Merck's Tepmetko: First Oral MET Inhibitor for NSCLC with METex14 Skipping Alterations

November 28, 2020 News /BioValleyBIOON/ -- Merck KGaA recently announced that the European Medicines Agency (EMA) has accepted the application for the targeted anticancer drug Tepmetko (tepotinib) and initiated the review process. Tepmetko is a highly selective, once-daily oral MET inhibitor indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations. Currently, in the United StatesFDAVia real-timeTumorPriority review of Tepmetko under the Real-Time Oncology Review (RTOR) pilot program; previously,FDATepmetko has been granted Orphan Drug Designation (ODD) and Breakthrough Therapy Designation (BTD).

In March this year, Tepmetko received the world’s first regulatory approval in Japan for the treatment of patients with unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations. The recommended dosage is 500 mg (two 250-mg tablets) once daily.

Notably, Tepmetko is the first oral MET inhibitor approved globally for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring MET gene alterations. In Japan, Tepmetko had previously been granted Orphan Drug Designation (ODD) and SAKIGAKE designation (for innovative drugs).

Tepmetko’s regulatory submission is based on data from the pivotal Phase II VISION study (NCT02864992). As of January this year, a total of 152 patients with NSCLC harboring MET exon 14 skipping alterations had received Tepmetko treatment, among whom 99 patients had been followed up for at least 9 months. The study results were published in the New England Journal of Medicine (NEJM) in May this year.

Results showed that, based on Independent Review Committee (IRC) assessment, the objective response rate (ORR) for Tepmetko treatment was 46% (95% CI: 36, 57), and the median duration of response (DOR) was 11.1 months (95% CI: 7.2–NE [not estimable]) in patients with NSCLC confirmed by liquid biopsy (LBx) or tissue biopsy (TBx) to harbor MET exon 14 skipping alterations.

Among the 66 patients in the LBx group, the ORR was 48% (95% CI: 37–63); among the 60 patients in the TBx group, the ORR was 50% (95% CI: 37–63). Twenty-seven patients had positive results by both methods. The response rate assessed by study investigators was 56% (95% CI: 45–66), with similar efficacy regardless of prior therapies for advanced or metastatic disease. Tepmetko was well tolerated in the study, with the most common treatment-emergent adverse events (TEAEs) being peripheral edema, nausea, and diarrhea. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 11% of patients.

Molecular Structure of Tepotinib (Image Source: chemicalbook.com)

Globally, lung cancer is the most common type of cancer and the leading cause of cancer-related deaths, with 2 million new cases diagnosed and 1.7 million deaths annually. Currently, among various types of cancers, three types of MET signaling pathway alterations (including MET exon 14 skipping alterations, MET amplification, and MET protein overexpression) have been identified, which are associated withTumorare associated with invasive behavior and poor clinical prognosis. It is estimated that alterations in the MET signaling pathway occur in 3–5% of NSCLC cases.

Tepotinib is an orally administered MET kinase inhibitor discovered internally by Merck KGaA. It potently and highly selectively inhibits oncogenic signaling driven by MET alterations—including MET exon 14 skipping, MET amplification, and MET protein overexpression—demonstrating the potential to improve therapeutic outcomes in patients with aggressive tumors harboring these specific MET alterations. In addition to non-small cell lung cancer (NSCLC), Merck KGaA is also actively evaluating tepotinib in combination with novel therapies for otherTumorIndications.

September 2019, United StatesFDAGranted Breakthrough Therapy Designation (BTD) to tepotinib for the treatment of patients with metastatic NSCLC harboring MET exon 14 skipping alterations who have progressed after platinum-based chemotherapy.

Currently, Merck is also conducting another study, INSIGHT 2 (NCT03940703), to evaluate the combination regimen of tepotinib and the tyrosine kinase inhibitor (TKI) osimertinib in patients with EGFR-mutated, MET-amplified, locally advanced or metastatic NSCLC who have acquired resistance to previously received EGFR TKIs. (Bioon.com)

Original Source: European Medicines Agency Validatesapplication for Tepotinib for the Treatment of Advanced NSCLC with METex14 Skipping Alterations