Merck's Tepotinib: First Global Oral MET Inhibitor Shows Strong Efficacy in NSCLC Patients with MET Exon 14 Skipping Mutations

September 07, 2020 /BioonBIOON/ -- Recently, the positive results of the pivotal single-arm Phase II VISION study (NCT02864992) evaluating Merck KGaA’s targeted anticancer drug tepotinib for the treatment of non-small cell lung cancer (NSCLC) were published in the New England Journal of Medicine (NEJM).Tepotinib is a highly selective MET inhibitor, for the treatment ofTumorpatients with metastatic NSCLC harboring mutations that cause MET exon 14 skipping (METex14).

From a regulatory perspective, tepotinib was approved in Japan this March, becomingThe World's First Oral MET Inhibitor, with the indication for the treatment of patients with unresectable, advanced or recurrent NSCLC harboring MET exon 14 skipping alterations. Currently, tepotinib is under review by the U.S.FDApriority review, having previously been granted Breakthrough Therapy Designation (BTD).

Chemical Structure of Tepotinib (Image source: chemicalbook.com)

In patients with non-small cell lung cancer (NSCLC), approximately 3–4% harbor splice site mutations that result in the transcriptional skipping of exon 14 of the oncogenic driver gene MET. The VISION study evaluated the efficacy and safety of tepotinib in this patient population. In the study, patients with advanced or metastatic NSCLC confirmed to carry MET exon 14 skipping alterations received monotherapy with tepotinib (500 mg once daily). The primary endpoint was the objective response rate (ORR) among patients with at least 9 months of follow-up, as assessed by independent review. Response rates were analyzed according to whether MET exon 14 skipping alterations were detected via liquid biopsy (LBx) or tissue biopsy (TBx).

As of January 1, 2020, a total of 152 patients received tepotinib treatment, with 99 patients followed up for at least 9 months. In the combined biopsy group (LBx or TBx), the objective response rate (ORR) determined by independent review assessment was 46% (95% CI: 36–57), and the median duration of response (DOR) was 11.1 months (95% CI: 7.2–NE). Among the 66 patients in the LBx biopsy group, the ORR was 48% (95% CI: 36–61); among the 60 patients in the TBx biopsy group, the ORR was 50% (95% CI: 37–63). Twenty-seven patients had positive results based on both biopsy methods.

The investigator-assessed objective response rate (ORR) was 56% (95% CI: 45–66), with similar response rates observed regardless of prior treatment regimens for advanced or metastatic non-small cell lung cancer. In this study, the incidence of grade ≥3 adverse events considered by investigators to be related to tepotinib treatment was 28%, including peripheral edema (7%). Adverse events led to permanent discontinuation of tepotinib in 11% of patients.

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. Alterations in the MET signaling pathway (including MET exon 14 skipping mutations and MET amplification) have been identified in various types of cancer, including NSCLC, which is associated withTumoris associated with invasive behavior and poor clinical prognosis. It is estimated that alterations in the MET signaling pathway occur in 3–5% of patients with non-small cell lung cancer (NSCLC).

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 mutations, MET amplification, or MET protein overexpression, demonstrating the potential to improve treatment outcomes for 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.

This May,NovartisMET Inhibitor Tabrecta (capmatinib) Receives USFDAAccelerated approval for the treatment of patients with metastatic NSCLC harboring MET exon 14 skipping mutations, including both treatment-naïve (first-line) and previously treated patients, regardless of prior therapy.

It is worth noting that,Tabrecta is the first to be approved by the U.S.FDAApproval of Therapies Specifically Targeting METex14-Mutant Metastatic NSCLC. AtClinical TrialIn China, the overall response rates (ORR) of Tabrecta in treatment-naïve and previously treated patients with METex14 mutations were 68% and 41%, respectively.

In China, at the end of July this year, Hutchison China MediTechMET Inhibitor SavolitinibGranted priority review by the National Medical Products Administration, this drug is indicated for the treatment of patients with non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations. This marks the first new drug application for savolitinib worldwide, and alsoChina’s First Selective MET Inhibitor: New Drug Marketing Application。

Data from the Phase II clinical trial (NCT02897479) presented at the 2020 ASCO Annual Meeting showed that among patients with MET exon 14 skipping-mutated NSCLC whose efficacy could be evaluated, the objective response rate (ORR) was 49.2%, the disease control rate (DCR) was 93.4%, and the duration of response (DOR) was 9.6 months. (Bioon.com)

Original source:Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations