Cancer treatment with a her2 inhibitor and a CYP3a and / or p-gp modulator

Abstract

The present invention relates to a HER2 inhibitor useful in the prevention and / or treatment of cancer, in particular, to methods of treatment or uses comprising avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. The present invention also relates to a HER2 inhibitor useful in the prevention and / or treatment of cancer, in particular, to methods of treatment or uses comprising concomitant use, co-administration or combination of a CYP3A and / or P-gp modulator.

Description

[0001]CANCER TREATMENT WITH A HER2 INHIBITOR FIELD OF THE INVENTION The present invention relates to a HER2 inhibitor useful in the prevention and / or treatment of cancer, in particular, to methods of treatment or uses comprising avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. The present invention also relates to a HER2 inhibitor useful in the prevention and / or treatment of cancer, in particular, to methods of treatment or uses comprising concomitant use, co-administration or combination of a CYP3A and / or P-gp modulator. BACKGROUND N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]- diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide, also herein referred to as compound (1) or zongertinib, is a HER2 (ErbB2) inhibitor described in WO 2021 / 213800. 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. CYP3A4 / 5 is primarily responsible for the hepatic oxidative metabolism of compound (1). Therefore, patients taking comedications that modulate CYP3A4 / 5 metabolism, i.e. inhibitors or inducers of CYP3A4 / 5, might achieve plasma levels of compound (1) that are outside of the therapeutic window. CYP3A4 / 5 inhibitors might increase plasma exposure of compound (1) which may impair its tolerability, while CYP3A4 / 5 inducers might decrease plasma exposure of compound (1), which may impair its efficacy. Therefore, there remains a need for increased understanding of drug-drug interactions and improved methods for administering cancer therapeutics in the form of compound (1) to individuals who are concomitantly being treated with other active agents like CYP3A and / or P- gp modulators. In addition, there is a need to inform the patients of the safety and tolerable use of concomitant medications in the label of compound (1), while maintaining efficacy of compound (1). BRIEF DESCRIPTION OF THE FIGURES Figure 1. (A) Overview of the trial design of Example 1. Each star represents an administration of compound (1). The black bars represent the administration of carbamazepine in different daily amounts. (B) Study design of Example 2. This open-label, two-period, fixed-sequence, drug-drug interaction study in healthy male subjects aimed to compare the test treatment (T) in Period 2 to the reference treatment (R) in Period 1. Treatment R was a single oral dose of zongertinib 60 mg film-coated tablet given alone on Day 1 of Period 1. Treatment T was a single oral dose of zongertinib 60 mg administered on Day 1 together with multiple oral doses of carbamazepine from Day -18 to Day 6 of Study Period 2. Carbamazepine was dosed at 200 mg QD for 4 days (Day -18 to Day -15), titrated to 400 mg QD for 7 days (Day -14 to Day -8), and then to a final dose of 600 mg QD for 13 days (Day -7 to Day 6). Blood samples were collected at various time points as indicated in the figure for zongertinib PK, carbamazepine PK, and 4βHC plasma concentrations. Multiple 24-hour urine collections were planned in Period 2 for the quantification of 6βHC to cortisol ratios (6βCR).4βHC, 4β- OH-cholesterol; 6βHC, 6β-OH-cholesterol; 6βCR, 6βHC to cortisol ratio; EoS, end of study; PK, pharmacokinetic; QD, once daily; R, reference; SCR, screening; T, test. Figure 2. Change in CYP3A induction biomarkers over time. Mean (± SD) of 6βCR in urine and 4βHC in plasma over time with multiple oral doses of carbamazepine and a single dose of zongertinib. Panels (A) and (B) show 6βCR and panels (C) and (D) depict 4βHC. Panels (A) and (C) are original values prior to baseline correction over time, and panels (B) and (D) are PCB over time.4βHC, 4β-OH- cholesterol; 6βCR, 6β-OH-cortisol to cortisol ratio; PCB, percent change from baseline calculated by (value-baseline) / baseline*100%; SD, standard deviation. Figure 3. Mean plasma concentration-time profiles of zongertinib after a single 60 mg oral dose of zongertinib in absence (R) and presence (T) of multiple doses of carbamazepine. Linear and semilogarithmic scale (mean ± SD). Only higher SD whiskers are displayed for R treatment, and lower SD whiskers are displayed for T treatment for clarity for both linear and semilogarithmic plots. Whiskers of SD reaching negative values were not displayed in the semilogarithmic plot. R: zongertinib 60 mg at Day 1 of Period 1. T: zongertinib 60 mg at Day 1 of Period 2 + CBZ 200 mg QD from Day -18 to Day -15, titrated to 400 mg QD from Day -14 to Day -8, to 600 mg QD from Day -7 to Day 6. CBZ, carbamazepine; QD, once daily; SD, standard deviation. Figure 4. Relative bioavailability of a single oral dose of 60 mg zongertinib coadministered with multiple oral doses of carbamazepine (T) relative to a single dose of 60 mg zongertinib alone (R). Adjusted gMean ratios and 90% confidence intervals. R: zongertinib 60 mg at Day 1 of Period 1. T: zongertinib 60 mg at Day 1 of Period 2 + carbamazepine 200 mg once daily from Day -18 to Day -15, titrated to 400 mg once daily from Day -14 to Day -8, to 600 mg once daily from Day -7 to Day 6. AUC0-∞, area under the plasma concentration-time curve over the time interval from 0 to infinity; AUC0-tz, area under the plasma concentration-time curve over the time interval from 0 to the last quantifiable data point; Cmax, maximum measured concentration of the analyte in plasma; gMean, geometric mean; R, reference; T, test. Figure 5. Individual and geometric mean plasma concentration-time profiles of carbamazepine after multiple oral doses of carbamazepine combined with a single dose of zongertinib. Dosing regimen: zongertinib 60 mg at Day 1 of Period 2 (defined as 0 hours) + carbamazepine 200 mg once daily from Day -18 to Day -15, titrated to 400 mg once daily from Day -14 to Day 8, and to 600 mg once daily from Day -7 to Day 6. gMean, geometric mean. SUMMARY OF THE INVENTION According to a first aspect is provided compound (1) as defined below or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Alternatively, a method of treating a patient suffering from cancer comprises administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof and avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. In embodiments, said use or method comprises avoiding co-administration of a CYP3A and / or P-gp modulator. According to a second aspect is provided compound (1) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately or sequentially. Alternatively, a method of treating a patient suffering from cancer comprises administering compound (1) as defined herein or a pharmaceutically acceptable salt thereof, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately or sequentially. These two aspects may share several features. In general, each embodiment presented below is intended as an embodiment of both aspects, unless stated otherwise. For example, in certain embodiments, there may be a time interval during which no CYP3A and / or P-gp modulator is administered. This time interval may be a feature of both the first (avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration) and second (combination) aspect. Similarly, certain embodiments refer to assessing the CYP3A and / or P-gp modulator drug status. These embodiments belong to both the first and the second aspect. All embodiments defining the CYP3A and / or P-gp modulator, the dosing of compound (1) and the identity of the cancer are embodiments of both aspects of the invention. In embodiments, the use comprises a contraindicated or avoided time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). Alternatively, a method of treating a patient suffering from cancer comprises a contraindicated or avoided time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). In embodiments, the contraindicated or avoided time interval is selected from the group consisting of at least 1 hour, at least 1 day, at least 3 days, at least 7 days, at least 14 days and at least 21 days. In embodiments, the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient prior to the administration of compound (1) and contraindicating or avoiding the administration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. Alternatively, a method of treating a patient suffering from cancer comprises assessing the CYP3A and / or P-gp modulator drug status of the patient prior to the administration of compound (1) and contraindicating or avoiding the administration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. In embodiments, the CYP3A and / or P-gp modulator drug status assessment is selected from the group consisting of a questionnaire, CYP3A and / or P-gp modulator blood, blood serum and / or plasma level determination, consultation with the patient, an endogenous biomarker and a combination thereof. In embodiments, the daily dose of administered compound (1) is below 240 mg, preferably below 200 mg, 180 mg or 150 mg, in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator. In embodiments, the daily dose of administered compound (1) is below 120 mg, preferably below 100 mg, 60 mg or 30 mg, in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator. In embodiments, the daily dose of administered compound (1) is above 120 mg, preferably above 150 mg, 180 mg, 200 mg or 240 mg, in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator. In embodiments, the daily dose of administered compound (1) is above 240 mg, preferably above 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator. In embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient; (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered at a higher than standard therapeutically effective amount to a patient; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. In embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient; (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered at total daily dose of 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. In embodiments, the standard therapeutically effective amount of compound (1) is a daily dose of 120 mg or 240 mg. In embodiments, the CYP3A and / or P-gp modulator is a CYP3A and / or P-gp inducer. In embodiments, the CYP3A and / or P-gp modulator is a strong CYP3A4 / 5 inducer. In embodiments, the use or method comprises avoiding co-administration of a strong CYP3A4 / 5 inducer. In embodiments, the CYP3A and / or P-gp inducer is selected from the group consisting of apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort, brigatinib, efavirenz, enzalutamide, dexamethasone, modafinil, nevirapine, oxcarbazepine, pioglitazone, rifabutin and troglitazone. In embodiments, the CYP3A and / or P-gp inducer is carbamazepine. In embodiments, said 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. In embodiments, said cancer is non-small cell lung cancer. In embodiments, said cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant. In embodiments, said cancer comprises a mutation in the tyrosine kinase domain of HER2. In embodiments, said cancer is unresectable, advanced and / or metastatic cancer. According to another aspect, a pharmaceutical composition is provided, said pharmaceutical composition comprising compound (1) as defined herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Alternatively, a method of treating a patient suffering from cancer comprises administering a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient and wherein the method comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. According to another aspect, a pharmaceutical composition is provided, said pharmaceutical composition comprising compound (1) as defined herein and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately or sequentially. Alternatively, a method of treating a patient suffering from cancer comprises administering a pharmaceutical composition comprising compound (1) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately or sequentially. In embodiments of the pharmaceutical composition, the use is as defined in any one of the embodiments above. In embodiments of the pharmaceutical composition, the CYP3A and / or P-gp modulator is as defined in any one of the embodiments above. In embodiments of the pharmaceutical composition, the cancer is as defined in any one of the embodiments above. DETAILED DESCRIPTION OF THE INVENTION It is a purpose of the present invention to provide a safe and efficacious treatment of cancer with compound (1) in case that CYP3A and / or P-gp modulators are already administered or are considered to be co-administered. Compound (1) As used herein, the term “compound (1)” refers to the compound as defined below or a pharmaceutically acceptable salt thereof: The IUPAC name of compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol- 5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. Compound (1) is also known as zongertinib. In case of discrepancy between IUPAC name and depicted formula, the formula shall prevail. Compound (1) is disclosed in WO 2021 / 213800 as example compound I-01. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines such as compound (1) as HER2 inhibitors and provides a synthesis procedure for compound (1). Properties of compound (1) and evidence 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. The term “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. In particular, any reference to “compound (1)” is meant to be read as “compound (1) or a pharmaceutically acceptable salt thereof”, unless otherwise stated. In embodiments, compound (1) is used as a free base. In embodiments, pharmaceutically acceptable salts of compound (1) are used. The term “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. As used herein “pharmaceutically acceptable salts” of compound (1) refers to compound (1) wherein the compound is modified by making acid or base salts thereof. The term 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. For example, 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. In embodiments, pharmaceutically acceptable salts are selected from chloride and fumarate salts. Pharmaceutically acceptable salts can be synthesized from compound (1) by conventional chemical methods. Generally, such salts can be prepared by reacting the free base form of compound (1) with a sufficient amount of the appropriate acid or base in water or in an organic diluent or solvent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. The term “solvate” as used herein refers to an association or complex of one or more solvent molecules and compound (1). Examples of solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, tert-butyl methyl ether, tetrahydrofuran, methylethyl ketone, N-methylpyrrolidone and ethanolamine. The term “hydrate” refers to a complex where the solvent molecule is water. Medical Uses and Methods of Treatment The terms used herein should be interpreted according to the meaning attributed to them in the art. As used herein, the term “contraindicating” and grammatical variants thereof are contemplated to have the meaning of a medical reason why someone should not use a particular drug or medical treatment. A contraindication is especially outlined in the documentation, label and the leaflet of a prescribed drug. As used herein, the term “reducing” and grammatical variants thereof are contemplated to have as alternatives “lowering”, “decreasing”, “lessen”, “diminish”, “bringing down”. As used herein, the term “drug status” and grammatical variants thereof refers in particular to determining whether the patient has taken the drug in a given time interval. The drug status can be assessed in different ways as further detailed below. A positive drug status indicates that the patient has taken the drug in a given time interval, whereas a negative drug status indicates that the patient has not taken the drug in a given time interval. As used herein, the term “positive drug status” and grammatical variants thereof is understood to encompass a situation, wherein the drug concentration in the body of a patient is higher compared to standard, based on the fact that the drug is administered prior or at the same time of assessing the drug status. As used herein, the term “negative drug status” and grammatical variants thereof is understood to encompass a situation, wherein the drug concentration in the body of a patient is lower compared to standard, based on the fact that the drug is not administered prior or at the same time of assessing the drug status. As used herein, the term “avoid” and grammatical variants thereof are contemplated to have as alternatives the terms abstain, desist, forbear, and refrain. In some cases, the alternative terms will be equivalent. For example, “avoiding” means “refraining from”. As used herein, the term “discontinue” and forms thereof are contemplated to have as alternatives the terms cease, stop, suspend, and quit. The expression “concomitant use” is understood to be interchangeable with “concurrent administration”, “co-administration” or “combination”. Thus, the terms are understood to encompass administration simultaneously or at different times, and by the same route or by different routes, as long as the two agents are given in a manner that allows both agents to be affecting the body at the same time. For example, concomitant use can refer to a medication concomitantly administered, whether prescribed by the same or a different practitioner, or for the same or a different indication. More particularly compound (1) may be administered orally while a CYP3A and / or P-gp modulator, e.g. a CYP3A and / or P-gp inducer, e.g. carbamazepine, may be administered orally, intravenously, via injection into a muscle, subcutaneously, intranasal delivery, rectal or through the cheeks. “Concomitant use”, “co-administration, “combination” or “concurrent administration” preferably appear in cases, wherein compound (1) and a CYP3A and / or P-gp modulator are administered each at least once within a time interval of 14 days. As used herein, the term “co-administration” and grammatical variants thereof is understood to be interchangeable with the term “concomitant use”, “combination” and “concurrent administration”. As used herein, the term “concurrent administration” and grammatical variants thereof is understood to be interchangeable with the term “concomitant use”, “combination” or “co- administration”. As used herein, the term “combination” and grammatical variants thereof is understood to be interchangeable with the term “concomitant use”, “concurrent administration” or “co- administration”. The term “simultaneously” and grammatical variants thereof refers to the administration of compound (1) and the CYP3A and / or P-gp modulator at substantially the same time. The term “sequentially” and grammatical variants thereof includes administration of one active ingredient during a first time period, for example over the course of a few hours, days or a week, using one or more doses, followed by administration of the other active ingredient during a second time period, for example over the course of a few hours, days or a week, using one or more doses. The term “separately” and grammatical variants thereof means that compound (1) and the CYP3A and / or P-gp modulator are both administered to a patient as separate entities, dosage forms or non-fixed combination, either simultaneously, concurrently, sequentially, successively, alternatively or otherwise separately with no specific time limits. “CYP3A” refers to the most abundant and most clinically significant subfamily of cytochrome P450 enzymes. The CYP3A subfamily has four human isoforms, 3A4, 3A5, 3A7 and 3A43, CYP3A4 being the most commonly associated with drug interactions. As used herein, “CYP3A” includes CYP3A4, CYP3A5, CYP3A7 and CYP3A43. Preferably, “CYP3A” as used herein refer to CYP3A4 and / or 5. The CYP3A isoforms make up approximately 50% of the liver’s total cytochrome P450 and are widely expressed throughout the gastrointestinal tract, kidneys and lungs and therefore are ultimately responsible for the majority of first-pass metabolism. This is important as increases or decreases in first-pass metabolism can have the effect of administering a much smaller or larger dose-equivalent of drug than usual. “P-gp” refers to the glycoprotein transmembrane transporter MDR1 / ABCB1, i.e. the transporter that is encoded by the ABCB1 gene. P-gp is particularly located at the interface tissues, such as intestinal, renal, hepatic and brain barrier and is involved in the transport and / or efflux of various compounds. As used herein, the term “modulator” and grammatical variants thereof refers to a molecule that increases or decreases the expression and / or activity of a protein, such as an enzyme or a transport protein, especially of CYP3A and / or P-gp. It is intended to include inducers as well as inhibitors. As used herein, the term “inducer” and grammatical variants thereof refers to a molecule that increases or enhances the expression and / or activity of a protein, such as an enzyme or a transport protein, especially of CYP3A and / or P-gp. Such increase or enhancement can derive from increased protein synthesis or reduced protein degradation and can be measured according to any method known in the art. In particular, “inducer” refers to a molecule that is recognized by the Food & Drug Administration (FDA) or by the European Medicine Agency (EMA) as an inducer of CYP3A and / or P-gp. As used herein, the expressions “strong CYP3A inducer” and “strong CYP3A4 / 5 inducer” have the same meaning given by FDA guidance and / or EMA guidance, e.g ICH M12 guideline on Drug Interaction Studies and FDA’s Table of Substrates Inhibitors and Inducers available at: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers, last modified on 06 / 05 / 2023. In particular, a strong inducer of CYP3A, or more specifically CYP3A4 / 5, can decrease the AUC of a sensitive index CYP substrate by ≥ 80 percent. Examples of strong CYP3A inducers include but are not limited to carbamazepine, phenytoin and rifampin. As used herein, CYP3A and / or P-gp modulator comprises and is interchangeable with: CYP3A modulator, P-gp modulator, CYP3A and P-gp modulator. As used herein, CYP3A and / or P-gp modulator preferably refers to a CYP3A and / or P-gp inducer, including CYP3A inducer, P-gp inducer, CYP3A and P-gp inducer. The terms “standard prescribed dose”, “normal prescribed dose”, “standard therapeutically effective amount”, “standard administration schedule”, “standard schedule”, “usual dose” and “standard dose” can be used interchangeably and refer to the standard and authorized prescribed drug dosage according to the label or the leaflet instruction. The standard dose may vary depending on the form or the route the drug is being administered. As used herein, the expression “a contraindicated or avoided time interval” refers to a period of time during which no CYP3A and / or P-gp modulator is administered. In preferred embodiments, the use comprises avoiding or discontinuing concomitant use or co- administration of a CYP3A and / or P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding or discontinuing concomitant use or co- administration of a CYP3A and / or P-gp modulator. In preferred embodiments, the use comprises concomitant use or co-administration of a CYP3A and / or P-gp modulator and compound (1). Alternatively, the method of treating a patient suffering from cancer comprises concomitant use or co-administration of a CYP3A and / or P- gp modulator and compound (1). In preferred embodiments, the use comprises avoiding or discontinuing concomitant use or co- administration of a CYP3A modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding or discontinuing concomitant use or co-administration of a CYP3A modulator. In preferred embodiments, the use comprises avoiding or discontinuing concomitant use or co-administration of a P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding or discontinuing concomitant use or co- administration of a P-gp modulator. In preferred embodiments, the use comprises avoiding or discontinuing concomitant use or co-administration of a CYP3A and P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding or discontinuing concomitant use or co-administration of a CYP3A and P-gp modulator. In preferred embodiments, the use comprises avoiding or discontinuing concomitant use or co- administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding or discontinuing concomitant use or co-administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator. In preferred embodiments, the use comprises concomitant use or co-administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator and compound (1). Alternatively, the method of treating a patient suffering from cancer comprises concomitant use or co-administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator and compound (1). In preferred embodiments, the use comprises avoiding concomitant use or co-administration of a therapeutically effective amount of a CYP3A modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding concomitant use or co-administration of a therapeutically effective amount of a CYP3A modulator. In preferred embodiments, the use comprises avoiding concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. In preferred embodiments, the use comprises avoiding concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises avoiding concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P- gp modulator. In preferred embodiments, the use comprises discontinuing concomitant use or co- administration of a therapeutically effective amount of a CYP3A modulator. Alternatively, the method of treating a patient suffering from cancer comprises discontinuing concomitant use or co-administration of a therapeutically effective amount of a CYP3A modulator. In preferred embodiments, the use comprises discontinuing concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises discontinuing concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. In preferred embodiments, the use comprises discontinuing concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises discontinuing concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P-gp modulator. In preferred embodiments, the use comprises contraindicating or reducing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating or reducing concomitant use or co- administration of a CYP3A and / or P-gp modulator. In preferred embodiments, the use comprises contraindicating or reducing concomitant use or co-administration of a CYP3A modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating or reducing concomitant use or co- administration of a CYP3A modulator. In preferred embodiments, the use comprises contraindicating or reducing concomitant use or co-administration of a P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating or reducing concomitant use or co-administration of a P-gp modulator. In preferred embodiments, the use comprises contraindicating or reducing concomitant use or co- administration of a CYP3A and P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating or reducing concomitant use or co- administration of a CYP3A and P-gp modulator. In preferred embodiments, the use comprises contraindicating or reducing concomitant use or co-administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating or reducing concomitant use or co-administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator. In preferred embodiments, the use comprises contraindicating concomitant use or co- administration of a therapeutically effective amount of a CYP3A modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating concomitant use or co-administration of a therapeutically effective amount of a CYP3A modulator. In preferred embodiments, the use comprises contraindicating concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. In preferred embodiments, the use comprises contraindicating concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises contraindicating concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P-gp modulator. In preferred embodiments, the use comprises reducing concomitant use or co-administration of a therapeutically effective amount of a CYP3A modulator. Alternatively, the method of treating a patient suffering from cancer comprises reducing concomitant use or co-administration of a therapeutically effective amount of a CYP3A modulator. In preferred embodiments, the use comprises reducing concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises reducing concomitant use or co-administration of a therapeutically effective amount of a P-gp modulator. In preferred embodiments, the use comprises reducing concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P-gp modulator. Alternatively, the method of treating a patient suffering from cancer comprises reducing concomitant use or co-administration of a therapeutically effective amount of a CYP3A and P- gp modulator. In preferred embodiments, the use comprises a contraindicated or avoided time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). In preferred embodiments, the use comprises a contraindicated or avoided time interval between the administration of the CYP3A modulator and the administration of compound (1). In preferred embodiments, the use comprises a contraindicated or avoided time interval between the administration of the P-gp modulator and the administration of compound (1). In preferred embodiments, the use comprises a contraindicated or avoided time interval between the administration of the CYP3A and P-gp modulator and the administration of compound (1). In preferred embodiments, the use comprises a contraindicated time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). In preferred embodiments, the use comprises an avoided time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). Within the contraindicated and / or avoided time interval no CYP3A and / or P-gp modulators are allowed to be administered to a patient prior to a treatment of the patient including compound (1). Within the contraindicated and / or avoided time interval no therapeutically effective amounts of CYP3A and / or P-gp modulators are allowed to be administered to a patient prior to a treatment of the patient including compound (1). In preferred embodiments, the method of treating a patient suffering from cancer comprises a contraindicated or avoided time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). In preferred embodiments, the method of treating a patient suffering from cancer comprises a contraindicated or avoided time interval between the administration of the CYP3A modulator and the administration of compound (1). In preferred embodiments, the method of treating a patient suffering from cancer comprises a contraindicated or avoided time interval between the administration of the P-gp modulator and the administration of compound (1). In preferred embodiments, the method of treating a patient suffering from cancer comprises a contraindicated or avoided time interval between the administration of the CYP3A and P-gp modulator and the administration of compound (1). In preferred embodiments, the method of treating a patient suffering from cancer comprises a contraindicated time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). In preferred embodiments, the method of treating a patient suffering from cancer comprises an avoided time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1). In preferred embodiments, the contraindicated or avoided time interval is selected from the group consisting of at least 1 hour, at least 1 day, at least 3 days, at least 7 days, at least 14 days and at least 21 days. In preferred embodiments, the contraindicated or avoided time interval is selected from the group consisting of at least 3 days, at least 7 days, at least 14 days, at least 21 days. Preferably, the contraindicated or avoided time interval is of at least 14 days. This applies to all embodiments described herein that include a contraindicated or avoided time interval. In preferred embodiments, the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and contraindicating or avoiding the administration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. In preferred embodiments, the use comprises assessing the CYP3A modulator drug status of the patient prior to the administration of compound (1) and contraindicating or avoiding the administration of compound (1) for a time interval in case that the CYP3A modulator drug status is positive. In preferred embodiments, the use comprises assessing the P-gp modulator drug status of the patient prior to the administration of compound (1) and contraindicating or avoiding the administration of compound (1) for a time interval in case that the P-gp modulator drug status is positive. Alternatively, provided herein is a method of treating a patient suffering from cancer comprising assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and contraindicating or avoiding the administration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. In preferred embodiments, the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. In preferred embodiments, the use comprises assessing the CYP3A modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administration of compound (1) for a time interval in case that the CYP3A modulator drug status is positive. In preferred embodiments, the use comprises assessing the P- gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administration of compound (1) for a time interval in case that the P-gp modulator drug status is positive. Adapting in the sense of this application means, that a standard administration schedule including administered daily compound (1) amounts, or the administration time schedule is altered with respect to a standard schedule valid for a patient without co-administration of a CYP3A and / or P-gp modulator. Adapting may for instance include the administration of an increased or a reduced daily dose of compound (1) and / or the CYP3A and / or P-gp modulator. The increase or reduction in daily dose is intended with respect to the dose of compound (1) as described here, in particular a standard therapeutic dose or a daily dose of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, preferably a daily dose of 120 mg or 240 mg. In preferred embodiments, the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administration of compound (1) for the time interval during which the patient is administered a CYP3A / P-gp modulator in case that the CYP3A and / or P-gp modulator drug status is positive. In preferred embodiments, the use comprises assessing the CYP3A modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administration of compound (1) for the time interval during which the patient is administered a CYP3A / P-gp modulator in case that the CYP3A modulator drug status is positive. In preferred embodiments, the use comprises assessing the P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administration of compound (1) for the time interval during which the patient is administered a CYP3A / P-gp modulator in case that the P-gp modulator drug status is positive. According to an aspect of the invention, it is provided compound (1) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administered daily concentration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. Alternatively, provided herein is a method of treating a patient suffering from cancer comprising assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administered daily concentration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. According to an aspect of the invention, it is provided compound (1) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administered daily concentration of the CYP3A and / or P-gp modulator for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. Alternatively, provided herein is a method of treating a patient suffering from cancer comprising assessing the CYP3A and / or P-gp modulator drug status of the patient, preferably prior to the administration of compound (1), and adapting the administered daily concentration of the CYP3A and / or P-gp modulator for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is not administered to a patient; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is not administered to a patient; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in therapeutically effective amounts. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is not administered to a patient for a time interval; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is not administered to a patient for at least 3 days, at least 7 days, at least 14 days, or at least 21 days; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is not administered to a patient for at least 3 days, at least 7 days, at least 14 days, or at least 21 days; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in therapeutically effective amounts. In preferred embodiments, the use or method comprises: (i) Assessing the carbamazepine drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the carbamazepine drug status is positive, compound (1) is not administered to a patient for at least 3 days, at least 7 days, at least 14 days, or at least 21 days; (iii) In case the carbamazepine drug status is negative, compound (1) is administered to a patient. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered at a lower than standard therapeutically effective amount to a patient; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered at a higher than standard therapeutically effective amount to a patient; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at a lower than standard therapeutically effective amount to a patient; (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 or 240 mg. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at total daily dose lower than 240 mg to a patient; (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 240 mg. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at total daily dose lower than 120 mg to a patient; (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 mg. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at total daily dose of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg to a patient, preferably of 30 mg, 60 mg or 100 mg; (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 or 240 mg. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at a higher than standard therapeutically effective amount to a patient; (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 or 240 mg. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at a total daily dose higher than 240 mg, preferably 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, to a patient; (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 240 mg. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at total daily dose higher than 120 mg, preferably 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, to a patient; (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 mg. In preferred embodiments, the use or method comprises: (i) Assessing the CYP3A and / or P-gp inducer drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered at total daily dose of 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg (preferably, 300 mg or 360 mg); (iii) In case the CYP3A and / or P-gp inducer drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 or 240 mg. In preferred embodiments, the use or method comprises: (i) Assessing the carbamazepine drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the carbamazepine drug status is positive, compound (1) is administered at a lower than standard therapeutically effective amount to a patient for at least 3 days, at least 7 days, at least 14 days, or at least 21 days; (iii) In case the carbamazepine drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 or 240 mg. In preferred embodiments, the use or method comprises: (i) Assessing the carbamazepine drug status of a patient, preferably prior to the administration of compound (1); (ii) In case the carbamazepine drug status is positive, compound (1) is administered at a higher than standard therapeutically effective amount to a patient for at least 3 days, at least 7 days, at least 14 days, or at least 21 days; (iii) In case the carbamazepine drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount. Preferably, the standard therapeutically effective amount is 120 or 240 mg. In preferred embodiments, the use or method comprises that the the CYP3A and / or P-gp modulator drug status assessment is selected from the group consisting of a questionnaire, CYP3A and / or P-gp modulator blood, blood serum and / or plasma level determination, consultation with the patient, an endogenous biomarker and a combination thereof. In preferred embodiments, the use comprises that the CYP3A and / or P-gp modulator drug status assessment is selected from the group consisting of a questionnaire, CYP3A and / or P-gp modulator blood, blood serum and / or plasma level determination, consultation with the patient or a combination thereof. In preferred embodiments, the method comprises that the CYP3A and / or P-gp modulator drug status assessment is selected from the group consisting of a questionnaire, CYP3A and / or P-gp modulator blood, blood serum and / or plasma level determination, consultation with the patient or a combination thereof. In preferred embodiments, the use or method comprises that the CYP3A and / or P-gp modulator drug status assessment is a CYP3A and / or P-gp modulator blood serum level determination. In preferred embodiments, the CYP3A and / or P-gp modulator drug status assessment is an endogenous biomarker, i.e. the measurement thereof. Preferably, the endogenous biomarker is the ratio of 6β-OH-cortisol to cortisol (6βCR) in urine or the amount of 4β-OH-cholesterol (4βHC) in plasma. In particular, the CYP3A and / or P-gp modulator drug status can be assessed by measuring 6βCR in urine and / or 4βHC in plasma, for example following the procedure described in Example 2. 6βCR in urine and 4βHC in plasma are not quantitative, but higher levels of these preferred endogenous biomarkers can indicate an increase in CYP3A activity, e.g. due to the administration of a CYP3A inducer. In preferred embodiments, the CYP3A and / or P-gp modulator is a CYP3A and / or P-gp inducer. In preferred embodiments, the CYP3A and / or P-gp modulator is a CYP3A inducer, a P-gp inducer, or a CYP3A and P-gp inducer. Further disclosed are embodiments corresponding to those recited herein where the expression “CYP3A and / or P-gp modulator” is replaced by “CYP3A and / or P-gp inducer”. In preferred embodiments, the CYP3A and / or P-gp modulator is a strong CYP3A inducer. Preferably, the strong CYP3A inducer is a strong CYP3A4 / 5 inducer. Further disclosed are embodiments corresponding to those recited herein where the expression “CYP3A and / or P-gp modulator” is replaced by “strong CYP3A inducer”. In preferred embodiments, the CYP3A and / or P-gp inducer is selected from the group consisting of apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort, brigatinib, efavirenz, enzalutamide, dexamethasone, modafinil, nevirapine, oxcarbazepine, pioglitazone, rifabutin and troglitazone. In preferred embodiments, the CYP3A and / or P-gp inducer is carbamazepine. In preferred embodiments, the use of compound (1) in the treatment of cancer avoids the concomitant use or co-administration of carbamazepine. In preferred embodiments, the use of compound (1) in the treatment of cancer is contraindicated by the concomitant use or co-administration of carbamazepine. In preferred embodiments, the use of carbamazepine is reduced by the concomitant use or co-administration of compound (1) in the treatment of cancer. Carbamazepine is a CYP3A inducer, particularly it is a strong inducer of CYP3A4 / 5, an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, P-gp, UGT and MRP2. Therefore, certain embodiments of the invention may additionally apply to inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT and / or MRP2, beyond CYP3A and / or P-gp. “UGT” refers to the UDP-glucuronosyltransferase superfamily, all members are included in the term “UGT” as used herein. “MRP2” refers to a multidrug resistance protein (MRPs), belonging to the family of ATP- binding cassette (ABC) transporters. It is encoded by the gene ABCC2. In preferred embodiments, the use of a therapeutically effective amount of compound (1) in the treatment of cancer avoids the concomitant use or co-administration of a therapeutically effective amount of carbamazepine. In preferred embodiments, the use of a therapeutically effective amount of compound (1) in the treatment of cancer is contraindicated by the concomitant use or co-administration of a therapeutically effective amount of carbamazepine. In preferred embodiments, the use of a therapeutically effective amount of carbamazepine is reduced by the concomitant use or co-administration of a therapeutically effective amount of compound (1) in the treatment of cancer. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of compound (1) and avoids the concomitant administration or co-administration of carbamazepine. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of compound (1) and contraindicates the concomitant use or co-administration of carbamazepine. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of compound (1) and reduces the concomitant use or co-administration of carbamazepine. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and avoids the concomitant administration or co-administration of a therapeutically effective amount of carbamazepine. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and contraindicates the concomitant use or co-administration of a therapeutically effective amount of carbamazepine. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and reduces the concomitant use or co-administration of a therapeutically effective amount of carbamazepine. In preferred embodiments, the use of compound (1) in the treatment of cancer avoids the concomitant use or co-administration of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, the use of compound (1) in the treatment of cancer is contraindicated by the concomitant use or co-administration of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, the use of carbamazepine is reduced for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days prior the concomitant use or co-administration of compound (1) in the treatment of cancer. In preferred embodiments, the use of a therapeutically effective amount of compound (1) in the treatment of cancer avoids the concomitant use or co-administration of a therapeutically effective amount of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, the use of a therapeutically effective amount of compound (1) in the treatment of cancer is contraindicated by the concomitant use or co-administration of a therapeutically effective amount of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, the use of a therapeutically effective amount of carbamazepine is reduced for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days prior to the concomitant use or co-administration of a therapeutically effective amount of compound (1) in the treatment of cancer. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of compound (1) and avoids the concomitant administration or co-administration of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of compound (1) and contraindicates the concomitant use or co- administration of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of compound (1) and reduces the concomitant use or co-administration of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days prior to the administration of compound (1). In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and avoids the concomitant administration or co-administration of a therapeutically effective amount of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and contraindicates the concomitant use or co-administration of a therapeutically effective amount of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and reduces the concomitant use or co-administration of a therapeutically effective amount of carbamazepine for a time interval of at least 3 days, at least 7 days, at least 14 days, or at least 21 days prior to the administration of compound (1). In preferred embodiments, the use or method as defined above comprises no administration of a CYP3A and / or P-gp modulator. According to an aspect of the invention, it is provided compound (1) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the use comprises administering no CYP3A and / or P-gp modulator. Alternatively, provided herein is a method of treating a patient suffering from cancer comprising the administration of compound (1) and no administration of a CYP3A and / or P-gp modulator. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and no administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator. Alternatively, compound (1) for use in the treatment of cancer comprises the administration of a therapeutically effective amount of compound (1) and no administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator. In preferred embodiments, the use comprises no administration of a CYP3A and / or P-gp modulator for a time interval. Alternatively, the method comprises no administration of a CYP3A and / or P-gp modulator for a time interval. Preferably, said time interval is as defined herein, for instance it is of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of compound (1) and no administration of carbamazepine. Alternatively, compound (1) for use in the treatment of cancer comprises the administration of compound (1) and no administration of carbamazepine. In preferred embodiments, a method of treating a patient suffering from cancer comprises the administration of a therapeutically effective amount of compound (1) and no administration of a therapeutically effective amount of carbamazepine. Alternatively, the use of compound (1) in the treatment of cancer comprises the administration of a therapeutically effective amount of compound (1) and no administration of a therapeutically effective amount of carbamazepine. It is also a purpose of the present invention to provide a safe and efficacious medical use and method of treatment for the co-administration of compound (1) or a pharmaceutical composition comprising compound (1) and other drugs like CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers. In such cases compound (1) or a pharmaceutical composition comprising compound (1) is administered to patients that are concomitantly using other drugs like CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers. This medical use or method of treatment is especially helpful in the treatment of cancer. All embodiments described herein directed to “avoiding” or “contraindicating” modulators, equally apply to a “combination”, “co-administration”, “concomitant use” or “concurrent administration” of compound (1) and CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately or sequentially. Preferably, compound (1) and the CYP3A and / or P-gp modulator are each administered at least once within a period of 14 days. According to another aspect is provided a pharmaceutical combination comprising: (i) Compound (1) as defined herein or a pharmaceutically acceptable salt thereof; and (ii) a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof; wherein (i) and (ii) are administered simultaneously, separately or sequentially. Preferably, said pharmaceutical combination is for use in treating or preventing cancer. Preferably, compound (1) and the CYP3A and / or P-gp modulator are each administered at least once within a period of 14 days. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. Preferably, compound (1) and the CYP3A and / or P-gp modulator are each administered at least once within a period of 14 days. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is decreased in case that compound (1) is administered in combination with CYP3A and / or P- gp modulator or a pharmaceutically acceptable salt thereof. The decrease in daily dose is intended with respect to the standard dose of compound (1), said decrease resulting in particular a daily dose of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, preferably a daily dose of 120 mg or 240 mg. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is decreased below 240 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is decreased below 240 mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is decreased to 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg or 200 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is decreased to 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg or 200 mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is decreased below 120 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is decreased below 120 mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is decreased to 30 mg, 60 mg or 100 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is decreased to 30 mg, 60 mg or 100 mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is increased in case that compound (1) is administered in combination with CYP3A and / or P- gp modulator or a pharmaceutically acceptable salt thereof. The increase in daily dose is intended with respect to the standard dose of compound (1), said increase resulting in particular a daily dose of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, preferably a daily dose of 120 mg or 240 mg. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is increased above 240 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is increased above 240 mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is increased to 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is increased to 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is increased above 120 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is increased above 120 mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided a method of treating and / or preventing cancer, wherein said method comprises administering compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, wherein the daily dose of administered compound (1) is increased to 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg in case that compound (1) is administered in combination with CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. According to another aspect is provided compound (1) as defined within this application or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the daily dose of administered compound (1) is increased to 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg mg in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator or a pharmaceutically acceptable salt thereof. Pharmaceutical composition Provided herein is a pharmaceutical composition comprising compound (1) as defined below and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Alternatively, a method of treating a patient suffering from cancer is disclosed, comprising administering a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient and wherein the method comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Preferably, in these embodiments, compound (1) is administered according to the doses and dose regimes described hereinbelow. All embodiments described herein 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 wherein the use or method comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Within a preferred embodiment, provided herein is a pharmaceutical composition comprising compound (1) as depicted above and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp inducer. Alternatively, a method of treating a patient suffering from cancer is disclosed, comprising administering a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient and wherein the method comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp inducer. Also provided herein is a pharmaceutical composition comprising compound (1) as depicted above and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein the use comprises co-administration, concomitant use or a combination of compound (1) and a CYP3A and / or P-gp modulator. Alternatively, a method of treating a patient suffering from cancer is disclosed, comprising administering a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient and wherein the method comprises co-administration, concomitant use or a combination of compound (1) and a CYP3A and / or P-gp modulator. Preferably, in these embodiments, compound (1) is administered according to the doses and dose regimes described hereinbelow. All embodiments described herein 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 wherein the use or method comprises co-administration, concomitant use or a combination of compound (1) and a CYP3A and / or P-gp modulator. Within a preferred embodiment, provided herein is a pharmaceutical composition comprising compound (1) as depicted above and at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein the use comprises co-administration, concomitant use or a combination of compound (1) and a CYP3A and / or P-gp inducer. Alternatively, a method of treating a patient suffering from cancer is disclosed, comprising administering a pharmaceutical composition comprising compound (1) as defined above and at least one pharmaceutically acceptable excipient and wherein the method comprises co-administration, concomitant use or a combination of compound (1) and a CYP3A and / or P-gp inducer. The term “pharmaceutically acceptable excipient” refers to a non-toxic component that does not destroy the pharmacological activity of the compound with which it is formulated. The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that may be used in the compositions of this invention include fillers, disintegrants, glidants, lubricants, and coating agents. The compositions may comprise 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. In a preferred embodiment, 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. In preferred embodiments, compound (1) or the pharmaceutical composition is in the form of a tablet. Use for treatment of cancer As used 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. As used herein, 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. In an embodiment compound (1) is provided in the dose regime as described herein for use in the treatment and / or prevention of cancer, wherein the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. 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 method comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. In an embodiment, 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 method comprises concomitant use or co-administration of a CYP3A and / or P-gp modulator. In an embodiment, 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 and the administration of a therapeutically effective amount of a CYP3A and / or P-gp modulator or a pharmaceutical composition comprising a CYP3A and / or P-gp modulator. A further aspect relates to compound (1) for use in the treatment and / or prevention of cancer, wherein the use comprises the step of administering compound (1) and concomitant use or co- administration of a CYP3A and / or P-gp modulator in the dose regime described herein or the administration of a pharmaceutical composition in the dose regime described herein. In embodiments, the cancer or tumor comprises a HER2 aberration. This means that the cells of the cancer or tumor harbor an aberration of HER2. As used herein, 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. in the tyrosine kinase domain, in exon 20, etc.) as well as gene rearrangements of HER2 and / or NRG1. When the cancer comprises a HER2 aberration, it can be referred to as HER2 aberrant. When the cancer comprises an overexpression of the HER2 protein, it can be referred to as HER2 overexpressed. When the cancer comprises an amplification of the HER2-encoding gene, it can be referred to as HER2 amplified. When the cancer comprises a mutation in the HER2- encoding gene and / or in the HER2 protein, it can be referred to as HER2 mutant. In embodiments, the cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant. In embodiments, the cancer comprises a mutation in the tyrosine kinase domain of HER2. In embodiments, the cancer is HER2 exon 20 mutant cancer. In embodiments, the cancer comprises a gene rearrangement of HER2 and / or NRG1. “HER2 overexpressed” as used herein 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. “HER2 amplified” as used herein 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 HER2 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. 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” as used herein 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. In embodiments of said HER2 mutant cancer, the mutation is a non-synonymous mutation. As used herein, the term “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. In embodiments of said HER2 mutant cancer, the mutation is a somatic mutation. As used herein, 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. In embodiments of said HER2 mutant cancer, the mutation is a non-synonymous somatic mutation. In embodiments of said HER2 mutant cancer, the mutation is a non-synonymous somatic mutation in the tyrosine kinase domain of HER2. In embodiments of said HER2 mutant cancer, the mutation is in the tyrosine kinase domain of HER2, in particular in the exon 20 of HER2. In the latter case, the cancer can be referred to as HER2 exon 20 mutant. As used herein, “HER2 mutant” may also refer to a rearrangement involving the HER2 gene ERBB2 and / or the NRG1 gene. As used herein, 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_delinsIC; p.A776_V777delinsCVC; p.V777_insE; V777_G778insV; p.V777_G778insC; p.V777_G778insCG; p.V777_S779dup; p.V777L; p.V777M; p.G778_P780dup (GSP); p.G778_S779insCPG; p.G778_S779insG; p.G776_delinsVC; p.G776_V777delinsAVGCV; p.G776delinsLC; p.G776_V777delinsAVCV; p.G776delinsVV; p.G776_V777insL; p.G776_V777insVGC; p.G776C; p.G776A; p.G776L; p.G776V; p.P780_Y781insGSP (“p.” is referring to the HER2 protein). In addition 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). Of these, examples of tyrosine kinase mutations include: p.G727A; p.T733I; p.L755S; p.L755A; p.L755F; p.L755P; p.L755S; p.V842I; p.D769Y; p.D769H; p.I767M; p.L869R; p.L869R; p.T733I; p.T862A; p.V697L. In embodiments, 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 (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); 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, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma); cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g. tumors / carcinomas / cancers of the esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g. childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), appendix; genitourinary system (including kidney, e.g. 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, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; sarcomas of the bone: e.g. 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. acoustic), spinal axis tumors; peripheral nervous system cancer; lymphomas and leukemias: e.g. B-cell non-Hodgkin lymphomas (NHL) (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 leukemia (BchlorineL), chronic T-cell lymphocytic leukemia (TchlorineL) B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin´s disease (HD) (including nodular lymphocyte predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed- cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous / myeloid leukemia (AML), acute lymphatic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphatic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML); cancers of unknown primary site (CUP). All 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. Preferably, 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 histopathological classification: 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; 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. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is manifested by at least one solid tumor. In some embodiments, 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. Preferably, said brain cancer is a glioblastoma or a glioma. Preferably, said breast cancer is lobular breast cancer. In addition or in alternative, said breast cancer is preferably metastatic. Preferably, said endocrine cancer is nerve sheath tumor, more preferably HER2 mutant nerve sheath tumor. Preferably, said gastrointestinal cancer is selected from the group consisting of anal cancer, appendix cancer, biliary tract cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophagus tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, liver cancer, pancreatic cancer and small bowel cancer. Preferably, said genitourinary system cancer is selected from the group consisting of bladder cancer, kidney cancer and prostate cancer. In addition or in alternative, said gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably HER2 mutant. Still preferably, said gastrointestinal cancer is selected from the group consisting of gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and esophageal adenocarcinoma, in particular metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma and metastatic esophageal adenocarcinoma. Preferably, said gynecologic cancer is selected from the group consisting of cervical cancer, uterine cancer, endometrial cancer and ovarian cancer. As used herein, “head and neck tumor” preferably refers to a head and neck cancer. Preferably, said head and neck tumor is a salivary gland cancer or tumor. Preferably, said lung cancer is non-small cell lung cancer (NSCLC). Preferably, said nervous system cancer is peripheral nervous system cancer, more preferably HER2 amplified peripheral nervous system cancer. Preferably, said skin cancer is not a melanoma, i.e. non-melanoma skin cancer. In some embodiments, 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. In some embodiments, 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 (NSCLC), peripheral nervous system cancer and non-melanoma skin cancer. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In embodiments, the cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant (in particular HER2 exon 20 mutant) cancer selected from 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. In other embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer or lung cancer. In further embodiments, the cancer is selected from cancers / tumors / carcinomas of the lung: e.g. non- small 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). In still further embodiments, the cancer is NSCLC. In still further embodiments, the cancer is HER2 exon 20 mutant NSCLC. In further embodiments, the cancer is unresectable. In still further embodiments, the cancer is unresectable HER2 exon 20 mutant NSCLC. In a preferred embodiment 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 alternatively, said cancer can be unresectable. In a preferred embodiment 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. In a preferred embodiment 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. In a preferred embodiment 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. In an embodiment, the cancer is advanced, unresectable or metastatic NSCLC harbouring a HER2 mutation, wherein said HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, compound (1) is administered as first line of therapy. Still preferably, in this embodiment, compound (1) as described herein is administered as second or further line of therapy. In embodiments, the cancer is HER2 positive metastatic breast cancer. Preferably, in this embodiment, compound (1) as described herein is administered as first line of therapy. Still preferably, in this embodiment, compound (1) as described herein is administered as second or further line of therapy. In embodiments, the cancer is HER2 positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, compound (1) as described herein is administered as first line of therapy. Still preferably, in this embodiment, compound (1) as described herein is administered as second or further line of therapy. Compound (1) Doses It is a purpose of the present invention to provide a safe and efficacious dose regime for the administration of compound (1) or a pharmaceutical composition comprising compound (1) in the described dose regime while avoiding other drugs like a CYP3A and / or P-gp modulator. This dose regime is especially helpful for use in the treatment of cancer. In addition, 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. In addition, 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. It is also a purpose of the present invention to provide a safe and efficacious dose regime for the co-administration of compound (1) or a pharmaceutical composition comprising compound (1) and other drugs like CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers. In such cases compound (1) or a pharmaceutical composition comprising compound (1) is administered to patients that are concomitantly using other drugs like CYP3A and / or P- gp modulators, especially CYP3A and / or P-gp inducers. This dose regime is especially helpful for use in the treatment of cancer. All embodiments in this section directed to “avoiding” or “contraindicating” modulators, equally apply to a “combination”, “co-administration” or “concomitant use” of compound (1) and CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers. As used herein “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. As used herein “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. In one aspect, it was surprisingly discovered that the use of compound (1) in the treatment of cancer in a daily dose of at least 30 mg is safe and efficacious as described above and in the example below in case that the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. In another aspect, it was surprisingly discovered that the use of compound (1) in the treatment of cancer in a daily dose of at least 30 mg is safe and efficacious as described above and in the example below in case that the use comprises concomitant use or co-administration of a CYP3A and / or P-gp modulator. The embodiments described below, especially referring to daily doses, dose schedules and the like, can be applied to each of the two aspects described in the previous two paragraphs. In preferred embodiments, compound (1) is administered in a daily dose of at least 60 mg. In preferred embodiments, compound (1) is administered in a daily dose of at least 60 mg and a CYP3A and / or P-gp modulator is administered in a daily dose of at least 100 mg. In preferred embodiments, compound (1) is administered in a daily dose of at least 80 mg. In preferred embodiments, compound (1) is administered in a daily dose of at least 120 mg. In preferred embodiments, compound (1) is administered in a daily dose of at least 180 mg. In preferred embodiments, compound (1) is administered in a daily dose of at least 200 mg. In preferred embodiments, compound (1) is administered in a daily dose of at least 240 mg. In preferred embodiments, compound (1) is administered in a daily dose of at least 300 mg. In preferred embodiments, compound (1) is administered in a daily dose of 30 mg to 600 mg. In preferred embodiments, compound (1) is administered in a daily dose of 60 mg to 600 mg. In preferred embodiments, compound (1) is administered in a daily dose of 80 mg to 600 mg. In preferred embodiments, compound (1) is administered in a daily dose of 120 mg to 600 mg. In a further preferred embodiment, compound (1) is administered in a daily dose of 30 mg to 300 mg. In a further preferred embodiment, compound (1) is administered in a daily dose of 30 mg to 300 mg. In a further preferred embodiment, compound (1) is administered in a daily dose of 60 mg to 300 mg. In a further preferred embodiment, compound (1) is administered in a daily dose of 80 mg to 300 mg. In a further preferred embodiment, compound (1) is administered in a daily dose of 120 mg to 300 mg. In preferred embodiments, 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 preferred embodiments, 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. In preferred embodiments, 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. In preferred embodiments, compound (1) is administered in a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg or 300 mg. In preferred 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. In preferred embodiments, compound (1) is administered in a daily dose of 120 mg or 240 mg. In preferred embodiments, compound (1) is administered in a daily dose of 30 mg. In preferred embodiments, compound (1) is administered in a daily dose of 60 mg. In preferred embodiments, compound (1) is administered in a daily dose of 80 mg. In preferred embodiments, compound (1) is administered in a daily dose of 120 mg. In preferred embodiments, compound (1) is administered in a daily dose of 180 mg. In preferred embodiments, compound (1) is administered in a daily dose of 200 mg. In preferred embodiments, compound (1) is administered in a daily dose of 240 mg. In preferred embodiments, compound (1) is administered in a daily dose of 300 mg. In preferred embodiments, compound (1) is administered in a daily dose of 360 mg. In preferred embodiments, compound (1) is administered in a daily dose of 400 mg. In preferred embodiments, compound (1) is administered in a daily dose of 420 mg. In preferred embodiments, compound (1) is administered in a daily dose of 480 mg. In preferred embodiments, compound (1) is administered in a daily dose of 500 mg. In preferred embodiments, compound (1) is administered in a daily dose of 540 mg. In preferred embodiments, compound (1) is administered in a daily dose of 600 mg. Within a preferred embodiment, 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 points at that day, i.e. within 24 h. When compound (1) is administered twice daily, the two separate administrations are preferably separated by a time interval of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours, preferably 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. In a preferred embodiment, compound (1) is administered once daily. In a preferred embodiment, compound (1) is administered as a single dose every 24 h. In a preferred embodiment, compound (1) is administered once or 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. In a further preferred embodiment, 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 of e.g. at least 1, 2, 3, 4, 5, 6 or 7 days is included. In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg. In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg. In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg or compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg and a CYP3A and / or P-gp modulator is administered once daily in a daily dose of 200 mg, 300 mg, 400 mg, 500 mg or 600 mg. In some embodiments, 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. In some embodiments, 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. In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg. In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg. In some embodiments, compound (1) is administered once daily in a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg. In some embodiments, compound (1) is administered once daily in a daily dose of 120 mg or 240 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 60 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 120 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 180 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 240 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 300 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 360 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 400 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 420 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 480 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 500 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 540 mg. In preferred embodiments, compound (1) is administered once daily in a daily dose of 600 mg. In some embodiments, 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. In some embodiments, 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. In some embodiments, compound (1) is administered twice daily in a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 30 mg. Preferably, in this embodiment, each of the two daily administrations is of 15 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 60 mg. Preferably, in this embodiment, each of the two daily administrations is of 30 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 120 mg. Preferably, in this embodiment, each of the two daily administrations is of 60 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 200 mg. Preferably, in this embodiment, each of the two daily administrations is of 100 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 300 mg. Preferably, in this embodiment, each of the two daily administrations is of 150 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 360 mg. Preferably, in this embodiment, each of the two daily administrations is of 180 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 400 mg. Preferably, in this embodiment, each of the two daily administrations is of 200 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 420 mg. Preferably, in this embodiment, each of the two daily administrations is of 210 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 480 mg. Preferably, in this embodiment, each of the two daily administrations is of 240 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 500 mg. Preferably, in this embodiment, each of the two daily administrations is of 250 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 540 mg. Preferably, in this embodiment, each of the two daily administrations is of 270 mg. In preferred embodiments, compound (1) is administered twice daily in a daily dose of 600 mg. Preferably, in this embodiment, each of the two daily administrations is of 300 mg. In embodiments, compound (1) is administered orally. In embodiments, compound (1) is administered as a tablet. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 200 mg, 300 mg, 400 mg, 500 mg or 600 mg. In some embodiments, 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. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 60 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 120 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 180 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 240 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 300 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 360 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 400 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 420 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 480 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 500 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 540 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 600 mg. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 30 mg. Preferably, in this embodiment, each of the two daily administrations is of 15 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 60 mg. Preferably, in this embodiment, each of the two daily administrations is of 30 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 120 mg. Preferably, in this embodiment, each of the two daily administrations is of 60 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 200 mg. Preferably, in this embodiment, each of the two daily administrations is of 100 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 300 mg. Preferably, in this embodiment, each of the two daily administrations is of 150 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 360 mg. Preferably, in this embodiment, each of the two daily administrations is of 180 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 400 mg. Preferably, in this embodiment, each of the two daily administrations is of 200 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 420 mg. Preferably, in this embodiment, each of the two daily administrations is of 210 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 480 mg. Preferably, in this embodiment, each of the two daily administrations is of 240 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 500 mg. Preferably, in this embodiment, each of the two daily administrations is of 250 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 540 mg. Preferably, in this embodiment, each of the two daily administrations is of 270 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, twice daily in a daily dose of 600 mg. Preferably, in this embodiment, each of the two daily administrations is of 300 mg. In a preferred embodiment, it is also possible to combine above defined dose regimes for compound (1) and to alter the daily doses in the course of the treatment. Therefore, it is for instance possible to start the treatment by administering a daily dose of 30 mg (once or twice daily) and to switch the dose to higher or lower daily doses (applied once or twice daily). In some embodiments, compound (1) is administered orally, preferably as a tablet, once or twice daily in a daily dose of 60 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 200 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once or twice daily in a daily dose of 60 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 200 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once or twice daily in a daily dose of 60 mg and a CYP3A and / or P-gp modulator is administered orally , preferably as a tablet, once daily in a daily dose of 400 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once or twice daily in a daily dose of 60 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 400 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once or twice daily in a daily dose of 60 mg and a CYP3A and / or P-gp modulator is administered orally , preferably as a tablet, once daily in a daily dose of 600 mg. Alternatively, the method of treating a patient suffering from cancer comprises administering compound (1) orally, preferably as a tablet, once or twice daily in a daily dose of 60 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 600 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once or twice daily in a daily dose of 120 mg or 240 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 200 mg. Alternatively, 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 and a CYP3A and / or P- gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 200 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 120 or 240 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 400 mg. Alternatively, 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 or 240 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 400 mg. In some embodiments, compound (1) is administered orally, preferably as a tablet, once daily in a daily dose of 120 or 240 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 600 mg. Alternatively, 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 or 240 mg and a CYP3A and / or P-gp modulator is administered orally, preferably as a tablet, once daily in a daily dose of 600 mg. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The example which follows serve to illustrate the invention in more detail but does not constitute a limitation thereof. Example 1: A study in healthy men to test whether carbamazepine influences the amount of compound (1) in the blood The involvement of the seven major hepatic CYP isoforms in the metabolism of compound (1) was assessed in human liver microsomes (HLM) treated with selective inhibitors of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 / 5. Based on these data, CYP3A4 / 5 is primarily responsible for the hepatic oxidative metabolism of compound (1). In addition, zongertinib is considered a weak substrate of P-gp. Thus, concomitant medication with inducers of CYP3A and / or P-gp could cause clinically relevant decreases of the plasma exposure of compound (1). It is therefore necessary to investigate the effect of an inducer of CYP3A and / or P-gp on the pharmacokinetics of compound (1) in plasma to establish concomitant treatment recommendations. The main objective of this trial is to investigate the effect of multiple oral doses of the strong CYP3A inducer carbamazepine on the pharmacokinetics of a single dose of compound (1) in plasma. Carbamazepine is an anticonvulsant medication indicated, amongst other indications, for the treatment of epilepsy and neuropathic pain. After oral administration, carbamazepine is slowly and nearly completely absorbed. Pharmacokinetic steady state is reached after 2 to 8 days. Plasma protein binding is between 70 and 80%. Carbamazepine is oxidated, desaminated, hydroxylated and esterified with glucuronic acid in the liver. After a single dose, carbamazepine t1 / 2 is approximately 36 hours. After multiple doses, t1 / 2 is reduced due to enzyme induction by about 50%. Therapeutic carbamazepine doses are usually given once (q.d.) or twice (b.i.d.) daily and range between 400 and 1200 mg per day. A maximal daily dose of 1600 mg should usually not be exceeded as higher doses are associated with a higher risk for side effects. It is recommended to take the extended release tablets together with or after a meal. The primary endpoints include the determination of the following pharmacokinetic parameters for compound (1): ^ AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) ^ Cmax(maximum measured concentration of the analyte in plasma) The secondary endpoint includes the determination of the following pharmacokinetic parameter for compound (1): ^ AUC0-tz(area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) Further pharmacokinetic endpoints are calculated as appropriate. Besides the pharmacokinetic parameters other safety parameters are assessed during the trial. The safety parameters include routine laboratory tests (e.g. haematological or coagulation parameters), electrocardiograms, skin inspection and neurological examinations (general level of arousal, orientation, eye movement, pupil size and pupil reactivity, reflexes, assessment of muscle strength, gait, Romberg test, tremor, point-to-point movements, sensitivity). The trial is performed as an open-label, two-treatment, two-period, fixed-sequence crossover trial in healthy male subjects in order to compare the test treatment (T) to the reference treatment (R). The treatments are: ^ Treatment R: One oral single dose of 60 mg compound (1) administered as film-coated tablet alone ^ Treatment T: One oral single dose of 60 mg compound (1) administered as film-coated tablet together with multiple oral doses of carbamazepine (doses titrated from 200 mg q.d. over 400 mg q.d. to 600 mg q.d.) Compound (1) is administered in the fasted state, and carbamazepine is administered after a dinner. Administration of compound (1) is performed after subjects have fasted overnight; fasting is to start no later than 10 h before the scheduled dosing. Administration of carbamazepine is performed after a dinner. It is acceptable if the dinner is only partly consumed. In the first treatment period (Period 1 = Visit 2), all subjects undergo treatment R, and in the second treatment period (Period 2 = Visit 3), all subjects undergo treatment T. Visit 3 follows immediately after Visit 2, i.e. Day 8 is the last day of Visit 2, and Day 8 of Visit 2 is the same day as Day -19 of Visit 3. Treatment periods Each subject participates in 2 treatment periods (Period 1: Days -1 to 8; Period 2: Days -19 to 8). Day 8 of Period 1 is the same day as Day -19 of Period 2. An overview of the trial design is provided in Figure 1(A). The following inclusion criteria apply: ^ Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests; ^ Age of 18 to 50 years (inclusive); ^ Body mass index (BMI) of 18.5 to 29.9 kg / m2(inclusive); ^ Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial. The following exclusion criteria apply: ^ Any finding in the medical examination (including BP, PR or ECG, the neurological examination, or the skin inspection) deviating from normal and assessed as clinically relevant by the investigator; ^ Repeated measurement of systolic blood pressure outside the range of 90 to 140 millimetre(s) of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 beats per minute (bpm); ^ Any laboratory value outside the reference range that the investigator considers to be of clinical relevance; ^ Any evidence of a concomitant disease assessed as clinically relevant by the investigator; ^ Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders; ^ Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair); ^ Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders; ^ History of relevant orthostatic hypotension, fainting spells, or blackouts; ^ Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT / QTc interval prolongation or any kind of vaccination). Further exclusion criteria apply. Selection of doses in the trial The doses of carbamazepine selected for this trial reflect standard clinical doses and are considered sufficient to yield significant CYP3A induction. The titration scheme has been used successfully in a previous study, with the modification that in the current study carbamazepine administration is q.d. instead of b.i.d. This is because the tolerability of carbamazepine is expected to be improved if dosed only in the evening. The dose of compound (1) selected for this trial, a dose of 60 mg compound (1), is expected to result in plasma concentrations that are in the range of concentrations that were explored so far in a previous trial and that were associated with good safety and tolerability. Blood sampling for pharmacokinetic analysis Blood Sampling Overview Table 1 provides an overview about compound (1) blood samplings. Trial Period Day Number of blood samplings PK compound (1) blood samplings Period 1 Day 1 11 Day 2 2 Day 3 1 Day 4 1 Day 6 1 Day 8 1 Period 2 Day 1 11 Day 2 2 Day 3 1 Day 4 1 Day 6 1 Day 8 1 Total number of PK compound (1) blood samplings: 34 Table 1 Table 2 provides an overview about carbamazepine blood samplings. Trial Period Day Number of blood samplings PK carbamazepine blood samplings Period 2 Day -18 1 Day -12 1 Day -7 1 Day -5 1 Day -3 1 Day -1 1 Day 2 1 Day 4 1 Day 7 1 Total number of PK carbamazepine blood samplings: 9 Table 2 Sample preparation The quantitative determination of compound (1) and carbamazepine is performed in plasma. For quantification of compound (1) and carbamazepine concentrations in plasma, 2.7 mL of blood is drawn from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in Table 1 for compound (1) and Table 2 for carbamazepine. Blood is withdrawn by means of either an indwelling venous catheter or by venipuncture with a metal needle. For the quantitative determination of compound (1) and carbamazepine the EDTA- anticoagulated blood samples are centrifuged for approximately 10 min at approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots are obtained and stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The process from blood collection until transfer of plasma aliquots into the freezer should be completed within 60 min (carbamazepine) or within 120 min (compound (1)), respectively, with interim storage of blood samples and aliquots at room temperature. The time each aliquot was placed in the freezer is documented. Until transfer on dry ice to the analytical laboratory, the aliquots are stored upright at approximately -20°C or below at the trial site. The second aliquot is transferred to the analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the plasma samples are stored at approximately -20°C or below until analysis. Analytical methods for the quantification of compound (1) and carbamazepine Compound (1) and carbamazepine concentrations in plasma are determined by a validated LC- MS / MS (liquid chromatography tandem mass spectrometry) assay. Statistical analyses are based on the following analysis sets: ^ Treated set (TS): The treated set includes all subjects who were treated with at least one dose of compound (1) or carbamazepine. The treated set will be used for safety analyses. ^ Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability (as specified in the following subsection ‘Pharmacokinetics’). Thus, a subject is included in the PKS, even if he contributes only one PK parameter value for one period to the statistical assessment. Descriptive and model-based analyses of PK parameters are based on the PKS. The extent of the drug-drug interaction is estimated by the ratios of the geometric means (test / reference) for the primary and secondary endpoints. Additionally, their two-sided 90% confidence intervals (CIs) are provided. This method corresponds to the two one-sided t-test procedure, each at a 5% significance level. Since the main focus is on estimation and not testing, a formal hypothesis test and associated acceptance range is not specified. The statistical model is an analysis of variance (ANOVA) on the logarithmic scale including effects for subject and treatment. CIs are calculated based on the residual error from the ANOVA. Descriptive statistics are calculated for all endpoints. Example 2: The effect of carbamazepine, a strong CYP3A inducer, on the pharmacokinetics of zongertinib in healthy male volunteers Abstract INTRODUCTION: Zongertinib is a potent, selective, and EGFR wild type sparing HER2 inhibitor. Based on in vitro data, the oxidative hepatic metabolism of zongertinib is principally driven by CYP3A4 / 5. Therefore, zongertinib may be a victim of strong CYP3A inducers, like carbamazepine. OBJECTIVE: This study aimed to investigate the effect of multiple oral doses of carbamazepine on the pharmacokinetics of a single oral dose of zongertinib in healthy male subjects. METHODS: This open-label, two-period, fixed-sequence clinical drug-drug interaction study examined the pharmacokinetics of a single 60 mg oral dose of zongertinib in the absence (R) or presence (T) of multiple oral doses of carbamazepine. The extent of drug-drug interaction was estimated using the adjusted geometric mean ratios of T versus R (GMR) and 90% confidence intervals (CIs) for areas under the plasma concentration-time curve from time 0 to infinity and to the last quantifiable time point (AUC0-∞, AUC0-tz) and maximum measured plasma concentration (Cmax). RESULTS: Sixteen subjects (all Caucasian males) received zongertinib alone in Period 1, and 15 of them received both zongertinib and carbamazepine in Period 2. Upon co-administration with carbamazepine, the AUC of zongertinib was reduced to 36.5% (GMR for AUC0-∞ and AUC0-tz), and the 90% CI was 32.0% to 41.6% for AUC0-∞ and 31.9% to 41.7% for AUC0-tz. The Cmaxof zongertinib was reduced to 56.4% (90% CI: 45.1% to 70.6%). CONCLUSION: Zongertinib exposure was moderately reduced when co-administered with the strong CYP3A inducer, carbamazepine. Key words ^ Drug interaction ^ Zongertinib ^ Pharmacokinetics ^ Non-small cell lung cancer • Tyrosine kinase inhibitor ^ Carbamazepine ^ Enzyme induction Introduction Human epidermal growth factor receptor 2 (HER2, also known as NEU, EGFR2, encoded by ERBB2) is a member of the epidermal growth factor receptor (EGFR) gene family of receptor tyrosine kinases. HER2 signalling is initiated upon heterodimerization with other EGFR family members or homodimerization under high HER2 concentrations, leading to a downstream phosphorylation signalling cascade involved in cell growth, proliferation, and differentiation.1–4HER2 is a well-recognized oncogenic target. In addition to HER2 amplification and overexpression, which have been successfully targeted in many cancer types such as breast and gastric cancers, activating-mutations in HER2 are identified as a distinct oncogenic driver and therapeutic target.1,2,5–8HER2 mutations have been identified in up to 4% of non-small cell lung cancer (NSCLC).1,2,9–14The most commonly identified mutation is in-frame insertion YVMA (p.A775_G776insYVMA) in exon 20.2,5,15Currently, there are only limited targeted therapy options for NSCLC with HER2 aberrations,16while conventional chemotherapy-based treatment options, associated with significant dose-limiting toxicity and inferior long-term efficacy, continue to be part of the first-line recommendations for patients with HER2-mutated NSCLC.14Clinically approved and investigated tyrosine kinase inhibitors are non-selective to HER2 and limited by EGFR wild type mediated dose limiting toxicity, highlighting the unmet medical need for NSCLC patients with HER2 insertion mutations.17Zongertinib is a highly potent and selective HER2 tyrosine kinase inhibitor based on in vitro testing. It covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions, while sparing wild type EGFR. It is being investigated in the Phase I Beamion LUNG-1 study (NCT04886804) in patients with HER2 aberration-positive solid tumors at multiple dose levels.18Zongertinib is being further investigated in the Phase III Beamion LUNG-2 study (NCT06151574) in patients with advanced NSCLC harboring HER2 mutations. Zongertinib is a low clearance drug. Based on identified metabolites generated when radiolabelled zongertinib was incubated with human hepatocytes, zongertinib is primarily metabolized via oxidation (48-62% of total metabolism), glucuronidation (13-25% of total metabolism), and glutathione conjugation (13-26% of total metabolism). In follow-up in vitro studies using human liver microsomes and recombinant enzymes, it was determined that CYP3A4 / 5 is primarily responsible for hepatic oxidative metabolism. In addition, zongertinib is considered a weak substrate of efflux transporters, P-glycoprotein (P-gp) and breast cancer– resistance protein (BCRP). Because CYP3A contributes to 48-62% of total hepatic metabolic clearance in vitro, co-medications that induce CYP3A activity may cause clinically relevant reduction in the plasma exposure of zongertinib. It is therefore important to evaluate the effect of a strong CYP3A inducer on the pharmacokinetics (PK) of zongertinib in human subjects. Carbamazepine, recommended by the U.S. Food and Drug Administration (FDA) as a strong CYP3A inducer, was selected as the perpetrator drug for this clinical drug-drug interaction (DDI) study.19Upon oral administration, carbamazepine is slowly and nearly completely absorbed.20–22As a substrate and inducer of CYP3A4 and 2B6, carbamazepine induces its own metabolism. Its half-life initially ranges from 25 to 65 hours, and with repeated dosing, can be shortened to 12 to 17 hours.21,23Beyond the strong induction effect on CYP3A, carbamazepine was also reported to induce multiple other CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19), UGT enzymes, and transporters P-gp and multidrug resistance protein 2 (MRP2).24,25The most common side effects of carbamazepine include dizziness, drowsiness, ataxia, nausea, and vomiting. A gradual up-titration of the daily dose is often employed to improve drug tolerability.26Endogenous biomarkers including 6β-OH-cortisol to cortisol ratio (6βCR) in urine and 4β-OH-cholesterol (4βHC) in plasma are often employed in DDI studies to assess CYP3A activities in vivo.27–32As the activities of CYP3A increase, there is a corresponding rise in cortisol and cholesterol metabolism, reflected by the rising levels of 6βCR in urine and 4βHC in plasma.29Although they are not quantitative, these endogenous biomarkers provide a minimally invasive and practical method for determining the time course of variations in CYP3A activities during clinical DDI studies.31,32The main objective of this study was to investigate the effect of multiple oral doses of carbamazepine, a strong CYP3A inducer and inducer of UGT enzymes and P-gp, on the PK of a single oral dose of zongertinib in healthy male subjects. Further objectives were to evaluate the carbamazepine plasma concentrations as well as to assess safety and tolerability of zongertinib and carbamazepine. In addition, 6βCR in urine and 4βHC in plasma were sampled frequently during carbamazepine dosing to investigate the time course of CYP3A induction by carbamazepine. Methods Study design This open-label, two-period, fixed-sequence, clinical DDI study (EU CT No. 2022- 503046-50-00; clinicaltrials.gov NCT06028464) in healthy male subjects aimed to compare the test treatment (T) to the reference treatment (R). R was a single oral dose of zongertinib 60 mg film-coated tablet alone on Day 1 of Study Period 1. T was a single oral dose of zongertinib 60 mg administered on Day 1 together with multiple oral doses of carbamazepine from Day -18 to Day 6 of Study Period 2 (Figure 1(B)). Carbamazepine was dosed at 200 mg once daily (QD) for 4 days (Day -18 to Day -15), titrated to 400 mg QD for 7 days (Day -14 to Day -8), and then to a final dose of 600 mg QD for 13 days (Day -7 to Day 6). Zongertinib was orally administered once with 240 mL of water after 10 hours of overnight fasting at approximately 8AM. Carbamazepine was orally administered with 240 mL of water after dinner at approximately 8PM daily. Study design is illustrated in Figure 1(B). Sixteen healthy male subjects with age between 18 to 55 years and a body mass index (BMI) of 18.5 to 29.9 kg / m2were planned to be admitted to the study, after signing and dating written informed consent in accordance with International Council for Harmonization (ICH)- Good Clinical Practice (GCP) and local legislation. Healthy subjects were identified according to the assessment of the investigator, based on a complete medical history including a physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests. Key exclusion criteria included clinically relevant concomitant disease; diseases of the central nervous system and other neurological or psychiatric disorder; surgery of gastrointestinal tract that could interfere with the PK of the trial medication; history of relevant orthostatic hypotension; relevant chronic or acute infection; history of relevant allergy; current smoker; alcohol abuse; drug abuse or positive drug screening; use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial; intake of an investigational drug in another clinical trial within 60 days or within five half-lives, whichever is longer; known Asian ancestry; any lifetime history of suicidal behavior or any suicidal ideation of type 2 to 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the past 12 months; hyponatremia; leukocytes, platelets, or blood hemoglobin below lower limit of normal; alanine transaminase (ALT) and / or aspartate transaminase (AST) exceeding 10% above upper limit of normal. No concomitant therapy was allowed. In case of adverse events (AEs) requiring analgesic treatment such as headache, short-term use of ibuprofen was acceptable. Grapefruits, Seville oranges and their juices, and dietary supplements and products containing St’ John's wort were not permitted from 7 days before the first administration of zongertinib in Period 1 until after the last PK sample of Period 2 was collected. Adverse events and concomitant therapy were assessed continuously from obtaining subject’s written informed consent until the end of trial examination. The study was conducted in compliance with the protocol, the ethical principles described in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for GCP, relevant Boehringer Ingelheim Standard Operating Procedures, the EU regulation 536 / 2014, and other relevant regulations. The study protocol was reviewed and approved by the National Competent Authority (Federal Institute for Drugs and Medical Devices ‘BfArM" - Germany) and an Independent Ethics Committee “Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen” (Essen, Germany). The informed consent documents were reviewed and approved by the Independent Ethics Committee, and all participants provided written informed consent before initiation of study procedures. Pharmacokinetics and Bioanalytical Methods Blood samples for zongertinib concentrations were collected in Periods 1 and 2 at pre- dose and for up to 168 hours after zongertinib dose. Blood samples for carbamazepine trough concentrations were collected throughout Period 2. Urine samples for 6βCR collected over 24- hour intervals and blood samples for 4βHC were collected in parallel to the carbamazepine blood samples in Period 2. Sampling scheme is illustrated in Figure 1(B). All blood samples for analysis of carbamazepine, zongertinib and 4βHC plasma concentrations were collected from an antecubital or forearm vein into EDTA-anticoagulant blood drawing tubes and centrifuged to obtain plasma aliquots. Zongertinib, 4βHC and carbamazepine plasma concentrations and 6β-OH-cortisol and cortisol urine concentrations were determined using validated liquid chromatography coupled with tandem mass spectrometric detection (LC-MS / MS) methods. The calibration curves of undiluted samples were linear over the required range of concentrations. The overall mean accuracy and precision of the quality control (QC) samples met the acceptance criteria. Pharmacokinetic analysis and statistical methods Zongertinib area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC0-∞) and maximum measured plasma concentration (Cmax) were the primary endpoints, and AUC from time 0 to the last quantifiable data point (AUC0-tz) was the secondary endpoint of the study. The extent of the DDI was estimated by the ratios of the geometric mean (gMean) of T versus R (T / R) and their two-sided 90% confidence intervals (CIs) for the primary and secondary endpoints. The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including effects for subject and treatment. Confidence intervals were calculated based on the residual error from the ANOVA. Additional PK parameters including time from dosing to maximum measured plasma concentration (tmax), terminal half-life in plasma (t1 / 2), and apparent clearance in the plasma after oral administration (CL / F) were calculated as further endpoints. Additional further endpoints included safety and tolerability of zongertinib and carbamazepine, plasma concentrations of carbamazepine, urine 6βCR and plasma 4βHC. Descriptive statistics were calculated for all endpoints. PK parameters were calculated using Phoenix WinNonlinTMsoftware (version Phoenix 8.1.1, Certara USA Inc., Princeton, NJ, USA). The statistical analyses were performed using SASTM(current Version 9.4, by SAS Institute Inc., Cary, NC, USA). Results Participants A total of 16 subjects entered the trial and were allocated to the same treatment sequence to receive two treatments in fixed order (R-T). All 16 subjects received the first treatment (R), and 15 subjects received the second treatment (T). One subject did not start the second treatment due to a positive drug test result prior to the second treatment period. No important protocol deviations were reported. All 16 subjects were male and Caucasian. The mean age (standard deviation [SD]; range) of subjects was 41.5 years (11.0; 26 to 55). The mean BMI (SD; range) was 25.9 kg / m2(3.1; 19.6 to 29.9). CYP3A induction by carbamazepine After multiple oral administrations of carbamazepine tablets, titrated from 200 mg QD to 400 mg QD and to a final dose of 600 mg QD, the plasma trough concentrations of carbamazepine steadily increased and peaked at 108 hours prior to zongertinib dose, followed by a shallow decline (Figure 5). Both 6βCR in urine and 4βHC in plasma increased over time during the pretreatment period with carbamazepine (Figure 2). The increase in 6βCR reached plateau at 60 hours prior to zongertinib dose (-60 hours), with gMean percent change from baseline (PCB) ranging from 228% to 250% between -60 hours and 156 hours. The interindividual variability of 6βCR in urine was moderate (gCV: 34.0% to 54.7%). For plasma 4βHC, the increase slowed down at 12 hours prior to the zongertinib dose, with gMean PCB of 332%. The plasma 4βHC slowly inclined until 156 hours, with a final gMean increase of 393%. The plasma 4βHC had low interindividual variability (gCV: 16.3% to 26.3%). Effect of carbamazepine on zongertinib In Period 1, upon a single oral dose of zongertinib 60 mg tablet, plasma concentrations of zongertinib increased rapidly and peaked at 2.0 hours (median tmax; range: 1.0 to 3.0 hours), with gMean Cmax of 914 nmol / L. After reaching the peak, plasma concentrations of zongertinib declined in a multiphasic manner, with gMean CL / F of 151 mL / min and gMean t1 / 2 of 38.7 hours. Upon carbamazepine coadministration in Period 2, plasma concentrations of zongertinib increased rapidly but to a lesser extent than in Period 1, with lower Cmax(gMean 516 nmol / L) but no relevant change in tmax (median: 1.5 hours; range: 1.0 to 4.0 hours). After reaching the peak, plasma concentrations of zongertinib declined faster with carbamazepine coadministration (Figure 3). The gMean CL / F of zongertinib increased to 2.75-fold as high, with a value of 415 mL / min, and the gMean t1 / 2 of zongertinib was shortened from 38.7 hours to 23.9 hours (Table 3). Interindividual variability of the key PK parameters was overall low to moderate in both periods (gCV: 10.7% to 45.1%; Table 3). All zongertinib pre-dose plasma concentrations were below limit of quantification in both periods, indicating sufficient washout between the two periods. Of note, carbamazepine appeared to reduce the intersubject variability (gCV) of zongertinib plasma concentrations (Figure 3). According to model-based analysis via ANOVA, the adjusted gMean ratios (T / R) of AUC0-∞ and AUC0-tz were 36.5% (90% CI: 32.0% to 41.6%) and 36.5% (90% CI: 31.9% to 41.7%), respectively, indicating an approximately 64% reduction in AUC with carbamazepine cotreatment. The adjusted gMean ratio (T / R) of Cmaxwas 56.4% (90% CI: 45.1% to 70.6%), indicating an approximately 44% reduction in Cmax with carbamazepine cotreatment (Figure 4). Table 3: Comparison of pharmacokinetic parameters of a single 60 mg oral dose of zongertinib in absence (R) or presence (T) of multiple doses of carbamazepine. zongertinib alone (R) zongertinib + carbamazepine (T) N = 16 N = 15 Parameter Unit gMean gCV [%] gMean gCV [%] Primary endpoints AUC0-∞[nmol∙h / L] 12300 27.2 4500 14.6 Cmax [nmol / L] 914 45.1 516 28.8 Secondary endpoint AUC0-tz[nmol∙h / L] 12100 27.6 4430 14.8 Selected further pharmacokinetic endpoints tmax[h] 2.0†1.0 to 3.0 1.5†1.0 to 4.0 t1 / 2[h] 38.7 10.7 23.9 26.0 CL / F [mL / min] 151 27.2 415 14.6 †Median value Range: Minimum to Maximum AUC, area under the concentration-time curve of the analyte in plasma; AUC0-∞, AUC over the time interval from 0 to infinity; AUC0-tz, AUC over the time interval from 0 to the last quantifiable data point; CL / F, apparent clearance of the analyte in plasma after oral administration; Cmax, maximum measured concentration of the analyte in plasma; gCV, geometric coefficient of variation; gMean, geometric mean; R, reference; T, test; t1 / 2, terminal half-life of the analyte in plasma; tmax, time from dosing to the maximum measured concentration of the analyte in plasma. Safety results summary Treatment-emergent AEs were reported for 13 out of 16 subjects (81%) in the study, and investigator-defined drug-related AEs were reported for 12 out of 16 subjects (75%) in the study. They were mostly observed in treatment T (i.e., treatment phases with carbamazepine; Tables 4 and 5). The most frequent drug-related AEs were fatigue (6 subjects [38%]) and constipation (3 subjects [19%]), which occurred primarily in the treatment phases with carbamazepine. The only other drug-related AEs that were reported for more than one subject were abdominal discomfort, back pain, and pruritus for two subjects each (13%), which occurred in the treatment phases with carbamazepine. In the treatment phase with zongertinib alone, fatigue was the only reported drug-related AE in one subject (6%). No Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or serious AEs were reported. Most AEs were of CTCAE grade 1, some of grade 2. During the treatment phase with carbamazepine alone, mild increases in gamma glutamyl transferase (up to 133 U / L; norm: <60 U / L) and ALT (up to 112 U / L, norm: <50 U / L) were reported from one subject. Otherwise, there were no clinically relevant findings in safety laboratory, vital signs, or ECGs. Adverse events tables The following tables show subjects with adverse events (AEs) sorted by different treatment phases. - Phase “zongertinib”: AEs occurring from dosing of zongertinib in Period 1 until first dosing of carbamazepine in Period 2. - Phase “zongertinib + carbamazepine loading”: AEs occurring during the start of the carbamazepine loading phase until 14 days after first zongertinib dosing. - Phase “carbamazepine loading”: AEs occurring during the subsequent part of the carbamazepine loading phase until zongertinib dosing in Period 2. - Phase “zongertinib + carbamazepine”: AEs occurring from second zongertinib dosing until 14 days thereafter. - Phase “total carbamazepine”: Summary of the phases with carbamazepine. - Phase “total zongertinib”: Summary of the phases with zongertinib. Table 4: Frequency [N (%)] of subjects with on-treatment adverse events by treatment, primary system organ class, and preferred Term – treated set. zonger zonger +carba carba zonger Total Total Total on- loading loading +carba carba zonger trt Total with on- treatment adverse 3 (19) 7 (47) 11 (73) 5 (33) 12 (80) 11 (69) 13 (81) events Gastrointestinal disorders 0 4 (27) 6 (40) 1 (7) 8 (53) 5 (31) 8 (50) ^ Constipatio 0 0 3 (20) 0 3 (20) 0 3 (19) n ^ Abdominal 0 1 (7) 1 (7) 0 2 (13) 1 (6) 2 (13) discomfort ^ Abdominal 1 (7) 0 0 1 (7) 1 (6) 1 (6) pain upper ^ Diarrhea 0 0 1 (7) 0 1 (7) 0 1 (6) ^ Dry mouth 0 1 (7) 0 0 1 (7) 1 (6) 1 (6) ^ Faeces 0 0 1 (7) 0 1 (7) 0 1 (6) hard ^ Flatulence 0 1 (7) 0 0 1 (7) 1 (6) 1 (6) ^ Gingival 0 0 0 1 (7) 1 (7) 1 (6) 1 (6) bleeding zonger zonger +carba carba zonger Total Total Total on- loading System organ class / Preferred N (%) N (%) N (%) N (%) N (%) N (%) N (%) term ^Toothache0 0 1 (7) 0 1 (7) 0 1 (6) General disorders and administration 1 (6) 3 (20) 4 (27) 0 5 (33) 4 (25) 6 (38) site conditions ^Fatigue1 (6) 3 (20) 4 (27) 0 5 (33) 4 (25) 6 (38) Musculoskeletal and connective 1 (6) 3 (20) 2 (13) 0 4 (27) 4 (25) 5 (31) tissue disorders ^Back pain0 3 (20) 1 (7) 0 3 (20) 3 (19) 3 (19) ^ Neck pain 1 (6) 1 (7) 0 0 1 (7) 2 (13) 2 (13) ^ Muscle 0 0 1 (7) 0 1 (7) 0 1 (6) twitching Skin and subcutaneous 0 0 2 (13) 2 (13) 3 (20) 2 (13) 3 (19) tissue disorders ^Pruritus0 0 1 (7) 1 (7) 2 (13) 1 (6) 2 (13) ^Alopecia0 0 0 1 (7) 1 (7) 1 (6) 1 (6) ^ Hyperhidro 0 0 1 (7) 0 1 (7) 0 1 (6) sis Infections and infestations 1 (6) 0 0 2 (13) 2 (13) 3 (19) 3 (19) Eye disorders 0 0 2 (13) 0 2 (13) 0 2 (13) ^ Conjunctiv al haemorrha 0 0 1 (7) 0 1 (7) 0 1 (6) ge ^Eye pain0 0 1 (7) 0 1 (7) 0 1 (6) zonger zonger +carba carba zonger Total Total Total on- loading trt System organ class / Preferred N (%) N (%) N (%) N (%) N (%) N (%) N (%) term Psychiatric disorders 0 1 (7) 0 1 (7) ^ Abnormal 0 1 (7) 0 0 1 (7) 1 (6) 1 (6) dreams ^ Initial 0 0 0 1 (7) 1 (7) 1 (6) 1 (6) insomnia Blood and lymphatic system 0 0 1 (7) 0 1 (7) 0 1 (6) disorders ^ Lymphade 0 0 1 (7) 0 1 (7) 0 1 (6) nopathy Investigations 0 0 1 (7) 0 1 (7) 0 1 (6) ^ ALT 0 0 1 (7) 0 1 (7) 0 1 (6) increased ^ Body temperatur 0 0 1 (7) 0 1 (7) 0 1 (6) e increased ^ GGT 0 0 1 (7) 0 1 (7) 0 1 (6) increased Nervous system disorders 0 0 1 (7) 0 1 (7) 0 1 (6) ^Headache0 0 1 (7) 0 1 (7) 0 1 (6) ALT, alanine aminotransferase; GGT, gamma-glutamyltransferase; zonger, zongertinib; carba, carbamazepine; on-trt, on-treatment Table 5: Frequency [N (%)] of subjects with drug related on-treatment adverse events by treatment, primary system organ class, and preferred term – treated set. zonger +carba carba zonger Total Total Total on- zonger loading loading +carba carba zonger trt System organ class / Preferred term N (%) N (%) N (%) N (%) N (%) N (%) N (%) Number of 16 (100) 15 (100) 15 (100) 15 (100) 15 (100) 16 (100) 16 (100) subjects Total with related 1 (6) 7 (47) 10 (67) 4 (27) 11 (73) 10 (63) 12 (75) on-treatment adverse events Gastrointestinal 0 4 (27) 5 (33) 1 (7) 7 (47) 5 (31) 7 (44) disorders ^ Constipatio 0 0 3 (20) 0 3 (20) 0 3 (19) n ^ Abdominal 0 1 (7) 1 (7) 0 2 (13) 1 (6) 2 (13) discomfort ^ Abdominal 0 1 (7) 0 0 1 (7) 1 (6) 1 (6) pain upper ^Diarrhoea0 0 1 (7) 0 1 (7) 0 1 (6) ^Dry mouth0 1 (7) 0 0 1 (7) 1 (6) 1 (6) ^Faeces hard0 0 1 (7) 0 1 (7) 0 1 (6)^Flatulence0 1 (7) 0 0 1 (7) 1 (6) 1 (6) ^ Gingival 0 0 0 1 (7) 1 (7) 1 (6) 1 (6) bleeding General disorders 1 (6) 3 (20) 4 (27) 0 5 (33) 4 (25) 6 (38) and administration site conditions ^Fatigue1 (6) 3 (20) 4 (27) 0 5 (33) 4 (25) 6 (38) Musculoskeletal 0 2 (13) 2 (13) 0 3 (20) 2 (13) 3 (19) and connective tissue disorders ^Back pain0 2 (13) 1 (7) 0 2 (13) 2 (13) 2 (13) ^ Muscle 0 0 1 (7) 0 1 (7) 0 1 (6) twitching zonger +carba carba zonger Total Total Total on- zonger loading loading +carba carba zonger trt System organ class / Preferred term N (%) N (%) N (%) N (%) N (%) N (%) N (%) Skin and 0 0 2 (13) 2 (13) 3 (20) 2 (13) 3 (19) subcutaneous tissue disorders ^Pruritus0 0 1 (7) 1 (7) 2 (13) 1 (6) 2 (13) ^Alopecia0 0 0 1 (7) 1 (7) 1 (6) 1 (6) ^ Hyperhidro 0 0 1 (7) 0 1 (7) 0 1 (6) sis Psychiatric 0 1 (7) 0 1 (7) 2 (13) 2 (13) 2 (13) disorders ^ Abnormal 0 1 (7) 0 0 1 (7) 1 (6) 1 (6) dreams ^ Initial 0 0 0 1 (7) 1 (7) 1 (6) 1 (6) insomnia Blood and 0 0 1 (7) 0 1 (7) 0 1 (6) lymphatic system disorders ^ Lymphade 0 0 1 (7) 0 1 (7) 0 1 (6) nopathy Investigations0 0 1 (7) 0 1 (7) 0 1 (6)^ ALT 0 0 1 (7) 0 1 (7) 0 1 (6) increased ^ GGT 0 0 1 (7) 0 1 (7) 0 1 (6) increased ALT, alanine aminotransferase; GGT, gamma-glutamyltransferase; zonger, zongertinib; carba, carbamazepine; on-trt, on-treatment Discussion The main objective of this study was to investigate the effect of multiple oral doses of carbamazepine on the PK of a single oral dose of zongertinib. The observed reduction of zongertinib exposure (by approximately 64% in AUC and 44% in Cmax) during carbamazepine coadministration suggests that zongertinib is susceptible to the induction of primarily CYP3A with potential contributions of UGT enzymes and P-gp. Indeed, carbamazepine achieves its induction effect mainly via activation of receptor transcription factors pregnane X receptor (PXR) and constitutive androstane receptor (CAR), mediating the gene transcription of multiple enzymes and transporters beyond the strong induction of CYP3A4 / 5.24,33The induction of additional enzymes and transporters such as UGT enzymes and P-gp could theoretically contribute to the reduced exposure of zongertinib, predicting the “worse-case scenario” than strong induction of CYP3A alone. Considering CYP3A contributes to 48-62% of total hepatic metabolic clearance of zongertinib in vitro, the reduction in zongertinib exposure is thought to be primarily driven by the strong induction of CYP3A. Carbamazepine is classified as a strong index CYP3A inducer by the FDA as defined by decreasing the AUC of sensitive substrates of a given metabolic pathway by ≥80%. In a previous study by Lutz et al., midazolam, a sensitive CYP3A substrate, exhibited a reduction of approximately 79% in AUC and 68% in Cmax upon coadministration with carbamazepine in a similar dosing regimen as done in this DDI study.34In comparison to the DDI results of midazolam, the decrease in zongertinib exposure observed in our study was considered moderate. The half-life of zongertinib was shorter and accompanied by an increased apparent clearance (CL / F), indicating an accelerated elimination phase due to CYP3A induction. The reduction in Cmax of zongertinib is likely a combined effect of the increased systemic clearance and possibly increased first-pass effect in the liver and gut wall. Interestingly, the plasma PK profiles of zongertinib with carbamazepine cotreatment seemed to be associated with lower intersubject variability than zongertinib given alone. The high variability in plasma concentrations in the reference period could be potentially explained by the variability in the expression of enzymes and transporters responsible for elimination of zongertinib. For instance, CYP3A4 expression has been reported with extremely high population variability (>100- fold).35Through the strong inductive effect of carbamazepine on CYP3A4 expression, subjects may achieve similarly high expression levels, thereby reducing the variability in plasma concentrations of zongertinib. Dose selection of carbamazepine in this study was based on a previous healthy volunteer study, which reported that a carbamazepine dosing regimen of 200 mg / day for 4 days, followed by 400 mg / day for 7 days, followed by 600 mg / day for 21 days resulted in a maximal induction of CYP3A (based on 6βCR in urine) on Day 18 of this regimen.36In our study, subjects were pretreated with carbamazepine for more than 14 days, a commonly accepted duration for maximal CYP3A induction by regulatory authorities like the FDA.37To further confirm the induction course of CYP3A in this study, we additionally collected 6βCR in urine and 4βHC in plasma at various time points of the carbamazepine treatment period and observed rapid increase in both biomarkers due to carbamazepine treatment. The plateau in 6βCR appears to have been reached 60 hours prior to zongertinib administration indicating that the interaction was investigated at a time of maximal induction. On the other hand, the peak of plasma 4βHC was more delayed and the concentrations were still increasing slowly at the last sampling point, possibly because plasma 4βHC has a much longer half-life (i.e., 17 days versus approximately 1 hour for cortisol and its metabolite).38Similar to evaluations in previous literature,38–41plasma 4βHC appeared to be a less sensitive but more stable biomarker with lower variability than 6βCR in urine. Overall, the increase in endogenous biomarkers indicate a high likelihood that the maximum induction of CYP3A was achieved prior to the administration of zongertinib. An up-titration scheme is commonly used for carbamazepine dosing to improve tolerability. The twice-daily dosing of carbamazepine used in the referenced study mentioned above36was modified to once-daily evening dosing in this study to further improve drug tolerability, as recommended by an investigator of a previous carbamazepine clinical study.25Safety and tolerability of carbamazepine in the current study were deemed to be good. Most AEs were of CTCAE grade 1, and only few were of grade 2. Dizziness or vertigo (reported in previous publications36,42,43) were not observed in this study, possibly because carbamazepine was given as once-daily doses in the evening instead of twice daily. Due to the risk profile of carbamazepine, close monitoring of safety parameters (including safety laboratory, neurological examination, skin inspection, ECG, vital signs, and suicidality assessment) are recommended in healthy volunteer trials with carbamazepine. This necessity is showcased by a recent report of a symptomatic thrombocytopenia in a carbamazepine study in a healthy volunteer that necessitated withdrawal of the subject.42Single doses of 60 mg zongertinib alone or together with carbamazepine were safe and well tolerated in this trial. Conclusion Zongertinib exposure was moderately reduced upon strong induction of CYP3A drug metabolism. After coadministration of zongertinib with multiple doses of carbamazepine, zongertinib AUC decreased by approximately 64% and Cmax decreased by approximately 44% as compared with zongertinib administered alone. Both zongertinib and carbamazepine were considered safe and well tolerated by the healthy male subjects in this study. References: 1. Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene.2007;26(45):6469-6487. doi:10.1038 / sj.onc.1210477 2. Jebbink M, Langen AJ de, Boelens MC, Monkhorst K, Smit EF. 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Claims

C l a i m s 1. Compound (1) as defined below or a pharmaceutically acceptable salt thereoffor use in the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P- gp modulator.

2. Compound (1) for use according to claim 1, wherein the use comprises avoiding co- administration of a CYP3A and / or P-gp modulator.

3. Compound (1) as defined below or a pharmaceutically acceptable salt thereoffor use in the treatment of cancer, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately or sequentially.

4. Compound (1) for use according to any one of claims 1 to 3, wherein the use comprises a contraindicated or avoided time interval between the administration of the CYP3A and / or P-gp modulator and the administration of compound (1).

5. Compound (1) for use according to claim 4, wherein the contraindicated or avoided time interval is selected from the group consisting of at least 1 hour, at least 1 day, at least 3 days, at least 7 days, at least 14 days and at least 21 days.

6. Compound (1) for use according to any one of claims 1 to 5, wherein the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient prior to the administration of compound (1) and contraindicating or avoiding the administration of compound (1) for a time interval in case that the CYP3A and / or P-gp modulator drug status is positive.

7. Compound (1) for use according to claim 6, wherein the CYP3A and / or P-gp modulator drug status assessment is selected from the group consisting of a questionnaire, CYP3A and / or P-gp modulator blood, blood serum and / or plasma level determination, consultation with the patient, an endogenous biomarker and a combination thereof.

8. Compound (1) for use according to any one of claims 1 to 7, wherein the daily dose of administered compound (1) is above 120 mg, preferably above 150 mg, 180 mg, 200 mg or 240 mg, in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator.

9. Compound (1) for use according to any one of claims 1 to 8, wherein the daily dose of administered compound (1) is above 240 mg, preferably above 300 mg, 360 mg, 420mg, 480 mg, 540 mg or 600 mg, in case that compound (1) is administered in combination with a CYP3A and / or P-gp modulator.

10. Compound (1) for use according to any one of claims 1 to 9, wherein the use comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient; (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered at a higher than standard therapeutically effective amount to a patient; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount.

11. Compound (1) for use according to any one of claims 1 to 10, wherein the use comprises: (i) Assessing the CYP3A and / or P-gp modulator drug status of a patient; (ii) In case the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered at total daily dose of 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg; (iii) In case the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to a patient in a standard therapeutically effective amount.

12. Compound (1) for use according to claim 10 or 11, wherein the standard therapeutically effective amount of compound (1) is a daily dose of 120 mg or 240 mg.

13. Compound (1) for use according to any one of claims 1 to 12, wherein the CYP3A and / or P-gp modulator is a CYP3A and / or P-gp inducer.

14. Compound (1) for use according to any one of claims 1 to 13, wherein the CYP3A and / or P-gp modulator is a strong CYP3A4 / 5 inducer.

15. Compound (1) for use according to claim 2, wherein the CYP3A and / or P-gp modulator is a strong CYP3A4 / 5 inducer.

16. Compound (1) for use according to any one of claims 1 to 15, wherein the CYP3A and / or P-gp modulator is selected from the group consisting of apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort, brigatinib, efavirenz, enzalutamide, dexamethasone, modafinil, nevirapine, oxcarbazepine, pioglitazone, rifabutin and troglitazone.

17. Compound (1) for use according to any one of claims 1 to 16, wherein the CYP3A and / or P-gp modulator is carbamazepine.

18. Compound (1) for use according to any one of claims 1 to 17, wherein said 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.

19. Compound (1) for use according to any one of claims 1 to 18, wherein said cancer is non-small cell lung cancer.

20. Compound (1) for use according to any one of claims 1 to 19, wherein said cancer is HER2 overexpressed, HER2 amplified and / or HER2 mutant.

21. Compound (1) for use according to any one of claims 1 to 20, wherein said cancer comprises a mutation in the tyrosine kinase domain of HER2.

22. Compound (1) for use according to any one of claims 1 to 21, wherein said cancer is unresectable, advanced and / or metastatic cancer.

23. A pharmaceutical composition comprising compound (1) as defined below or a pharmaceutically acceptable salt thereofand at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator.

24. A pharmaceutical composition comprising compound (1) as defined below or a pharmaceutically acceptable salt thereofand at least one pharmaceutically acceptable excipient for use in the treatment of cancer, wherein compound (1) is administered in combination with a CYP3A and / or P-gpmodulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately or sequentially.

25. The pharmaceutical composition according to claim 23 or 24, wherein the use is as defined in any one of claims 2 or 4 to 12.

26. The pharmaceutical composition according to any one of claims 23 to 25, wherein the CYP3A and / or P-gp modulator is as defined in any one of claims 13 to 17.

27. The pharmaceutical composition according to any one of claims 23 to 26, wherein the cancer is as defined in any one of claims 18 to 22.

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