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

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 KimGee-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

Research output: Contribution to journalArticlepeer-review

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.).

Original languageEnglish
Pages (from-to)931-943
Number of pages13
JournalThe New England journal of medicine
Volume383
Issue number10
DOIs
Publication statusPublished - Sep 3 2020

Keywords

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

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