The FDA accepted a New Drug Application for tepotinib and granted it priority review for the treatment of adult patients with metastatic non–small cell lung cancer who harbor a mutation that leads to mesenchymal-epithelial transition exon 14 skipping, as detected by an FDA-approved test.
The FDA accepted a New Drug Application (NDA) for tepotinib (Tepmetko) and granted it priority review for the treatment of adult patients with metastatic non–small cell lung cancer (NSCLC) who harbor a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping, as detected by an FDA-approved test, announced EMD Serano in a press release.1
The NDA will be reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which is designed to more quickly and efficiently analyze efficacy and safety data. The data that will be evaluated for the potential FDA approval are from the phase 2 VISION study (NCT02864992) of single-agent tepotinib as treatment of patients with NSCLC with MET exon 14 skipping alterations assessed by liquid and/or tissue biopsy.
"With this acceptance and review under the RTOR program, we look forward to working with FDA and to making this precision medicine available to patients in the US as soon as possible,” said Luciano Rossetti, global head of Research & Development for EMD Serono, in a statement.
In the primary analysis of the single-arm VISION trial, 152 patients with NSCLC and either EGFR/ALK wild-type or MET exon 14 skipping alterations received tepotinib 500 mg once daily. The primary end point of the study was objective response rate (ORR) by independent review committee (IRC). The secondary end points were ORR per investigator assessment, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The study included a circulating tumor DNA (ctDNA) analysis, which observed depletion of MET exon 14 mutant allele frequency during the course of treatment.2,3
A total of 99 patients were included in the efficacy analysis, including 66 who were confirmed positive for MET exon 14 skipping alterations by liquid biopsy and 60 who were identified by tissue biopsy.
At data cutoff, the IRC observed a combined liquid-biopsy group and tumor-biopsy group ORR of 46.5% (95% CI, 36.4%-56.8%). The median DOR was 11.1 months (95% CI, 7.2-not estimable [NE]). The DCR per IRC assessment was 65.7% (95% CI, 55.4%-74.9%). Per investigator assessment, the combined ORR was 55.6% (95% CI, 45.2%-65.5%). The median DOR was 14.0 months (95% CI, 9.7-18.3), and the DCR was 72.7% (95% CI, 62.9%-81.2%).
The best response observed was a partial response occurring in 48% of patients in the (95% CI, 36%-61%) in the liquid biopsy group and 50% (95% CI, 37%-63%) in the tumor biopsy group, and tumor shrinkage occurred in 89% of patients.3
In terms of survival, the combined median PFS was 8.5 months (95% CI, 6.7-11.0) per IRC, and was 8.6 months (95% CI, 6.7-11.2) per investigator assessment. The median OS per IRC was 17.1 months (95% CI, 12.0-26.8) and per investigator assessment, the median OS was 22.3 months (95% CI, 15.3 to not estimable [NE]).2,3
Efficacy with tepotinib was also demonstrated in patients with brain metastases at baseline. The ORR in the brain metastasis population (n = 11) was 54.5% (95% CI, 23.4%-83.3%) by IRC. The median DOR was 9.5 months (95% CI, 6.6-NE). The median PFS observed in these patients was 10.9 months (95% CI, 8.0-NE).
Of the 51 patients who were included in the biomarker analysis, 34 (67%) had a molecular ctDNA response of depletion of MET exon 14 mutant allele frequency. Of the patients who responded, 71% had a radiographic response per IRC and 85% per investigator assessment. Disease control was observed in 88% of this patient group per IRC and 94% per investigator assessment.
All patients in the study were included in the safety analysis. The most common any-grade adverse events were peripheral edema (63.2%), nausea (25.7%), and diarrhea (21.7%). Grade 3 or higher treatment-related adverse events (TRAEs) were reported in 27.6% of patients. The most common grade 3 or higher TRAEs were peripheral edema and an increase in amylase. TRAEs of any grade led to dose reductions of tepotinib in 32.9% of patients and treatment discontinuation in 11.2%.
Overall the study concluded that tepotinib could induce durable clinical activity in patients with NSCLC with MET exon 14 skipping mutations.
Tepotinib is an oral MET inhibitor that currently has no regulatory approvals outside of Japan. In addition to being explored as treatment of patients with MET exon 14 skipping mutation–positive NSCLC, tepotinib is being studied as treatment of patients with EGFR-positive NSCLC in the phase 2 INSIGHT 2 clinical trial (NCT03940703) in combination with osimertinib (Tagrisso).1
1. FDA accepts filing of New Drug Application for tepotinib for the treatment of patients with metastatic NSCLC with metex14 skipping alterations. News release. EMD Serano. August 25, 2020. Accessed August 25, 2020. https://bit.ly/3jejv4Q
2. Le X, Felip E, Veillon R, et al. Primary efficacy and biomarker analyses from the VISION study of tepotinib in patients (pts) with non-small cell lung cancer (NSCLC) with METex14 skipping. J Clin Oncol. 2020;38 (suppl):9556. doi:10.1200/JCO.2020.38.15_suppl.9556
3. Paik P, Felip E, Veillon R, et al. Tepotinib in non–small-cell lung cancer with met exon 14 skipping mutations. N Engl J Med. Published online May 29, 2020. doi:10.1056/NEJMoa2004407