Trial of New RET Inhibitor Aims to Overcome Resistance in NSCLC and MTC

Nathan Pennell, MD, PhD, medical oncologist at the Taussig Cancer Center and professor of medicine at the Cleveland Clinic Lerner College of Medicine, discusses a first-in-human trial of a novel RET inhibitor for patients with non–small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC).

The single-arm phase 1 trial (NCT05241834) of LOXO-260 enrolled patients with locally advanced, unresectable, or metastatic NSCLC, MTC, or other solid tumors with a documented RET fusion or RET mutation who received a prior selective RET inhibitor.

According to Pennell, patients develop resistance to selective RET inhibitors such as selpercatinib (Retevmo) and pralsetinib (Gavreto) due to 2 types of resistance-linked mutations called solvent front mutations and gatekeeper mutations. The oral agent LOXO-260 was developed to overcome resistance to first-generation RET inhibitors with activity against both of these types of resistance mutations, whether they are present individually or together.

The dose escalation part of the trial is designed to determine the maximum tolerated dose and recommended phase 2 dose of LOXO-260 and monitor for safety and preliminary antitumor activity. The dose expansion part will measure the antitumor activity and pharmacokinetics of this agent based on progression-free survival, time to response, and duration of response.

TRANSCRIPTION:

0:08 | We now know that some people develop resistance to selective RET inhibitors. There have been a couple of specific kinds of acquired resistance mutations, known as either solvent front mutations, or a second type of mutation called gatekeeper mutations, which can develop in people and cause resistance to drugs like selpercatinib and pralsetinib. And so LOXO-260 is a newer drug that was developed specifically to be able to overcome those secondary mutations in people who develop resistance to the first-generation drugs. We are participating in a first-in-human phase 1 dose-escalation study in RET-positive NSCLC as well as other types of solid tumors.