Safety

The safety profile of TEPMETKO® (tepotinib) reflects exposure to TEPMETKO in 506 patients with various solid tumors. These patients were enrolled in 5 open-label, single-arm studies, in which they received TEPMETKO as a single agent at a dose of 450 mg once daily. This included 313 patients with NSCLC positive for METex14 skipping alterations who received TEPMETKO in VISION.

Interstitial lung disease (ILD)/Pneumonitis 

ILD/pneumonitis, which can be fatal, occurred in patients treated with TEPMETKO. 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.

Hepatotoxicity 

Hepatotoxicity occurred in patients treated with TEPMETKO. 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.

Pancreatic Toxicity

Elevations in amylase and lipase levels occurred in patients treated with TEPMETKO. 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.

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.

The safety and tolerability profile of TEPMETKO was studied in 313 patients in the VISION Trial¹

• 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%)
• 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%)

Adverse reactions in ≥10% of patients with NSCLC harboring METex14+¹*

• Permanent discontinuation – 25%
  • The most frequent ARs (>1%) leading to permanent discontinuations of TEPMETKO were edema (8%), pleural effusion (1.6%), and general health deterioration (1.6%)
• Dosage interruptions – 53%
  • ARs 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 – 36%
  • ARs 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%)
    

• Selected laboratory abnormalities (≥20%) from baseline in patients receiving TEPMETKO in descending order were: decreased albumin (81%), increased creatinine (60%), decreased lymphocytes (57%), increased ALP (52%), increased ALT (50%), increased AST (40%), decreased sodium (36%), decreased hemoglobin (31%), increased GGT (29%), increased potassium (26%), increased amylase (25%), decreased leukocytes (25%), decreased platelets (24%), and increased lipase (21%)
• The most common Grade 3-4 laboratory abnormalities (≥2%) in descending order were: decreased lymphocytes (15%), decreased albumin (9%), decreased sodium (9%), increased GGT (6%), increased amylase (5%), increased lipase (5%), increased ALT (4.9%), increased AST (3.6%), decreased hemoglobin (3.6%)

*Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. ^†Edema includes eye edema, face edema, generalized edema, localized edema, edema, genital edema, peripheral edema, peripheral swelling, periorbital edema, and scrotal edema. ^‡Fatigue includes asthenia and fatigue. ^§Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, and hepatic pain. ^‖Vomiting includes retching and vomiting. ^¶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. ^#Dyspnea includes dyspnea, dyspnea at rest, and dyspnea exertional. **Cough includes cough, and productive cough. ^††Rash includes rash, palmar-plantar erythrodysaesthesia 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. ^‡‡Pneumonia includes pneumonia, pneumonia aspiration, and pneumonia bacterial. ^§§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.