FDA Accepts NDA Filing for Tepotinib for Metastatic NSCLC with METex14 Skipping Alterations

EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, has announced the US Food and Drug Administration (FDA) has accepted and granted Priority Review to the new drug application (NDA) for once-daily, orally-dosed tepotinib for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition exon 14 (METex14) skipping, as detected by an FDA-approved test. Tepotinib was granted Priority Review and is being reviewed by the FDA under its Real-Time Oncology Review (RTOR) pilot program, which is intended to create a more efficient review process to bring safe and effective treatments to patients as early as possible. Priority Review is intended to accelerate evaluation of applications for drugs that could offer improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. Tepotinib was granted Breakthrough Therapy Designation by the FDA in September 2019 for the treatment of patients with metastatic NSCLC harboring METex14 skipping alterations who progressed following platinum-based cancer therapy.

The application is based on results from the pivotal ongoing, single-arm Phase II VISION study (NCT02864992) evaluating tepotinib as monotherapy in patients with advanced NSCLC with MET exon 14 (METex14) skipping alterations prospectively assessed by liquid and/or tissue biopsy. Results demonstrate consistent response rate and durable anti-tumor activity across lines of treatment including in patients with brain metastases and in patients assessed by both liquid biopsy (LBx) and tissue biopsy (TBx).

"METex14 skipping alterations drive a particularly aggressive form of NSCLC in a patient population that is generally elderly, facing poor clinical prognosis and in urgent need of new therapeutic options," said Luciano Rossetti, Global Head of Research & Development for EMD Serono. "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 U.S. as soon as possible."

In the US in 2020, there were approximately 228,000 new cases of lung cancer and more than 135,000 deaths from lung cancer. Alterations of the MET signaling pathway are found in various cancer types, including 3% to 5% of NSCLC cases, and correlate with aggressive tumor behavior and poor clinical prognosis. Patients with NSCLC harboring METex14 skipping tend to be older than those with NSCLC harboring other alterations. In the Phase II VISION study, the patient population is generally characterized as elderly, with a median age of 74.0 years, and as having poor clinical prognosis typical of NSCLC with METex14 skipping alterations.

In March 2020, tepotinib became the first oral MET inhibitor indicated for the treatment of advanced NSCLC harboring MET gene alterations to receive a regulatory approval globally, with the Japanese Ministry of Health, Labour and Welfare (MHLW) approval for the treatment of patients with unresectable, advanced or recurrent NSCLC with METex14 skipping alterations.

Tepotinib is currently under clinical investigation and not yet approved in any markets outside of Japan.

With 2 million cases diagnosed annually, lung cancer (including trachea, bronchus and lung) is the most common type of cancer worldwide and the leading cause of cancer-related death, with 1.9 million mortality cases worldwide. Alterations of the MET signaling pathway, including MET exon 14 (METex14) skipping alterations and MET amplifications, occur in 3% to 5% of NSCLC cases.

Tepotinib is an oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations. Discovered and developed in-house at Merck KGaA, Darmstadt, Germany, it has been designed to have a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations. In March 2020, tepotinib became the first oral MET inhibitor indicated for the treatment of advanced NSCLC harboring MET gene alterations to receive a regulatory approval globally, with the Japanese Ministry of Health, Labour and Welfare (MHLW) approval for the treatment of patients with unresectable, advanced or recurrent NSCLC with METex14 skipping alterations. In September 2019, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for tepotinib in patients with metastatic NSCLC harboring METex14 skipping alterations whose disease progressed following platinum-based cancer therapy. Tepotinib is also being investigated in the Phase II INSIGHT 2 study in combination with osimertinib in MET amplified, advanced or metastatic NSCLC harboring activating EGFR mutations that has progressed following first-line treatment with osimertinib.