • the estimated relationship and the 95% confidence band are reported in Figure 10.
  • the relationship of dose level (total daily dose) and best percentage change of the sum of longest diameters of target tumor lesions from baseline (tumor shrinkage) was assessed using a (regular/non-Bayesian) linear regression model based on the set of patients that have at least one post-baseline tumor assessment.
  • the estimated relationship and the 95% confidence band are reported (Figure 11).
  • Exposure-toxicity analyses were also conducted. In terms of toxicity endpoints, the occurrence of AEs of Grade 2 or higher and of AEs of Grade 3 or higher was considered. For all considered exposure endpoints, the general exposure-toxicity relationship considering all AEs is relatively flat, with no indication of a higher incidence of general AEs of Grade 2/3 (and higher) for patients with higher exposure. However, for specific AEs, e.g., diarrhoea AEs, a trend for a potentially higher incidence for higher exposure was observed.
  • the median treatment duration at the data snapshot date was 126.0 days.
  • the median number of treatment cycles initiated was 4.0 (range: 1 to 15).
  • Example 2 shows an update of the results of Example 1, where the data are reported until a cut-off of January 2024.
  • Trial design and protocol are identical to Example 1 (see paragraph 1.1 and sub-sections), except that the dose level of 360 mg QD was added. It is noted that in April 2023, the dose expansion part of the trial was opened. After this timepoint, patients that have NSCLC with HER2 Tyrosine Kinase Domain mutations were no longer allowed to be enrolled in Phase la of the trial, but were instead enrolled to Phase lb (dose expansion, see Example 3) of the trial. NSCLC patients not eligible for Phase lb were still allowed to participate in Phase la provided they met the remaining criteria for enrolment in Phase la. Further, after the dose expansion was opened, investigators were allowed to enroll patients in Phase la at a dose of their choice among the dose levels that were explored and considered safe by the DEC in the QD schedule, i.e., doses up to 360 mg QD.
  • Table 1-A Overall summary of adverse events during on-treatment period, cohort BID escalation, treated set at the data lock of January 2024. Values in bold are updated compared to Table 1.
  • Table 2-A Overall summary of adverse events during on-treatment period, cohort QD escalation, treated set at the data lock of January 2024. Values in bold are updated compared to Table 2.
  • Example 1 For the updated analyses of data accrued within the dose escalation part of the trial, the longer follow-up allowed to analyze confirmed best overall response instead of objective response regardless of confirmation for the earlier data-cut off presented in Example 1. That is, in contrast to Example 1, patients are only considered to have a partial response if an assessment of partial response is made at two subsequent tumor assessments for a patient, i.e., if a second tumor assessment confirmed the initial partial response at a later timepoint.
  • Table 4-A Best overall response according to RECIST vl.l (investigator assessment), with the requirement of confirmation at the data lock of January 2024 - dose escalation, BID schedule, treated set. Values in bold are updated compared to Table 4.
  • Table 5-A Best overall response according to RECIST vl.l (investigator assessment), with the requirement of confirmation at the data lock of January 2024 - dose escalation, QD schedule, treated set. Values in bold are updated compared to Table 5.
  • Table 6-A Best overall response according to RECIST vl.l (investigator assessment), with the requirement of confirmation for NSCLC patients at the data lock of January 2024 - dose escalation, BID schedule, treated set. Values in bold are updated compared to Table 6.
  • the highest treatment duration of an individual patient was around 2 years (24 months, patient at 30 mg BID). Due to trial design, patients on higher dose levels were recruited later than patients on lower doses, so that patients on higher doses have been on treatment for shorter time periods compared to those on lower doses by design. Still, at 120 mg QD, the highest treatment duration is 18 months, and for 240 mg QD, the highest treatment duration is 13 months at the cut-off date, where many patients within these higher dose levels are still ongoing, indicating that the higher dose levels are well -tolerated by patients.
  • the median duration of disease control from 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 BID cohorts and 10.3 months in QD cohorts.
  • long durability of disease control was observed across a broad range of doses, including lower dose levels. For instance, at 120 mg QD, 17.2 months median duration of disease control was observed across 3 patients with disease control and at 30 mg BID, one patient had a duration of disease control of 20.8 months at the time of the data cut-off.
  • PFS was estimated to be higher than in the set of all treated patients based on a Kaplan-Meier analysis as plotted in Figure 13: for the BID schedule, the estimate is a median PFS of 13.8 months (confidence interval: 2.3 months to NC), and for the QD schedule, it was 12.3 months (confidence interval: 7.6 to 17.2 months). Similar PFS was observed across the explored dose range in lung cancer patients.
  • Example 3 Dose expansion part (Phase lb) of the clinical trial of Examples 1 and 2
  • This Example focuses on the dose expansion part (Phase lb) of the Phase I study described in Examples 1 and 2. Approximately 275 patients diagnosed with advanced or metastatic refractory NSCLC harbouring mutations in the HER2 gene are enrolled. Elements specific to Phase lb are reported in the protocol below. For other elements that are not specified, the protocol remains as in Example 1. Patients are divided into 5 cohorts according to the main inclusion criteria listed below.
  • the trial objectives of Phase lb include:
  • cohort 2 For cohort 1, cohort 2, and cohort 5, assess objective tumor response rate by central independent review;
  • Phase lb For all cohorts, continue evaluating safety, and patient-reported outcomes.
  • the primary endpoints of Phase lb include:
  • the secondary endpoints include:
  • DC - Disease control
  • EORTC QLQ-C30, NSCLC-SAQ and EORTC IL46 are patient reported outcome measures (PROMs).
  • EORTC QLQ-C30 (IL19) physical functioning domain score is a 5- item functional scale from the EORTC QLQ-C30, which is a questionnaire specific for the assessment of health-related quality of life (QoL) in patients with cancer.
  • 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 were identified as symptoms of NSCLC: cough (1 item), pain (2 items), dyspnea (1 item), fatigue (2 items), and appetite (1 item).
  • EORTC IL46 (item 168) is a validated single-item question that assesses overall side effect impact. Other PROM may be measured in the course of the study.
  • the main inclusion criteria include:
  • FFPE formalin-fixed paraffin embedded
  • TKD Tyrosine Kinase Domain
  • TKD Tyrosine Kinase Domain
  • Compound (1) is administered, orally, at a dose of 120 mg or 240 mg QD.
  • the treatment consists of reiterated cycles of 3 weeks as long as the patient has clinical benefit or until undue drug toxicity or withdrawal of consent, whichever occurs first (similar to Example 1).
  • Example 4 Efficacy of compound (1) (zongertinib) in NSCLC cells resistant to T-DXd Zongertinib (i.e. compound (1)) consistently inhibits downstream signaling of HER2 and the proliferation of cancer cells dependent on high expressions of HER2 WT and its mechanism of action is different from those of antibody-based therapeutics, offering the opportunity of addressing resistance. Therefore, this Example investigates if zongertinib is efficacious against human cancer cells that are dependent on high expression of HER2 WT but resistant to HER2 targeting ADCs. First, a tumor model resistant to trastuzumab deruxtecan (T-DXd) was generated.
  • T-DXd trastuzumab deruxtecan
  • the NCI-N87 model is used and tumor-bearing mice are treated with three cycles of T-DXd, tumors that regrow are harvested and then tumor cells are cultivated in vitro, as shown in Figure 15.
  • Parental and T-DXd-resistant NCI-N87 cells are treated with deruxtecan, T-DXd or zongertinib.
  • NCI-N87 cells are suspended at 2.5* 10 7 cells in PBS (Gibco, #14190-094) with 5% FBS (Gibco, #26140-079).
  • the cell suspension is then injected subcutaneously in the right flank of BomTac:NMRI-Foxnlnu mice with a volume of 100 pl (2.5*10 6 cells per mouse).
  • mice are randomized based on s.c. tumor volume at an average size of 120 mm 3 .
  • treatment is started with 3 mg/kg T-DXd i.v.. From that point on, tumor sizes are measured three times weekly using a caliper.
  • a second treatment is injected at 10 mg/kg T-DXd.
  • Treatments are followed on days 43; 64; 85 and 106 with 7 mg/kg i.v.. Afterwards outgrowth is observed. Tumors are harvested on day 174 (#18 at 514.09 mm 3 ) and day 209 (#17 at 626.21 mm 3 ) and taken into culture in PBS on ice.
  • Tumors are cut into 1 mm 3 pieces and homogenized using Tumor Dissociation Kit, mouse (Miltenyi Biotec, #130-096-730), in combination with the gentleMACSTM Octo Dissociator (Miltenyi).
  • Cells are resuspended in 3 ml RPMI medium (PAN-Biotech, #P04-18047) supplemented with 10% FBS (Gibco, #26140-079), lx GlutaMAXTM (Gibco, #35050-038), lx Pen Strep (Gibco, #15140-122), and cell numbers are measured.
  • 6.8*10 6 cells are plated in 3 ml medium per well in a TC-treated 6 well cell culture plate (Corning, #3506) and grown in a humidified incubator at +37 °C and 5% CO2. For the next 2 days cells are washed daily with 3 ml PBS (Gibco, #14190-094) to remove unattached cells and medium is replaced. Cells are passaged at 60-80% confluency by washing with 1 ml PBS, subsequently dissociating with 500 pL Trypsin (PAN-Biotech, #P 10-0210300), and incubating cells at 37 °C until cells detach.
  • PBS Gibco, #14190-094
  • Trypsin is blocked with 1 mL medium, and 500 pL of cell suspension is plated back to a 6 well plate with 3 ml medium or T25 cell culture flask with 7 ml medium (Corning, #353109). Cells are grown for 5 passages until no residual fibroblasts are visible before performing proliferation assay upon drug treatment.
  • zongertinib inhibits the growth of HER2-dependent human NSCLC cells resistant to trastuzumab deruxtecan.
  • 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.

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Abstract

La présente invention concerne un schéma posologique d'un inhibiteur d'HER2 utile dans la prévention et/ou le traitement du cancer, en particulier ses doses et son administration en deuxième intention ou plus.
PCT/EP2024/058464 2023-03-29 2024-03-28 Schéma posologique d'un inhibiteur d'her2 Ceased WO2024200637A2 (fr)

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AU2024247020A AU2024247020A1 (en) 2023-03-29 2024-03-28 Dosing schedule of a her2 inhibitor
CN202480032966.5A CN121263188A (zh) 2023-03-29 2024-03-28 Her2抑制剂的给药安排方案
KR1020257036057A KR20260004349A (ko) 2023-03-29 2024-03-28 Her2 억제제의 투여 일정
EP24717127.5A EP4687907A2 (fr) 2023-03-29 2024-03-28 Schéma posologique d'un inhibiteur d'her2
MX2025011417A MX2025011417A (es) 2023-03-29 2025-09-25 Programa de dosificacion de un inhibidor de her.2
IL323596A IL323596A (en) 2023-03-29 2025-09-28 HER2 inhibitor dosing schedule

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