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Tepotinib Shows Activity in Advanced NSCLC with a MET Exon 14 Skipping Mutation

Findings from the VISION study
09 Sep 2020
Anticancer agents & Biologic therapy;  Lung and other thoracic tumours;  Personalised medicine

In patients with advanced non-small cell lung cancer (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 oedema was the main side effect of grade 3 or higher. The results from the VISION study are published by Dr. Paul K. Paik of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues in 3rd September 2020 issue of The New England Journal of Medicine.

The authors wrote in the study background that MET alterations are primary oncogenic

drivers that occur in 3-4% of patients with NSCLC and can be detected in liquid biopsy or tissue biopsy samples. These tumours typically do not contain other known oncogenic drivers. NSCLC patients with MET exon 14 skipping mutations are typically 70 years of age or older.

Tepotinib is a highly selective, oral MET inhibitor that has shown promising clinical activity in patients with MET-driven tumours. The VISION team conducted the multicohort, open-label, phase II study to evaluate the efficacy and side effect profile of tepotinib in patients with advanced NSCLC with MET alterations. In their article, published in the NEJM, they reported the results in patients with MET exon 14 skipping mutations.

The study primary endpoint was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.

Tepotinib was administered at a dose of 500 mg once daily. As of 1 January 2020, 152 patients had received tepotinib and 99 patients have been followed for at least 9 months.

The response rate by independent review was 46% (95% confidence interval [CI] 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined biopsy group.

The response rate was 48% (95% CI 36 to 61) among 66 patients in the liquid biopsy group and 50% (95% CI 37 to 63) among 60 patients in the tissue biopsy group; 27 patients had positive results according to both methods.

The investigator assessed response rate was 56% (95% CI 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease.

A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid biopsy samples at baseline and during treatment.

Side effects of grade 3 or higher that were considered related to tepotinib were reported in 28% of the patients, including peripheral oedema in 7%. Proactive monitoring for peripheral oedema is recommended and can be managed with temporary discontinuation of tepotinib or dose reduction. Side effects led to permanent discontinuation of tepotinib in 11% of the patients. The patients’ quality of life was maintained during tepotinib treatment.

The authors concluded that their results show that the selective MET inhibitor tepotinib has durable clinical activity in patients with NSCLC with MET mutations associated with exon 14 skipping. Furthermore, results from the VISION study have led to regulatory approval of tepotinib and its companion diagnostic assay for the detection of MET alterations, ArcherMET CDx, in March 2020 in Japan.

The findings from the VISION study validate MET exon 14 skipping mutation as a therapeutic target and emphasize the importance of routine testing for these MET alterations by liquid or tissue biopsy.

The study was funded by Merck (Darmstadt, Germany).

Reference

Paik PK, Felip E, Veillon R, et al. Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med 2020;383:931-43. DOI: 10.1056/NEJMoa2004407.

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