On February 3, 2021, tepotinib was granted accelerated approval for treatment of adult patients with metastatic non–small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14–skipping alterations.1,2
Supporting Efficacy Data
Approval was supported by findings from the phase II multicohort, multicenter VISION trial (ClinicalTrials.gov identifier NCT02864992).2,3 In the trial, 152 patients (efficacy population) with advanced or metastatic NSCLC with MET exon 14–skipping alterations received oral tepotinib at 450 mg once daily until disease progression or unacceptable toxicity. Patients with symptomatic central nervous system metastases or clinically significant uncontrolled cardiac disease and those who had received treatment with any MET or hepatocyte growth factor inhibitor were not eligible for the study. The presence of MET exon 14–skipping alterations was prospectively determined by central laboratories using either polymerase chain reaction–based or next-generation sequencing–based clinical trial assays using tissue (58%) or plasma (65%) samples.
Tepotinib has warnings/precautions for interstitial lung disease/pneumonitis, hepatotoxicity, and embryofetal toxicity.
The main efficacy outcome measures were overall response rate, as determined by a blinded independent review committee using Response Evaluation Criteria in Solid Tumors version 1.1 and response duration. Among 69 treatment-naive patients, the overall response rate was 43% (95% confidence interval [CI] = 32%–56%), with a median response duration of 10.8 months (95% CI = 6.9 months to not estimable); responses lasted for at least 6 and at least 9 months in 67% and 30% of responders. Among 83 previously treated patients, the overall response rate was 43% (95% CI = 33%–55%), with a median response duration of 11.1 months (95% CI = 9.5–18.5 months); responses lasted for at least 6 and at least 9 months in 75% and 50% of responders.
How It Works
Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14–skipping alterations. Tepotinib inhibits hepatocyte growth factor–dependent and –independent MET phosphorylation and MET-dependent downstream signaling pathways. Tepotinib also inhibits melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations. In studies 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 exon 14–skipping alterations, tepotinib inhibited tumor growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases.
How It Is Used
The recommended dose of tepotinib in the current indication is 450 mg once daily, with treatment continuing until disease progression or unacceptable toxicity.
Patients must be selected for treatment 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 with no available tumor biopsy. If an alteration is not detected in a plasma specimen, the feasibility of biopsy for tumor tissue testing should be reevaluated. A U.S. Food and Drug Administration–approved test for detection of MET exon 14–skipping alterations in NSCLC for selecting patients for treatment is not available.
For management of adverse reactions, the recommended dose reduction of tepotinib is to 225 mg once daily; treatment should be permanently discontinued in patients unable to tolerate the reduced dose. Prescribing information provides information on dosage modification, including dose reduction and withholding and discontinuation of treatment, for adverse reactions including interstitial lung disease/pneumonitis, increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) without increased total bilirubin, increased ALT or AST with increased total bilirubin in the absence of cholestasis or hemolysis, increased total bilirubin without concurrent increased ALT or AST, and other grade 2 to 4 adverse reactions.
Concomitant use of tepotinib should be avoided with dual strong CYP3A inhibitors and P-glycoprotein (gp) inhibitors (eg, ketoconazole, clarithromycin, diltiazem), strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort), and P-gp substrates (eg, colchicine, digoxin), concurrent use of which can cause changes in the minimal concentration of the substrate that may lead to serious or life-threatening toxicities.
Safety data are from a total of 255 patients with metastatic NSCLC with MET exon 14–skipping alterations who received tepotinib at 450 mg once daily in the VISION trial.
The most common adverse events of any grade (≥ 20% of patients) were edema (70%), fatigue (27%), nausea (27%), diarrhea (26%), musculoskeletal pain (24%), and dyspnea (20%). The most common grade 3 or 4 adverse events included edema (9%), pleural effusion (5%), and pneumonia (3.9%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (11%), decreased albumin (9%), and decreased sodium (8%). Increased ALT and increased AST of any grade occurred in 44% and 35% of patients.
Serious adverse events occurred in 45% of patients, the most common being pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). Adverse events led to dosage interruptions in 44%—the most common causes being edema (23%), increased blood creatinine (6%), and pleural effusion (4.3%)—and to dose reductions in 30%, the most common causes being edema (19%), pleural effusion (2.7%), and increased blood creatinine (2.7%). Permanent treatment discontinuation due to adverse events occurred in 20%. Adverse events led to death in three patients, with causes consisting of pneumonitis, hepatic failure, and dyspnea from fluid overload in one patient each.
Tepotinib has warnings/precautions for interstitial lung disease/pneumonitis, hepatotoxicity, and embryofetal toxicity. Treatment should be permanently discontinued for interstitial lung disease/pneumonitis of any severity. Liver function tests should be regularly monitored. Patients should be advised not to breastfeed while receiving tepotinib.
1. U.S. Food and Drug Administration: FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-tepotinib-metastatic-non-small-cell-lung-cancer. Accessed February 16, 2021.
2. Tepmetko (tepotinib) tablets prescribing information, EMD Serono, Inc. February 2021, Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214096s000lbl.pdf. Accessed February 16, 2021.