Tepmetko Drug Information

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.

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.

Recommended Dosage

The recommended dosage of TEPMETKO is 450 mg orally once daily with food 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. 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.

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.

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 Any Grade Withhold TEPMETKO if ILD is suspected. Increased ALT and/or AST without increased total bilirubin Grade 3 Withhold TEPMETKO until recovery to baseline ALT/AST.

Grade 4 Permanently discontinue TEPMETKO. Increased ALT and/or AST with increased total bilirubin in the absence of cholestasis or hemolysis ALT and/or AST greater than 3 times ULN with total bilirubin greater than 2 times ULN Permanently discontinue TEPMETKO.

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.

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. Serious adverse reactions occurred in 51% of patients who received TEPMETKO. Fatal adverse reactions occurred in 1.9% of patients who received TEPMETKO, including pneumonitis ( %).

Permanent discontinuation due to an adverse reaction occurred in 25% of patients who received TEPMETKO. Dosage interruptions due to an adverse reaction occurred in 53% of patients who received TEPMETKO. Dose reductions due to an adverse reaction occurred in 36% of patients who received TEPMETKO.

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 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 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.

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, 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.

Pregnancy Risk Summary Based on findings in animal studies and the mechanism of action, 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 respectively. Data Animal Data In embryo-fetal development studies, pregnant rabbits received oral doses of 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 calcaneus 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.

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