Tepotinib Hydrochloride

1 INDICATIONS AND USAGE TEPMETKO is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations. TEPMETKO is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations. ( 1 )

2 DOSAGE AND ADMINISTRATION Select patients for treatment with TEPMETKO on the presence of MET ex14 skipping. ( 2.1 , 14 ) Recommended dosage : 450 mg orally once daily with food until disease progression or unacceptable toxicity. ( 2.2 ) 2.1 Patient Selection for METex14 Skipping Alterations Select patients for treatment with TEPMETKO based on the presence of MET exon 14 skipping alterations in plasma or tumor specimens. Testing for the presence of MET exon 14 skipping alterations in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If an alteration is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. An FDA-approved test for detection of MET exon 14 skipping alterations in NSCLC for selecting patients for treatment with TEPMETKO is not available. 2.2 Recommended Dosage The recommended dosage of TEPMETKO is 450 mg orally once daily with food [see Clinical Pharmacology (12.3) ] until disease progression or unacceptable toxicity. Instruct patients to take their dose of TEPMETKO at approximately the same time every day and to swallow tablets whole. Do not chew, crush or split tablets. Patients who have difficulty swallowing solids can disperse tablets in water [see Dosage and Administration (2.3) ]. Advise patients not to make up a missed dose within 8 hours of the next scheduled dose. If vomiting occurs after taking a dose of TEPMETKO, advise patients to take the next dose at the scheduled time. 2.3 Administration to Patients Who Have Difficulty Swallowing Solids Place TEPMETKO tablet(s) in a glass containing 30 mL (1 ounce) of non-carbonated water. No other liquids should be used or added. Stir, without crushing, until the tablet(s) is dispersed into small pieces (tablets will not completely dissolve) and drink immediately or within 1 hour. Swallow the tablet dispersion. Do not chew pieces of the tablet. Rinse the glass with an additional 30 mL and drink immediately ensuring no residue remains in the glass and the full dose is administered. If an administration via a naso-gastric tube (with at least 8 French gauge) is required, disperse the tablet(s) in 30 mL of non-carbonated water as described above. Administer the 30 mL of liquid immediately or within 1 hour as per naso-gastric tube manufacturer's instructions. Immediately rinse twice with 30 mL each time to ensure that no residue remains in the glass or syringe and the full dose is administered. 2.4 Dose Modifications for Adverse Reactions The recommended dose reduction of TEPMETKO for the management of adverse reactions is 225 mg orally once daily. Permanently discontinue TEPMETKO in patients who are unable to tolerate 225 mg orally once daily. The recommended dosage modifications of TEPMETKO for adverse reactions are provided in Table 1. Table 1: Recommended TEPMETKO Dosage Modifications for Adverse Reactions Adverse Reaction Severity Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5. Dose Modification Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1) ] Any Grade Withhold TEPMETKO if ILD is suspected. Permanently discontinue TEPMETKO if ILD is confirmed. Increased ALT and/or AST without increased total bilirubin [see Warnings and Precautions (5.2) ] Grade 3 Withhold TEPMETKO until recovery to baseline ALT/AST. If recovered to baseline within 7 days, then resume TEPMETKO at the same dose; otherwise resume TEPMETKO at a reduced dose. Grade 4 Permanently discontinue TEPMETKO. Increased ALT and/or AST with increased total bilirubin in the absence of cholestasis or hemolysis [see Warnings and Precautions (5.2) ] ALT and/or AST greater than 3 times ULN with total bilirubin greater than 2 times ULN Permanently discontinue TEPMETKO. Increased total bilirubin without concurrent increased ALT and/or AST [see Warnings and Precautions (5.2) ] Grade 3 Withhold TEPMETKO until recovery to baseline bilirubin. If recovered to baseline within 7 days, then resume TEPMETKO at a reduced dose; otherwise permanently discontinue. Grade 4 Permanently discontinue TEPMETKO. Increased lipase or amylase [see Warnings and Precautions (5.3) ] Grade 3 Withhold TEPMETKO until ≤ Grade 2 or baseline. If recovered to baseline or ≤ Grade 2 within 14 days, resume TEPMETKO at a reduced dose; otherwise permanently discontinue TEPMETKO. Grade 4 Permanently discontinue TEPMETKO. Pancreatitis [see Warnings and Precautions (5.3) ] Grade 3 or 4 Permanently discontinue TEPMETKO. Other adverse reactions [see Adverse Reactions (6.1) ] Grade 2 Maintain dose level. If intolerable, consider withholding TEPMETKO until resolved, then resume TEPMETKO at a reduced dose. Grade 3 Withhold TEPMETKO until resolved, then resume TEPMETKO at a reduced dose. Grade 4 Permanently discontinue TEPMETKO.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail elsewhere in the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Pancreatic Toxicity [see Warnings and Precautions (5.3) ] Most common adverse reactions (≥ 20%) were edema, nausea, fatigue, musculoskeletal pain, diarrhea, dyspnea, decreased appetite, and rash. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased lipase, increased ALT, increased AST, and decreased hemoglobin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to TEPMETKO in 506 patients with solid tumors enrolled in five open-label, single-arm studies receiving TEPMETKO as single agent at a dose of 450 mg once daily. This included 313 patients with NSCLC positive for MET ex14 skipping alterations, who received TEPMETKO in VISION. Among 506 patients who received TEPMETKO, 44% were exposed for 6 months or longer, and 22% were exposed for more than one year. The data described below reflect exposure to TEPMETKO 450 mg once daily in 313 patients with metastatic non-small cell lung cancer (NSCLC) with MET ex14 skipping alterations in VISION [see Clinical Studies (14) ]. Serious adverse reactions occurred in 51% of patients who received TEPMETKO. Serious adverse reactions in > 2% of patients included pleural effusion (6%), pneumonia (6%), edema (5%), general health deterioration (3.8%), dyspnea (3.5%), musculoskeletal pain (2.9%), and pulmonary embolism (2.2%). Fatal adverse reactions occurred in 1.9% of patients who received TEPMETKO, including pneumonitis (0.3%), hepatic failure (0.3%), dyspnea from fluid overload (0.3%), pneumonia (0.3%), sepsis (0.3%), and death of unknown cause (0.3%). Permanent discontinuation due to an adverse reaction occurred in 25% of patients who received TEPMETKO. The most frequent adverse reactions (> 1%) leading to permanent discontinuations of TEPMETKO were edema (8%), pleural effusion (1.6%), and general health deterioration (1.6%). Dosage interruptions due to an adverse reaction occurred in 53% of patients who received TEPMETKO. Adverse reactions which required dosage interruption in > 2% of patients who received TEPMETKO included edema (28%), increased blood creatinine (6%), pleural effusion (3.5%), nausea (3.2%), increased ALT (2.9%), pneumonia (2.6%), decreased appetite (2.2%), and dyspnea (2.2%). Dose reductions due to an adverse reaction occurred in 36% of patients who received TEPMETKO. Adverse reactions which required dose reductions in > 2% of patients who received TEPMETKO included edema (22%), increased blood creatinine (2.9%), fatigue (2.2%), and pleural effusion (2.2%). The most common adverse reactions (≥ 20%) in patients who received TEPMETKO were edema, nausea, fatigue, musculoskeletal pain, diarrhea, dyspnea, decreased appetite, and rash. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased lipase, increased ALT, increased AST, and decreased hemoglobin. Table 2 summarizes the adverse reactions in VISION. Table 2: Adverse Reactions in ≥ 10% of Patients with NSCLC with METex14 Skipping Alterations Who Received TEPMETKO in VISION Adverse Reactions TEPMETKO (N=313) All Grades Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. (%) Grades 3 to 4 (%) General disorders and administration-site conditions Edema Edema includes eye edema, face edema, generalized edema, localized edema, edema, genital edema, peripheral edema, peripheral swelling, periorbital edema, and scrotal edema. 81 16 Fatigue Fatigue includes asthenia and fatigue. 30 1.9 Gastrointestinal disorders Nausea 31 1.3 Diarrhea 29 0.6 Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, and hepatic pain. 19 0.6 Constipation 19 0.3 Vomiting Vomiting includes retching and vomiting. 15 1 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, non-cardiac chest pain, pain in extremity, and spinal pain. 30 3.2 Respiratory, thoracic, and mediastinal disorders Dyspnea Dyspnea includes dyspnea, dyspnea at rest, and dyspnea exertional. 24 2.6 Cough Cough includes cough, and productive cough. 18 0.3 Pleural effusion 14 4.2 Metabolism and nutrition disorders Decreased appetite 21 1.9 Skin and Subcutaneous Tissue Disorders Rash Rash includes rash, palmar-plantar erythrodysesthesia syndrome, rash maculo-papular, eczema, exfoliative rash, rash erythematous, rash pustular, skin exfoliation, dermatitis acneiform, drug eruption, dermatitis, rash pruritic, dermatitis bullous, toxic skin eruption. 21 1.3 Infections and Infestations Pneumonia Pneumonia includes pneumonia, pneumonia aspiration, and pneumonia bacterial. 12 3.8 Clinically relevant adverse reactions in < 10% of patients who received TEPMETKO included ILD/pneumonitis, fever, dizziness, pruritus, and headache. Table 3 summarizes the laboratory abnormalities observed in VISION. Table 3: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients Who Received TEPMETKO in VISION Laboratory Abnormalities TEPMETKO The denominator used to calculate the rate varied from 268 to 309 based on the number of patients with a baseline value and at least one post-treatment value. Grades 1 to 4 Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. (%) Grades 3 to 4 (%) Chemistry Decreased albumin 81 9 Increased creatinine 60 1 Increased alkaline phosphatase aminotransferase 52 1.6 Increased alanine aminotransferase 50 4.9 Increased aspartate aminotransferase 40 3.6 Decreased sodium 36 9 Increased gamma-glutamyltransferase 29 6 Increased potassium 26 1.9 Increased amylase 25 5 Increased lipase 21 5 Hematology Decreased lymphocytes 57 15 Decreased hemoglobin 31 3.6 Decreased leukocytes 25 1.9 Decreased platelets 24 0.6 Increased Creatinine A median increase in serum creatinine of 30% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion .

12.3 Pharmacokinetics The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib exposure (AUC 0-12h and C max ) increases dose-proportionally over the dose range of 27 mg (0.06 times the recommended daily dosage) to 450 mg. At the recommended dosage, the geometric mean (coefficient of variation [CV] %) steady state C max was 1,291 ng/mL (48.1%) and the AUC 0-24h was 27,438 ng∙h/mL (51.7%). The oral clearance of tepotinib did not change with respect to time. The median accumulation was 2.5-fold for C max and 3.3-fold for AUC 0-24h after multiple daily doses of tepotinib. Absorption The median T max of tepotinib is 8 hours (range from 6 to 12 hours). The geometric mean (CV%) absolute bioavailability of TEPMETKO in the fed state was 71.6% (10.8%) in healthy subjects. Effect of Food The mean AUC 0-INF of tepotinib increased by 1.6-fold and C max increased by 2-fold, following administration of a high-fat, high-calorie meal (approximately 800 to 1,000 calories, 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat). The median T max shifted from 12 hours to 8 hours. Distribution The geometric mean (CV%) apparent volume of distribution (V Z /F) of tepotinib is 1,038 L (24.3%). Protein binding of tepotinib is 98% and is independent of drug concentration at clinically relevant exposures. Elimination The apparent clearance (CL/F) of tepotinib is 23.8 L/h (87.5%) and the half-life is 32 hours following oral administration of TEPMETKO in patients with cancer. Metabolism Tepotinib is primarily metabolized by CYP3A4 and CYP2C8. One major circulating plasma metabolite (M506) has been identified. Excretion Following a single oral administration of a radiolabeled dose of 450 mg tepotinib, approximately 85% of the dose was recovered in feces (45% unchanged) and 13.6% in urine (7% unchanged). The major circulating metabolite M506 accounted for about 40.4% of the total radioactivity in plasma. Specific Populations No clinically significant effects on tepotinib pharmacokinetics were observed based on age (18 to 89 years), race/ethnicity (White, Black, Asian, Japanese, and Hispanic), sex, body weight (35.5 to 136 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min), or mild to moderate hepatic impairment (Child-Pugh A and B). The effect of severe renal impairment (CLcr < 30 mL/min) and severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of tepotinib has not been studied. Drug Interaction Studies Clinical Studies and Model-Informed Approaches No clinically significant differences in the pharmacokinetics of tepotinib were observed when coadministered with the following drugs: itraconazole (strong CYP3A and P-gp inhibitor), carbamazepine (strong CYP3A inducer) or omeprazole (proton pump inhibitor/acid reducing agent) under fed conditions. No clinically significant differences in the pharmacokinetics of the following drugs were observed or predicted when coadministered with tepotinib: midazolam (sensitive CYP3A substrate) or CYP2C9 substrates. P-gp Substrates: Coadministration of TEPMETKO with dabigatran etexilate (P-gp substrate) increased dabigatran C max by 40% and AUC 0-INF by 50%. MATE2 and OCT2 Substrates: No clinically relevant differences in glucose levels were observed when metformin (MATE2 and OCT2 substrate) was coadministered with tepotinib. In Vitro Studies Cytochrome P450 Enzymes: Tepotinib is a substrate of CYP3A4 and CYP2C8. Tepotinib and M506 do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 or CYP2E1, and do not induce CYP1A2 or 2B6 at clinically relevant concentrations. UDP-Glucuronosyltransferase (UGT ): Tepotinib and M506 do not inhibit UGT 1A1, 1A9, 2B17, 1A3/4/6 and 2B7/15 at clinically relevant concentrations. Transporter Systems : Tepotinib is a P-gp substrate. Tepotinib may inhibit intestinal BCRP at clinically relevant concentrations. Tepotinib does not inhibit bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1, B3, or organic anion transporter (OAT) 1 and 3.