As reported in The New England Journal of Medicine by Paul K. Paik, MD, and colleagues, the phase II VISION trial has shown durable responses with the highly selective MET inhibitor tepotinib in patients with non–small cell lung cancer (NSCLC) and MET exon 14–skipping mutation.

As noted by the investigators, a splice-site mutation resulting in loss of transcription of exon 14 in the oncogenic driver MET occurs in 3% to 4% of patients with NSCLC.

Paul K. Paik, MD

Study Details

In the trial, 152 patients with advanced or metastatic disease received tepotinib at 500 mg once daily by January 2020 (safety population), with 99 having follow-up of ≥ 9 months (efficacy population). Among the 99 patients in the efficacy population, presence of a MET exon 14–skipping mutation was determined by liquid biopsy in 66 patients and by tissue biopsy in 60, with 27 having diagnosis determined by both. Among patients in the efficacy population, 56% had received one or more prior therapies for advanced or metastatic disease. The primary endpoint was objective response on independent review in the efficacy population, with response rates also being analyzed according to whether presence of a MET exon 14–skipping mutation was detected by a liquid or tissue biopsy.

Responses

Median follow-up in the efficacy population was 17.4 months. Among the 99 patients in the efficacy population, the objective response rate (all partial responses) was 46% (95% confidence interval [CI] = 36%–57%), with a median duration of response of 11.1 months (95% CI = 7.2 months–not estimable). Objective response rates were 48% among the 66 patients in the liquid biopsy­–detected group and 50% among the 60 patients in the tissue biopsy­–detected group. Response rates were similar regardless of baseline characteristics and number of lines of previous therapy. The investigator-assessed objective response rate was 56%. Among 51 patients with matched baseline liquid biopsy samples, molecular response measured in circulating free DNA was observed in 34 (67%).

Median progression-free survival on independent review was 8.5 months among all 99 patients, 8.5 months in the liquid biopsy group, and 11.0 months in the tissue biopsy group.

Adverse Events

Among 152 patients in the safety population, treatment-related grade ≥ 3 adverse events occurred in 28% of patients, with the most common being peripheral edema (7%). Treatment-related serious adverse events occurred in 15% of patients. Treatment-related adverse events led to dose reduction in 33% of patients and to permanent discontinuation of tepotinib in 11%. Dose reductions and discontinuations were primarily due to peripheral edema, pleural effusion, and dyspnea. Peripheral edema of any grade was the most common treatment-related adverse event (63%) and led to dose reduction in 16% of patients, dose interruption in 18%, and permanent discontinuation in 5%. One death, due to respiratory failure and dyspnea secondary to interstitial lung disease, was considered related to treatment.

The investigators concluded, “Among patients with advanced NSCLC with a confirmed MET exon 14–skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher.”

Disclosure: The study was funded by Merck. For full disclosures of the study authors, visit nejm.org.