Tepotinib

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.

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 m

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.