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) ] Most common adverse reactions (≥ 20%) were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased lipase, 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 448 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 255 patients with NSCLC positive for MET ex14 skipping alterations, who received TEPMETKO in VISION. Among 448 patients who received TEPMETKO, 32% were exposed for 6 months or longer, and 12% were exposed for greater than one year. The data described below reflect exposure to TEPMETKO 450 mg once daily in 255 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 45% of patients who received TEPMETKO. Serious adverse reactions in > 2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received TEPMETKO. The most frequent adverse reactions (> 1%) leading to permanent discontinuations of TEPMETKO were edema (5%), pleural effusion (2%), dyspnea (1.6%), general health deterioration (1.6%), and pneumonitis (1.2%). Dosage interruptions due to an adverse reaction occurred in 44% of patients who received TEPMETKO. Adverse reactions which required dosage interruption in > 2% of patients who received TEPMETKO included edema (23%), increased blood creatinine (6%), pleural effusion (4.3%), increased ALT (3.1%), and pneumonia (2.4%). Dose reductions due to an adverse reaction occurred in 30% of patients who received TEPMETKO. Adverse reactions which required dose reductions in > 2% of patients who received TEPMETKO included edema (19%), pleural effusion (2.7%), and increased blood creatinine (2.7%). The most common adverse reactions (≥ 20%) in patients who received TEPMETKO were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased lipase, 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 = 255) All Grades (%) 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. 70 9 Fatigue Fatigue includes asthenia and fatigue. 27 1.6 Gastrointestinal disorders Nausea 27 0.8 Diarrhea 26 0.4 Abdominal Pain Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, and hepatic pain. 16 0.8 Constipation 16 0 Vomiting Vomiting includes retching and vomiting. 13 1.2 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. 24 2.4 Respiratory, thoracic, and mediastinal disorders Dyspnea Dyspnea includes dyspnea, dyspnea at rest, and dyspnea exertional. 20 2 Cough Cough includes cough, and productive cough. 15 0.4 Pleural effusion 13 5 Metabolism and nutrition disorders Decreased appetite 16 1.2 Infections and Infestations Pneumonia Pneumonia includes pneumonia, pneumonia aspiration, and pneumonia bacterial. 11 3.9 Clinically relevant adverse reactions in < 10% of patients who received TEPMETKO included ILD/pneumonitis, rash, 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 207 to 246 based on the number of patients with a baseline value and at least one post-treatment value. Grades 1 to 4 (%) Grades 3 to 4 (%) Chemistry Decreased albumin 76 9 Increased creatinine 55 0.4 Increased alkaline phosphatase aminotransferase 50 1.6 Increased alanine aminotransferase 44 4.1 Increased aspartate aminotransferase 35 2.5 Decreased sodium 31 8 Increased potassium 25 1.6 Increased gamma-glutamyltransferase 24 5 Increased amylase 23 4.6 Hematology Decreased lymphocytes 48 11 Decreased hemoglobin 27 2 Decreased leukocytes 23 0.8 A clinically relevant laboratory abnormality in < 20% of patients who received TEPMETKO was increased lipase in 18% of patients, including 3.7% Grades 3 to 4. Increased Creatinine A median increase in serum creatinine of 31% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion .

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Tepotinib is a kinase inhibitor. TEPMETKO (tepotinib) tablets for oral use are formulated with tepotinib hydrochloride hydrate. The chemical name for tepotinib hydrochloride hydrate is 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile hydrochloride hydrate. The molecular formula is C 29 H 28 N 6 O 2 ∙HCl∙H 2 O and the molecular weight is 547.05 g/mol for tepotinib hydrochloride hydrate and 492.58 g/mol for tepotinib (free base). The chemical structure is shown below: Tepotinib hydrochloride hydrate is a white to off-white powder with a pKa of 9.5. TEPMETKO is supplied as film-coated tablets containing 225 mg of tepotinib (equivalent to 250 mg tepotinib hydrochloride hydrate). Inactive ingredients in the tablet core are mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, and colloidal silicon dioxide. The tablet coating consists of hypromellose, titanium dioxide, lactose monohydrate, polyethylene glycol, triacetin, and red iron oxides. Chemical Structure

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. 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 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. 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.

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. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 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 ) This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. ( 1 )

7 DRUG INTERACTIONS Certain P-gp substrates : Avoid coadministration of TEPMETKO with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.1 ) 7.1 Effects of TEPMETKO on Other Drugs Certain P-gp Substrates Tepotinib is a P-gp inhibitor. Concomitant use of TEPMETKO increases the concentration of P-gp substrates [see Clinical Pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of these substrates. Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits hepatocyte growth factor (HGF)-dependent and -independent MET phosphorylation and MET-dependent downstream signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations. In vitro, tepotinib inhibited tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. In mice implanted with tumor cell lines with oncogenic activation of MET, including MET ex14 skipping alterations, tepotinib inhibited tumor growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases. 12.2 Pharmacodynamics Exposure-Response Tepotinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology At the recommended dosage, no large mean increases in QTc (i.e. > 20 ms) were detected in patients with various solid tumors. A concentration-dependent increase in QTc interval was observed. The QTc effect of tepotinib at high clinical exposures has not been evaluated. 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.

12.1 Mechanism of Action Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits hepatocyte growth factor (HGF)-dependent and -independent MET phosphorylation and MET-dependent downstream signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations. In vitro, tepotinib inhibited tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. In mice implanted with tumor cell lines with oncogenic activation of MET, including MET ex14 skipping alterations, tepotinib inhibited tumor growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases.

12.2 Pharmacodynamics Exposure-Response Tepotinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology At the recommended dosage, no large mean increases in QTc (i.e. > 20 ms) were detected in patients with various solid tumors. A concentration-dependent increase in QTc interval was observed. The QTc effect of tepotinib at high clinical exposures has not been evaluated.

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.

20230330

6

3 DOSAGE FORMS AND STRENGTHS Tablets: 225 mg, white-pink, oval, biconvex film-coated tablets with embossment "M" on one side and plain on the other side. Tablets: 225 mg. ( 3 )

TEPMETKO Tepotinib Hydrochloride Tepotinib Hydrochloride Tepotinib Mannitol Microcrystalline Cellulose Crospovidone, Unspecified Magnesium stearate Silicon Dioxide Hypromellose, Unspecified Lactose monohydrate Polyethylene Glycol, Unspecified Triacetin Ferric oxide red Titanium dioxide White-pink oval, biconvex M

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with tepotinib. Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay , or a mouse lymphoma assay. In vivo, tepotinib was not genotoxic in a rat micronucleus test. Fertility studies of tepotinib have not been performed. There were no morphological changes in male or female reproductive organs in repeat-dose toxicity studies in dogs.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with tepotinib. Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay , or a mouse lymphoma assay. In vivo, tepotinib was not genotoxic in a rat micronucleus test. Fertility studies of tepotinib have not been performed. There were no morphological changes in male or female reproductive organs in repeat-dose toxicity studies in dogs.

NDA214096

TEPMETKO

Tepotinib Hydrochloride

44087-5000

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 30 Tablet Blister Pack Carton NDC 44087-5000-3 TEPMETKO ® (tepotinib) tablets 225 mg per tablet Rx Only Each tablet contains 225 mg of tepotinib (equivalent to 250 mg tepotinib hydrochloride hydrate) Each carton contains 3 child resistant blister cards of 10 tablets each 30 tablets EMD SERONO PRINCIPAL DISPLAY PANEL - 30 Tablet Blister Pack Carton

Dosage and Administration ( 2.3 ) 03/2023

Manufactured for: EMD Serono, Inc. Rockland, MA 02370 U.S.A. TEPMETKO is a trademark of Merck KGaA, Darmstadt, Germany

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Interstitial Lung Disease (ILD)/Pneumonitis Inform patients of the risk of severe or fatal ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.1) ] . Hepatotoxicity Inform patients that they will need to undergo lab tests to monitor liver function. Advise patients to immediately contact their healthcare provider for signs and symptoms of liver dysfunction [see Warnings and Precautions (5.2) ] . Embryo-Fetal Toxicity Advise males and females of reproductive potential that TEPMETKO can cause fetal harm. Advise females of reproductive potential to use effective contraception during and for one week after the final dose of TEPMETKO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.3) ] . Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the final dose of TEPMETKO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.3) ]. Lactation Advise women not to breastfeed during treatment with TEPMETKO and for one week after the final dose [see Use in Specific Populations (8.2) ] . Drug Interactions Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs and herbal products [see Drug Interactions (7) ]. Dosing and Administration Instruct patients to take 450 mg TEPMETKO once daily with food [see Dosage and Administration (2.2) ] . Missed Dose Advise patients that a missed dose of TEPMETKO can be taken as soon as remembered on the same day, unless the next dose is due within 8 hours. If vomiting occurs after taking a dose of TEPMETKO, advise patients to take the next dose at the scheduled time [see Dosage and Administration (2.2) ] .

14 CLINICAL STUDIES The efficacy of TEPMETKO was evaluated in a single-arm, open-label, multicenter, non-randomized, multicohort study (VISION, NCT02864992). Eligible patients were required to have advanced or metastatic NSCLC harboring MET ex14 skipping alterations, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 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. Identification of MET ex14 skipping alterations was prospectively determined using central laboratories employing either a PCR-based or next-generation sequencing-based clinical trial assay using tissue (58%) and/or plasma (65%) samples. Patients received TEPMETKO 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by a Blinded Independent Review Committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC. The efficacy population included 69 treatment naïve patients and 83 previously treated patients. The median age was 73 years (range 41 to 94 years); 48% female; 71% White, 25% Asian; 27% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 73% had ECOG PS 1; 43% never smoked; 86% had adenocarcinoma; 98% had metastatic disease; and 10% had CNS metastases. Amongst previously treated patients, 89% received prior platinum-based chemotherapy. Efficacy results are presented in Table 4. Table 4: Efficacy Results in the VISION study Efficacy parameter Treatment-Naïve N = 69 Previously Treated N = 83 CI=confidence interval, NE=Not estimable Overall response rate, % (95% CI) Blinded Independent Review Committee (BIRC) review , Confirmed Responses 43 (32, 56) 43 (33, 55) Median duration of response, months Product-limit (Kaplan-Meier) estimates, 95% CI for the median using the Brookmeyer and Crowley method. (95% CI) 10.8 (6.9, NE) 11.1 (9.5, 18.5) Patients with DOR ≥ 6 months, % 67 75 Patients with DOR ≥ 9 months, % 30 50

8.5 Geriatric Use Of 255 patients with MET ex14 skipping alterations in VISION who received 450 mg TEPMETKO once daily, 79% were 65 years or older, and 43% were 75 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

8.4 Pediatric Use The safety and efficacy of TEPMETKO in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Based on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ], TEPMETKO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TEPMETKO in pregnant women. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at maternal exposures less than the human exposure based on area under the curve (AUC) at the 450 mg 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 embryo-fetal development studies, pregnant rabbits received oral doses of 0.5, 5, 25, 50, 150, or 450 mg/kg tepotinib hydrochloride hydrate daily during organogenesis. Severe maternal toxicity occurred at the 450 mg/kg dose (approximately 0.75 times the human exposure at the 450 mg clinical dose). At 150 mg/kg (approximately 0.5 times the human exposure by AUC at the 450 mg clinical dose), two animals aborted and one animal died prematurely; mean fetal body weight was also decreased. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus, occurred at doses ≥ 5 mg/kg (approximately 0.003 times the human exposure by AUC at the 450 mg clinical dose); there was also an incidence of spina bifida at the 5 mg/kg dose level.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ], TEPMETKO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TEPMETKO in pregnant women. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at maternal exposures less than the human exposure based on area under the curve (AUC) at the 450 mg 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 embryo-fetal development studies, pregnant rabbits received oral doses of 0.5, 5, 25, 50, 150, or 450 mg/kg tepotinib hydrochloride hydrate daily during organogenesis. Severe maternal toxicity occurred at the 450 mg/kg dose (approximately 0.75 times the human exposure at the 450 mg clinical dose). At 150 mg/kg (approximately 0.5 times the human exposure by AUC at the 450 mg clinical dose), two animals aborted and one animal died prematurely; mean fetal body weight was also decreased. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus, occurred at doses ≥ 5 mg/kg (approximately 0.003 times the human exposure by AUC at the 450 mg clinical dose); there was also an incidence of spina bifida at the 5 mg/kg dose level. 8.2 Lactation Risk Summary There are no data regarding the secretion of tepotinib or its metabolites in human milk or its effects on the breastfed infant or milk production. Advise women not to breastfeed during treatment with TEPMETKO and for one week after the final dose. 8.3 Females and Males of Reproductive Potential Based on animal data, TEPMETKO can cause malformations at doses less than the human exposure based on AUC at the 450 mg clinical dose [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TEPMETKO [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the final dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the final dose. 8.4 Pediatric Use The safety and efficacy of TEPMETKO in pediatric patients have not been established. 8.5 Geriatric Use Of 255 patients with MET ex14 skipping alterations in VISION who received 450 mg TEPMETKO once daily, 79% were 65 years or older, and 43% were 75 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients. 8.6 Renal Impairment No dosage modification is recommended in patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) [see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment No dosage modification is recommended in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. The pharmacokinetics and safety of tepotinib in patients with severe hepatic impairment (Child Pugh Class C) have not been studied [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING TEPMETKO (tepotinib) tablets: 225 mg tepotinib, white-pink, oval, biconvex film-coated tablet with embossment "M" on one side and plain on the other side. NDC number Size 44087-5000-3 Box of 30 tablets: 3 blister cards each containing 10 tablets 44087-5000-6 Box of 60 tablets: 6 blister cards each containing 10 tablets The blister cards consist of a child-resistant blister foil. Store TEPMETKO at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP-NF Controlled Room Temperature]. Store in original package.

Store TEPMETKO at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP-NF Controlled Room Temperature]. Store in original package.