Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations
Journal
New England Journal of Medicine
Journal Volume
383
Journal Issue
10
Pages
931-943
Date Issued
2020
Author(s)
Paik P.K.
Felip E.
Veillon R.
Sakai H.
Cortot A.B.
Garassino M.C.
Mazieres J.
Viteri S.
Senellart H.
van Meerbeeck J.
Raskin J.
Reinmuth N.
Conte P.
Kowalski D.
Cho B.C.
Patel J.D.
Horn L.
Griesinger F.
Han J.-Y.
Kim Y.-C.
Chang G.-C.
Tsai C.-L.
Chen Y.-M.
Smit E.F.
van der Wekken A.J.
Kato T.
Juraeva D.
Stroh C.
Bruns R.
Straub J.
Johne A.
Scheele J.
Heymach J.V.
Le X.
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.). Copyright ? 2020 Massachusetts Medical Society.
SDGs
Other Subjects
alanine aminotransferase; amylase; aspartate aminotransferase; creatinine; scatter factor receptor; tepotinib; triacylglycerol lipase; antineoplastic agent; piperidine derivative; protein kinase inhibitor; pyridazine derivative; pyrimidine derivative; scatter factor receptor; tepotinib; adult; advanced cancer; aged; alanine aminotransferase blood level; alopecia; amylase blood level; antineoplastic activity; Article; aspartate aminotransferase blood level; asthenia; cohort analysis; creatinine blood level; decreased appetite; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; dyspnea; exon skipping; fatigue; female; follow up; gene amplification; gene deletion; gene mutation; human; human tissue; hypoalbuminemia; liquid biopsy; major clinical study; male; median survival time; MET gene; metastasis; multicenter study; nausea; non small cell lung cancer; open study; overall survival; peripheral edema; phase 2 clinical trial; pleura effusion; priority journal; progression free survival; proto oncogene; quality of life; respiratory failure; side effect; treatment duration; treatment response; triacylglycerol lipase blood level; tumor biopsy; upper abdominal pain; vomiting; clinical trial; edema; exon; genetics; lung tumor; middle aged; mutation; non small cell lung cancer; very elderly; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Edema; Exons; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines
Publisher
Massachussetts Medical Society
Type
journal article