TEPMETKO

5 WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD)/Pneumonitis : Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis. Permanently discontinue TEPMETKO in patients diagnosed with ILD/pneumonitis of any severity. ( 2.4 , 5.1 ) Hepatotoxicity : Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. ( 5.2 ) Pancreatic Toxicity : Monitor amylase and lipase. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity. ( 5.3 ) Embryo-fetal toxicity : TEPMETKO can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease (ILD)/Pneumonitis ILD/pneumonitis, which can be fatal, occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1) ]. ILD/pneumonitis occurred in 2% patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death. Five patients (1%) discontinued TEPMETKO due to ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.4) ]. 5.2 Hepatotoxicity Hepatotoxicity occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1) ] . Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 18% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.7% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). Four patients (0.8%) discontinued TEPMETKO due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 47 days (range 1 to 262). Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, 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 TEPMETKO [see Dosage and Administration (2.4) ] . 5.3 Pancreatic Toxicity Elevations in amylase and lipase levels occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1) ]. Increased amylase and/or lipase occurred in 13% of patients treated with TEPMETKO. Grade 3 and 4 increased amylase and/or lipase occurred in 5% and 1.2% of patients, respectively. Monitor amylase and lipase at baseline and regularly during treatment with TEPMETKO. Based on the severity of the adverse drug reaction, temporarily withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.4) ]. 5.4 Embryo-Fetal Toxicity Based on findings in animal studies and its mechanism of action TEPMETKO can cause fetal harm when administered to a pregnant woman. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the last dose. [See Use in Specific Populations (8.1 , 8.3) ]

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 .

<table width="90%"><caption>Table 2: Adverse Reactions in &#x2265; 10% of Patients with NSCLC with METex14 Skipping Alterations Who Received TEPMETKO in VISION</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Adverse Reactions</th><th styleCode="Rrule" colspan="2">TEPMETKO (N=313)</th></tr><tr><th styleCode="Rrule" align="center">All Grades<footnote ID="t2f1">Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.</footnote> (%)</th><th styleCode="Rrule">Grades 3 to 4<footnoteRef IDREF="t2f1"/> (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General disorders and administration-site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema<footnote>Edema includes eye edema, face edema, generalized edema, localized edema, edema, genital edema, peripheral edema, peripheral swelling, periorbital edema, and scrotal edema.</footnote></td><td styleCode="Rrule">81</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Fatigue includes asthenia and fatigue.</footnote></td><td styleCode="Rrule">30</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">31</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">29</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnote>Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, and hepatic pain.</footnote></td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting<footnote>Vomiting includes retching and vomiting.</footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Musculoskeletal pain<footnote>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.</footnote></td><td styleCode="Rrule">30</td><td styleCode="Rrule">3.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea<footnote>Dyspnea includes dyspnea, dyspnea at rest, and dyspnea exertional.</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">2.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough<footnote>Cough includes cough, and productive cough.</footnote></td><td styleCode="Rrule">18</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pleural effusion</td><td styleCode="Rrule">14</td><td styleCode="Rrule">4.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and nutrition disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">21</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash<footnote>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.</footnote></td><td styleCode="Rrule">21</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Infections and Infestations</content></td></tr><tr><td styleCode="Lrule Rrule"> Pneumonia<footnote>Pneumonia includes pneumonia, pneumonia aspiration, and pneumonia bacterial.</footnote></td><td styleCode="Rrule">12</td><td styleCode="Rrule">3.8</td></tr></tbody></table>

<table width="90%"><caption>Table 3: Select Laboratory Abnormalities (&#x2265; 20%) That Worsened from Baseline in Patients Who Received TEPMETKO in VISION</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Laboratory Abnormalities</th><th styleCode="Rrule" colspan="2">TEPMETKO<footnote>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.</footnote></th></tr><tr><th styleCode="Rrule" align="center">Grades 1 to 4<footnote ID="t3f2">Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.</footnote> (%)</th><th styleCode="Rrule">Grades 3 to 4<footnoteRef IDREF="t3f2"/> (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased albumin</td><td styleCode="Rrule">81</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased creatinine</td><td styleCode="Rrule">60</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased alkaline phosphatase aminotransferase</td><td styleCode="Rrule">52</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased alanine aminotransferase</td><td styleCode="Rrule">50</td><td styleCode="Rrule">4.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased aspartate aminotransferase</td><td styleCode="Rrule">40</td><td styleCode="Rrule">3.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased sodium</td><td styleCode="Rrule">36</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased gamma-glutamyltransferase</td><td styleCode="Rrule">29</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased potassium</td><td styleCode="Rrule">26</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased amylase</td><td styleCode="Rrule">25</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased lipase</td><td styleCode="Rrule">21</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased lymphocytes</td><td styleCode="Rrule">57</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased hemoglobin</td><td styleCode="Rrule">31</td><td styleCode="Rrule">3.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased leukocytes</td><td styleCode="Rrule">25</td><td styleCode="Rrule">1.9</td></tr><tr><td styleCode="Lrule Rrule"> Decreased platelets</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0.6</td></tr></tbody></table>