Tabrecta Drug Information

is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. TABRECTA is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

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 . Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity (N = 373). Among patients who received TABRECTA, 37% were exposed for at least 6 months and 22% were exposed for at least one year. Serious adverse reactions occurred in 53% of patients who received TABRECTA. Serious adverse reactions in ≥ 2% of patients included dyspnea (7%), pneumonia (7%), pleural effusion (4.3%), musculoskeletal pain (3.8%), general physical health deterioration (2.9%), ILD/pneumonitis (2.7%), edema (2.4%), and vomiting (2.4%). Fatal adverse reactions occurred in 0.5% of patients who received TABRECTA, including pneumonitis (0.3%) and death, not otherwise specified (0.3%). Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 17% of patients.

The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of TABRECTA were ILD/pneumonitis (2.4%), edema (2.4%), fatigue (1.3%), and pneumonia (1.1%). Dose interruptions due to an adverse reaction occurred in 57% of patients who received TABRECTA. Adverse reactions requiring dosage interruption in > 2% of patients who received TABRECTA included edema, increased blood creatinine, nausea, increased lipase, vomiting, increased ALT, dyspnea, pneumonia, fatigue, increased amylase, increased AST, musculoskeletal pain, abdominal pain, and increased blood bilirubin. Dose reductions due to an adverse reaction occurred in 26% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in > 2% of patients who received TABRECTA included edema, increased ALT and increased blood creatinine. The most common adverse reactions (≥ 20%) in patients who received TABRECTA were edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite.

Table 3 summarizes the adverse reactions in GEOMETRY mono-1. Table 3: Adverse Reactions (≥ 10%) in Patients Who Received TABRECTA in GEOMETRY mono-1 a Edema includes edema peripheral, generalized edema, face edema, edema, localized edema, edema genital, eyelid edema, peripheral swelling, scrotal edema, and penile edema. b Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, spinal pain. c Fatigue includes fatigue and asthenia. d Pyrexia includes pyrexia and body temperature increased. e Cough includes cough, upper airway cough syndrome, and productive cough. f Pneumonia includes pneumonia aspiration, pneumonia, pneumonia influenzal, pneumonia bacterial, lower respiratory tract infection, and lung abscess. g Rash includes rash, dermatitis acneiform, rash maculo-papular, eczema, erythema multiforme, rash macular, dermatitis, rash erythematous, rash pustular, dermatitis bullous, and rash vesicular. h Dizziness includes dizziness, vertigo, and vertigo positional. Adverse reactions TABRECTA (N = 373) Grades 1 to 4 (%) Grades 3 to 4 (%) General disorders and administration-site conditions Edema a 59 13 Musculoskeletal pain b 40

Fatigue c 34 8 Pyrexia d 14 0.8 Weight decreased 11 0.5

Gastrointestinal disorders Nausea 46

Vomiting 28 2.4 Constipation 19 0.8 Diarrhea 19 0.5 Respiratory, thoracic, and

mediastinal disorders Dyspnea 25 7 Cough e 21

Pneumonia f 13 6 Metabolism and nutrition disorders Decreased appetite 21 1.1

Skin and subcutaneous tissue disorders Rash g 13

Nervous system disorders Dizziness h 13 0.5 Clinically relevant adverse reactions occurring

in < 10% of patients treated with TABRECTA included pruritus (including allergic pruritus), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis. Table 4 summarizes the laboratory abnormalities in GEOMETRY mono-1. Table 4: Select Laboratory Abnormalities (≥ 20%) Worsening From Baseline in Patients Who Received TABRECTA in GEOMETRY mono-1 a The denominator used to calculate the rate varied from 359 to 364 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory abnormalities TABRECTA a Grades 1 to 4 (%) Grades 3 to 4 (%) Chemistry Decreased albumin 72

Increased alkaline phosphatase 32 0.6 Increased gamma-glutamyltransferase 30 6 Increased lipase 29

9 Increased aspartate aminotransferase 28 6 Decreased phosphate 26

Increased potassium 25 4.1 Decreased sodium 24 6 Decreased glucose 23 0.3

Hematology Decreased lymphocytes 45 14 Decreased leukocytes 25

Decreased hemoglobin 24 2.8 Other Clinical Trials Experience

The following adverse reactions have been reported following administration of TABRECTA: hypersensitivity and thrombocytopenia.

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 . 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 . 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 . 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 . 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 . 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.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action , 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 ). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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.

Pediatric Use Safety and effectiveness of TABRECTA in pediatric patients have not been established.