Dr. Awad on Acquired Resistance to MET Inhibitors in NSCLC

Mark M. Awad, MD, PhD, clinical director of the Thoracic Oncology Treatment Center and physician at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, discusses acquired resistance to MET inhibitors in MET exon 14 skipping (METex14)–mutated non–small cell lung cancer (NSCLC).

Mechanisms of resistance in METex14-mutant NSCLC are varied and can be complex, says Awad.

Some patients develop on-target acquired resistance mutations, wherein MET mutates a second time, leading to secondary mutations within the MET kinase domain. This is particularly common in certain recurring positions, such as D1228, Y1230, L1195, and others. Additionally, a subset of patients can develop acquired amplification of the MET mutation.

A number of off-target resistance mechanisms or bypass track activations can also manifest, such as amplification of wild-type KRAS or EGFR, other HER family receptors, and BRAF or other MAP kinase pathway molecules, says Awad. This increases the complexity of resistance mechanisms in this subtype of lung cancer. The ultimate goal is to develop improved therapies that prevent resistance from emerging, concludes Awad.