Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.

Abstract

BACKGROUND:

A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.

METHODS:

In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point 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.

RESULTS:

As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had 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. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. 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.

CONCLUSIONS:

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. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

• Authors: Paul K Paik, Enriqueta Felip, Remi Veillon, Hiroshi Sakai, Alexis B Cortot, Marina C Garassino, Julien Mazieres, Santiago Viteri, Helene Senellart, Jan Van Meerbeeck, Jo Raskin, Niels Reinmuth, Pierfranco Conte, Dariusz Kowalski, Byoung Chul Cho, Jyoti D Patel, Leora Horn, Frank Griesinger, Ji-Youn Han, Young-Chul Kim, Gee-Chen Chang, Chen-Liang Tsai, James C-H Yang, Yuh-Min Chen, Egbert F Smit, Anthonie J van der Wekken, Terufumi Kato, Dilafruz Juraeva, Christopher Stroh, Rolf Bruns, Josef Straub, Andreas Johne, Jürgen Scheele, John V Heymach, Xiuning Le
• Journal: The New England journal of medicine (N Engl J Med) Vol. 383 Issue 10 Pg. 931-943 (09 03 2020) ISSN: 1533-4406 [Electronic] United States
• PMID: 32469185 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Massachusetts Medical Society.

Chemical References

• Antineoplastic Agents
• Piperidines
• Protein Kinase Inhibitors
• Pyridazines
• Pyrimidines
• tepotinib
• Proto-Oncogene Proteins c-met

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Edema (chemically induced)
• Exons
• Female
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Male
• Middle Aged
• Mutation
• Piperidines (adverse effects, therapeutic use)
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics)
• Pyridazines (adverse effects, therapeutic use)
• Pyrimidines (adverse effects, therapeutic use)