FDA Grants Breakthrough Designation to Tepotinib For Previously Treated METex14+ NSCLC

The FDA has granted a breakthrough therapy designation to tepotinib, an investigational MET inhibitor, for the treatment of patients with metastatic non–small cell lung cancer harboring a MET exon 14 skipping alteration who have progressed following platinum-based therapy.

The FDA has granted a breakthrough therapy designation to tepotinib, an investigational MET inhibitor, for the treatment of patients with metastatic non—small cell lung cancer (NSCLC) harboring aMETexon 14 skipping alteration who have progressed following platinum-based therapy.1

Data supporting the designation come from the ongoing phase II VISION trial (NCT02864992). According to preliminary data presented at the 2019 ASCO Annual Meeting, tepotinib demonstrated an objective response rate (ORR) by independent review of 50% for patients withMETexon 14 skipping alterations as identified by liquid biopsy and 45.1% for alterations identified by tissue biopsy.2

"Tepotinib was associated with robust objective responses with durability that has not previously been seen in patients with metastatic NSCLC harboringMETexon 14 skipping alterations, selected by either tissue or liquid biopsy approaches," Luciano Rossetti, global head of research & development for the biopharma business of Merck KGaA, Darmstadt, Germany, said in a statement. "This breakthrough therapy designation further underscores the potential of tepotinib, and we aim to advance this program and deliver this medicine as quickly as possible to patients [with NSCLC] who may benefit."

The VISION study enrolled patients with NSCLC andMETalterations into one of 2 cohorts: those withMETexon 14 skipping mutations and those withMETamplifications. The first cohort included a total of 87 patients with alterations that had been identified by either liquid biopsy (n = 57) or tumor tissue biopsy (n = 58). Additionally, 33 of the patients were treatment-naïve and 54 were previously treated. Across both cohorts, patients received 500 mg of tepotinib once daily in a 21-day cycle.

Seventy-three patients were evaluable for efficacy in the skipping mutation cohort. The overall ORR by independent review was 50% in those with alterations identified by liquid biopsy and the disease control rate (DCR) was 66.7%. The median duration of response (DOR) was 12.4 months. Among those identified by tissue biopsy, the ORR by independent review was 45.1% and the DCR was 72.5%; the median DOR was 15.7 months.

By investigator assessment, the ORR for those identified by liquid biopsy was 55.3% and was 54.9% for those identified by tumor biopsy. The median DORs were 17.1 and 14.3 months, respectively.

The ORR by independent review among treatment-naïve patients identified by liquid biopsy was 58.8% and was 44.4% among patients identified by tissue biopsy. Among the previously treated patients, the ORRs were 53.3% and 50%, respectively.

Overall, the median progression-free survival was 9.5 months by investigator review among patients with liquid biopsy—identified tumors and was 10.8 months in patients with tissue biopsy–assessed tumors. The median DOR was 14.3 months for both groups.

The most common treatment-related adverse events (TRAEs) experienced with tepotinib were peripheral edema (48.3%), nausea (23.0%), diarrhea (20.7%), and blood creatinine increase (12.6%). Grade 3 treatment-related peripheral edema was observed in 8% of patients. No signs of kidney impairment or grade 4/5 TRAEs were reported. Four patients discontinued treatment due to TRAEs, including 2 due to peripheral edema, 1 due to interstitial lung disease, and 1 due to diarrhea and nausea.

Tepotinib is the second MET inhibitor to receive a breakthrough therapy designation from the FDA this month.Capmatinib was also granted with the FDA’s breakthrough therapy designationfor the treatment of patients with untreated NSCLC who have METexon 14 skipping mutations.

Previously, the FDA granted tepotinib a fast track designation for the treatment of patients with advanced NSCLC harboringMETexon 14 mutations, and the MET inhibitor has also received the SAKIGAKE fast track designation from the Japanese Ministry of Health, Labour and Welfare.

The agent is also being investigated in the phase II INSIGHT 2 trial in combination with osimertinib (Tagrisso) for the treatment of patients with locally advanced or metastatic NSCLC who haveEGFR-mutated,MET-amplified disease after developing acquired resistance to prior treatment with an EGFR tyrosine kinase inhibitor.


  1. Merck KGaA, Darmstadt, Germany, Announces FDA Breakthrough Therapy Designation for Investigational Therapy Tepotinib in Patients with Metastatic NSCLC with METex14 Skipping Alterations [press release]. Darmstadt, Germany: Merck KGaA; September 11, 2019. https://prn.to/2kuDROO. Accessed September 11, 2019.
  2. Pain PK, Veillon R, Cortot AB, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations.J Clin Oncol.2019;37(suppl; abstr 9005).