FDA Approves TEPMETKO (Tepotinib) for Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring MET Exon 14 Skipping Alterations

 

On February 3, 2021, the U.S. Food and Drug Administration (FDA) approved TEPMETKO (tepotinib) for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymalepithelial transition (MET) exon 14 skipping alterations. 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 trial(s).

The approved recommended dosage of TEPMETKO is 450 mg orally once daily with food until disease progression or unacceptable toxicity. Select patients for treatment with TEPMETKO based on the presence of METex14 skipping alterations in plasma or tumor specimens. Testing for the presence of METex14 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 METex14 skipping alterations in NSCLC for selecting patients for treatment with TEPMETKO is not available.

Additional information regarding dosage and administration as well as warnings and precautions about interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations.

General PK: The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib AUC0-12h and Cmax increases dose-proportionally over the dose range of 27 mg (0.06 times the recommended daily dosage) to 450 mg. The geometric mean (CV%) steady state Cmax was 1,291 ng/mL (48.1%) and AUC0-24h 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 Cmax and 3.3-fold for AUC0-24h after multiple daily doses of tepotinib.

Absorption: The geometric mean (CV%) absolute bioavailability of TEPMETKO in the fed state was 71.6% (10.8%) in healthy subjects. The median (range) Tmax of tepotinib is 8 hours (6 to 12 hours).The mean AUC0-INF of tepotinib increased by 1.6-fold and Cmax 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).

Distribution: The geometric mean (CV%) apparent volume of distribution (Vz/F) of tepotinib is 1,038 L (24.3%). Protein binding of tepotinib is 98% and is independent of drug concentration.

Elimination: The apparent clearance (CL/F) of tepotinib is 23.8 L/h (87.5%) and the half-life is 32 hours.

Metabolism: Tepotinib is primarily metabolized by CYP3A4 and CYP2C8.

Excretion: Following a single oral administration of a radiolabeled dose of tepotinib 450 mg, approximately 85% of the dose was recovered in feces (45% unchanged) and 13.6% in urine (7% unchanged).

Drug Interactions

Dual Strong CYP3A Inhibitors and P-gp Inhibitors: Avoid concomitant use. The effect of strong CYP3A inhibitors or P-gp inhibitors on TEPMETKO has not been studied clinically.

Strong CYP3A Inducers: Avoid concomitant use. The effect of strong CYP3A inducers on TEPMETKO has not been studied clinically.

Certain P-gp Substrates: Avoid coadministration of TEPMETKO with 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. 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.

Use in 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.

Efficacy and Safety

Efficacy of TEPMETKO was evaluated in a single-arm, open-label, multicenter, non-randomized, multicohort study. 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. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

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 AST, and decreased hemoglobin.

Full prescribing information is available at https://go.usa.gov/xAJrF.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.