Tabrecta

Capmatinib.

Tabrecta 150 mg film-coated tablets: Each film-coated tablet contains 150 mg of capmatinib (as capmatinib dihydrochloride monohydrate).
Tabrecta 200 mg film-coated tablets: Each film-coated tablet contains 200 mg of capmatinib (as capmatinib dihydrochloride monohydrate).
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose, Crospovidone, Magnesium stearate, Mannitol, Povidone, Anhydrous colloidal silica, Sodium laurilsulfate.
Film coating: Hypromellose, Black iron oxide (E172), Red iron oxide (E172), Yellow iron oxide (E172), Titanium dioxide (E171), Macrogol 4000, Talc.

Pharmacology: Pharmacodynamics: Mechanism of action: Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in a protein with a missing regulatory domain that reduces its negative regulation leading to increased downstream MET signaling. Capmatinib inhibited cancer cell growth driven by a mutant MET variant lacking exon 14 at clinically achievable concentrations and demonstrated anti-tumor activity in murine tumor xenograft models derived from human lung tumors with either a mutation leading to MET exon 14 skipping or MET amplification. Capmatinib inhibited the phosphorylation of MET triggered by binding of hepatocyte growth factor or by MET amplification, as well as MET-mediated phosphorylation of downstream signaling proteins and proliferation and survival of MET-dependent cancer cells.
Exposure-Response: Capmatinib exposure-response relationships and the time course of pharmacodynamics response are unknown.
Cardiac Electrophysiology: No large mean increase in QTc (i.e. > 20 ms) was detected following treatment with Tabrecta at the recommended dosage of 400 mg orally twice daily.
Clinical efficacy and safety: Metastatic NSCLC with a Mutation that Leads to MET Exon 14 Skipping: The efficacy of Tabrecta was evaluated in GEOMETRY mono-1, a multicenter, non-randomized, open-label, multi-cohort study (NCT02414139). Eligible patients were required to have NSCLC with a mutation that leads to MET exon 14 skipping, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the study.
Out of the 97 patients enrolled in GEOMETRY mono-1 following the central confirmation of MET exon 14 skipping by a RNA-based clinical trial assay, 78 patient samples were retested with the FDA-approved FoundationOne CDx (22 treatment-naïve and 56 previously treated patients) to detect mutations that lead to MET exon 14 skipping. Out of 78 samples retested with FoundationOne CDx, 73 samples were evaluable (20 treatment-naïve and 53 previously treated patients), 72 (20 treatment-naïve and 52 previously treated patients) of which were confirmed to have a mutation that leads to MET exon 14 skipping, demonstrating an estimated positive percentage agreement of 99% (72/73) between the clinical trial assay and the FDA-approved assay.
Patients received Tabrecta 400 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) as determined by a Blinded Independent Review Committee (BIRC) according to RECIST 1.1. An additional efficacy outcome measure was duration of response (DOR) by BIRC.
The efficacy population included 28 treatment-naïve patients and 69 previously treated patients. The median age was 71 years (range: 49 to 90 years); 60% female; 75% White; 24% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 75% had ECOG PS 1; 60% never smoked; 80% had adenocarcinoma; and 12% had CNS metastases. Amongst previously treated patients, 88% received prior platinum-based chemotherapy.
Efficacy results are presented in Table 1. (See Table 1.)

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Pharmacokinetics: Capmatinib exposure (AUC0-12h and Cmax) increased approximately proportionally over a dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day 3 following twice daily dosing, with a mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%).
Absorption: After administration of Tabrecta 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (Cmax) were reached in approximately 1 to 2 hours (Tmax). The absorption of capmatinib after oral administration is estimated to be greater than 70%.
Effect of Food: A high-fat meal (containing approximately 1000 calories and 50% fat) in healthy subjects increased capmatinib AUC0-INF by 46% with no change in Cmax compared to under fasted conditions. A low-fat meal (containing approximately 300 calories and 20% fat) in healthy subjects had no clinically meaningful effect on capmatinib exposure. When capmatinib was administered at 400 mg orally twice daily in cancer patients, exposure (AUC0-12h) was similar after administration of capmatinib with food and under fasted conditions.
Distribution: Capmatinib plasma protein binding is 96%, independent of capmatinib concentration. The apparent mean volume of distribution at steady-state is 164 L.
The blood-to-plasma ratio was 1.5, but decreased at higher concentrations to 0.9.
Elimination: The effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%).
Metabolism: Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase.
Excretion: Following a single oral administration of radio-labeled capmatinib to healthy subjects, 78% of the total radioactivity was recovered in feces with 42% as unchanged and 22% was recovered in urine with negligible as unchanged.
Specific Populations: No clinically significant effects on the pharmacokinetic parameters of capmatinib were identified for the following covariates assessed: age (26 to 90 years), sex, race (White, Asian, Native American, Black, unknown), body weight (35 to 131 kg), mild to moderate renal impairment (baseline CLcr 30 to 89 mL/min by Cockcroft-Gault) and mild, moderate or severe hepatic impairment (Child-Pugh classification). The effect of severe renal impairment (baseline CLcr 15 to 29 mL/min) on capmatinib pharmacokinetics has not been studied.
Drug Interaction Studies: Clinical Studies and Model-Informed Approaches: Strong CYP3A Inhibitors: Coadministration with itraconazole (a strong CYP3A inhibitor) increased capmatinib AUC0-INF by 42% with no change in capmatinib Cmax.
Strong CYP3A Inducers: Coadministration with rifampicin (a strong CYP3A inducer) decreased capmatinib AUC0-INF by 67% and decreased Cmax by 56%.
Moderate CYP3A Inducers: Coadministration with efavirenz (a moderate CYP3A inducer) was predicted to decrease capmatinib AUC0-12h by 44% and decrease Cmax by 34%.
Proton Pump Inhibitors: Coadministration with rabeprazole (a proton pump inhibitor) decreased capmatinib AUC0-INF by 25% and decreased Cmax by 38%.
Substrates of CYP Enzymes: Coadministration of capmatinib increased caffeine (a CYP1A2 substrate) AUC0-INF by 134% with no change in its Cmax. Coadministration of capmatinib had no clinically meaningful effect on exposure of midazolam (a CYP3A substrate).
P-gp Substrates: Coadministration of capmatinib increased digoxin (a P-gp substrate) AUC0-INF by 47% and increased Cmax by 74%.
BCRP Substrates: Coadministration of capmatinib increased rosuvastatin (a BCRP substrate) AUC0-INF by 108% and increased Cmax by 204%.
In Vitro Studies: Transporter Systems: Capmatinib is a substrate of P-gp, but not a substrate of BCRP or MRP2. Capmatinib reversibly inhibits MATE1 and MATE2K, but does not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or MRP2.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were not conducted with capmatinib. Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Capmatinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.
Dedicated fertility studies were not conducted with capmatinib. No effects on male and female reproductive organs occurred in general toxicology studies conducted in rats and monkeys at doses resulting in exposures of up to approximately 3.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose.
Animal Toxicology and/or Pharmacology: In rats, capmatinib administration resulted in vacuolation of white matter of the brain in both 4- and 13-week studies at doses ≥ 2.2 times the human exposure (AUC) at the 400 mg twice daily clinical dose. In some cases, the brain lesions were associated with early death and/or convulsions or tremors. Concentrations of capmatinib in the brain tissue of rats was approximately 9% of the corresponding concentrations in plasma.
In vitro and in vivo assays demonstrated that capmatinib has some potential for photosensitization; however, the no-observed-adverse-effect level for in vivo photosensitization was 30 mg/kg/day (Cmax of 14000 ng/mL), about 2.9 times the human Cmax at the 400 mg twice daily clinical dose.

Tabrecta is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a MET exon 14 skipping mutation (see Pharmacology: Pharmacodynamics under Actions).

Select patients for treatment with Tabrecta based on the presence of a mutation that leads to MET exon 14 skipping in tumor specimens.
Posology: The recommended dosage of Tabrecta is 400 mg orally twice daily with or without food.
Dose modifications: The recommended dose reductions for the management of adverse reactions are listed in Table 2. (See Table 2.)

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Permanently discontinue Tabrecta in patients who are unable to tolerate 200 mg orally twice daily.
The recommended dosage modifications of Tabrecta for adverse reactions are provided in Table 3. (See Table 3.)

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Special populations: Pediatric Use: Safety and effectiveness of Tabrecta in pediatric patients have not been established.
Geriatric Use: In GEOMETRY mono-1, 57% of the 334 patients were 65 years or older and 16% were 75 years or older. No overall differences in the safety or effectiveness were observed between these patients and younger patients.
Renal Impairment: No dosage adjustment is recommended in patients with mild (baseline creatinine clearance [CLcr] 60 to 89 mL/min by Cockcroft-Gault) or moderate renal impairment (CLcr 30 to 59 mL/min) (see Pharmacology: Pharmacokinetics under Actions). Tabrecta has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min).
Method of administration: Swallow Tabrecta tablets whole. Do not break, crush or chew the tablets.
If a patient misses or vomits a dose, instruct the patient not to make up the dose, but to take the next dose at its scheduled time.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis, which can be fatal, occurred in patients treated with Tabrecta (see Adverse Reactions). ILD/pneumonitis occurred in 4.5% of patients treated with Tabrecta in GEOMETRY mono-1, with 1.8% of patients experiencing Grade 3 ILD/pneumonitis and one patient experiencing death (0.3%). Eight patients (2.4%) discontinued Tabrecta due to ILD/pneumonitis. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 1.4 months (range: 0.2 months to 1.2 years).
Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold Tabrecta in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified (see Dosage & Administration).
Hepatotoxicity: Hepatotoxicity occurred in patients treated with Tabrecta (see Adverse Reactions). Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 13% of patients treated with Tabrecta in GEOMETRY mono-1. Grade 3 or 4 increased ALT/AST occurred in 6% of patients. Three patients (0.9%) discontinued Tabrecta due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 1.4 months (range: 0.5 to 4.1 months).
Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of Tabrecta, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue Tabrecta (see Dosage & Administration).
Risk of Photosensitivity: Based on findings from animal studies, there is a potential risk of photosensitivity reactions with Tabrecta (see Pharmacology: Toxicology: Preclinical safety data under Actions). In GEOMETRY mono-1, it was recommended that patients use precautionary measures against ultraviolet exposure such as use of sunscreen or protective clothing during treatment with Tabrecta. Advise patients to limit direct ultraviolet exposure during treatment with Tabrecta.
Effects on ability to drive and use machines: No relevant studies have been conducted. Caution is advised when driving and using machines as taking Tabrecta may cause nausea or fatigue (see Adverse Reactions).
Use in Pregnancy: Embryo-Fetal Toxicity: Based on findings from animal studies and its mechanism of action, Tabrecta can cause fetal harm when administered to a pregnant woman. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at exposures less than the human exposure based on area under the curve (AUC) at the 400 mg twice daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Tabrecta and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Tabrecta and for 1 week after the last dose (see Use in Pregnancy & Lactation).

Pregnancy: Risk Summary: Based on findings from animal studies and its mechanism of action (see Pharmacology: Pharmacodynamics under Actions), Tabrecta can cause fetal harm when administered to a pregnant woman. There are no available data on Tabrecta use in pregnant women. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice daily clinical dose (see Data as follows). Advise pregnant women of the potential risk to a fetus.
Data: Animal Data: In rats, maternal toxicity (reduced body weight gain and food consumption) occurred at 30 mg/kg/day (approximately 1.4 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included reduced fetal weights, irregular/incomplete ossification, and increased incidences of fetal malformations (e.g., abnormal flexure/inward malrotation of hindpaws/forepaws, thinness of forelimbs, lack of/reduced flexion at the humerus/ulna joints, and narrowed or small tongue) at doses of ≥ 10 mg/kg/day (approximately 0.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose).
In rabbits, no maternal effects were detected at doses up to 60 mg/kg/day (approximately 1.5 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included small lung lobe at ≥ 5 mg/kg/day (approximately 0.016 times the human exposure based on AUC at the 400 mg twice daily clinical dose), and reduced fetal weights, irregular/incomplete ossification and increased incidences of fetal malformations (e.g., abnormal flexure/malrotation of hindpaws/forepaws, thinness of forelimbs/hindlimbs, lack of/reduced flexion at the humerus/ulna joints, small lung lobes, narrowed or small tongue) at the dose of 60 mg/kg/day.
Lactation: Risk Summary: There are no data on the presence of capmatinib or its metabolites in either human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Tabrecta and for 1 week after the last dose.
Females and Males of Reproductive Potential: Based on animal data, Tabrecta can cause malformations at doses less than the human exposure based on AUC at the 400 mg twice daily clinical dose (see Data as previously mentioned).
Pregnancy Testing: Verify pregnancy status for females of reproductive potential prior to starting treatment with Tabrecta.
Contraception: Females: Advise females of reproductive potential to use effective contraception during treatment with Tabrecta and for 1 week after the last dose.
Males: Advise males with female partners of reproductive potential to use effective contraception during treatment with Tabrecta and for 1 week after the last dose.

The following clinically significant adverse reactions are described elsewhere in the labeling: ILD/Pneumonitis (see Precautions); Hepatotoxicity (see Precautions).
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Metastatic Non-Small Cell Lung Cancer: The safety of Tabrecta was evaluated in GEOMETRY mono-1 (see Pharmacology: Pharmacodynamics under Actions). Patients received Tabrecta 400 mg orally twice daily until disease progression or unacceptable toxicity (N=334). Among patients who received Tabrecta, 31% were exposed for at least 6 months and 16% were exposed for at least one year.
Serious adverse reactions occurred in 51% of patients who received Tabrecta. Serious adverse reactions in ≥ 2% of patients included dyspnea (7%), pneumonia (4.8%), pleural effusion (3.6%), general physical health deterioration (3%), vomiting (2.4%), and nausea (2.1%). A fatal adverse reaction occurred in one patient (0.3%) due to pneumonitis.
Permanent discontinuation of Tabrecta due to an adverse reaction occurred in 16% of patients. The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of Tabrecta were peripheral edema (1.8%), pneumonitis (1.8%), and fatigue (1.5%).
Dose interruptions due to an adverse reaction occurred in 54% of patients who received Tabrecta. Adverse reactions requiring dosage interruption in > 2% of patients who received Tabrecta included peripheral edema, increased blood creatinine, nausea, vomiting, increased lipase, increased ALT, dyspnea, increased amylase, increased AST, increased blood bilirubin, fatigue, and pneumonia.
Dose reductions due to an adverse reaction occurred in 23% of patients who received Tabrecta. Adverse reactions requiring dosage reductions in > 2% of patients who received Tabrecta included peripheral edema, increased ALT, increased blood creatinine, and nausea.
The most common adverse reactions (≥ 20%) in patients who received Tabrecta were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.
Table 4 summarizes the adverse reactions in GEOMETRY mono-1. (See Table 4.)

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Clinically relevant adverse reactions occurring in < 10% of patients treated with Tabrecta included pruritus (allergic and generalized), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis.
Table 5 summarizes the laboratory abnormalities in GEOMETRY mono-1. (See Table 5.)

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Effect of Other Drugs on Tabrecta: Strong CYP3A Inhibitors: Coadministration of Tabrecta with a strong CYP3A inhibitor increased capmatinib exposure, which may increase the incidence and severity of adverse reactions of Tabrecta (see Pharmacology: Pharmacokinetics under Actions). Closely monitor patients for adverse reactions during coadministration of Tabrecta with strong CYP3A inhibitors.
Strong and Moderate CYP3A Inducers: Coadministration of Tabrecta with a strong CYP3A inducer decreased capmatinib exposure. Coadministration of Tabrecta with a moderate CYP3A inducer may also decrease capmatinib exposure. Decreases in capmatinib exposure may decrease Tabrecta anti-tumor activity (see Pharmacology: Pharmacokinetics under Actions). Avoid coadministration of Tabrecta with strong and moderate CYP3A inducers.
Effect of Tabrecta on Other Drugs: CYP1A2 Substrates: Coadministration of Tabrecta increased the exposure of a CYP1A2 substrate, which may increase the adverse reactions of these substrates (see Pharmacology: Pharmacokinetics under Actions). If coadministration is unavoidable between Tabrecta and CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, decrease the CYP1A2 substrate dosage in accordance with the approved prescribing information.
P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates: Coadministration of Tabrecta increased the exposure of a P-gp substrate and a BCRP substrate, which may increase the adverse reactions of these substrates (see Pharmacology: Pharmacokinetics under Actions). If coadministration is unavoidable between Tabrecta and P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions, decrease the P-gp or BCRP substrate dosage in accordance with the approved prescribing information.
MATE1 and MATE2K Substrates: Coadministration of Tabrecta may increase the exposure of MATE1 and MATE2K substrates, which may increase the adverse reactions of these substrates (see Pharmacology: Pharmacokinetics under Actions). If coadministration is unavoidable between Tabrecta and MATE1 or MATE2K substrates where minimal concentration changes may lead to serious adverse reactions, decrease the MATE1 or MATE2K substrate dosage in accordance with the approved prescribing information.

Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C. Protect from moisture. Store in the original packaging.
Shelf-life: 2 years.

Targeted Cancer Therapy

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