Dr. Liu on the Use of MET-targeted Agents in EGFR-mutant NSCLC

Stephen V. Liu, MD, associate professor of medicine, Georgetown University, director of Thoracic Oncology, head of Developmental Therapeutics, Georgetown Lombardi Comprehensive Cancer Center, discusses the future of MET-targeted agents in non–small cell lung cancer (NSCLC) based on the FDA breakthrough designation for telisotuzumab vedotin (ABBV-399; teliso-V).

On January 4th, 2022, the FDA granted breakthrough designation to telisotuzumab vedotin for patients with advanced or metastatic EGFR wild-type NSCLC showing high levels of c-Met overexpression and disease progression on or after prior platinum-based chemotherapy. 

The MET-targeted kinase inhibitors capmatinib (Tabrecta) and tepotinib (Tepmetko) previously gained FDA approval for the treatment of patients with metastatic NSCLC harboring a MET exon 14 skipping mutation, Liu begins. Based on their high clinical activity and selectivity, these agents have been incorporated as standard treatments in this population, he continues. Moreover, current research has shown MET amplification is a common driver of EGFR inhibitor resistance. Ongoing studies in EGFR-mutated NSCLC aim to utilize MET kinase inhibitors in patients who have acquired resistance to EGFR inhibitors, Liu says. 

Unlike these previously approved agents, the antibody-drug conjugate (ADC) telisotuzumab vedotin targets MET amplification through protein expression, Liu explains. The agent was previously studied in EGFR-mutant lung cancer and in squamous lung cancer but met the criteria for futility in these settings. However, the agent has shown encouraging activity and durable responses in EGFR wild-type NSCLC with high levels of c-Met overexpression, Liu says.

There are several toxicities associated with telisotuzumab vedotin that should be considered, including peripheral neuropathy, nausea, and edema, Liu notes. However, these toxicities are typically low grade.

This designation indicates that MET is a more versatile target for the development of novel agents than previously understood, Liu states. Current biomarker screening with next-generation sequencing allows for the detection of genetic mutations and fusions but does not identify protein biomarkers, Liu says. If telisotuzumab vedotin gains FDA approval, current biomarker assays should expand to include MET immunohistochemistry, he concludes.

Editor’s Note: Dr. Liu reports serving as consultant or on a paid advisory board for AstraZeneca, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardent Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; he reports receiving a research grant at his institution from Alkermes, Elevation Oncology, Genentech/Roche, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics; he reports serving on the data safety monitoring board for Candel Therapeutics.