Novel RET Inhibitor Tested in Patients With NSCLC, MTC

ARIELA KATZ | September 11, 2018
Investigators are evaluating the potential of LOXO-292, an oral small molecule inhibitor of RET signaling, to improve outcomes in patients with RET fusion–positive non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other tumors with increased RET activity. LOXO-292 is designed to inhibit RET signaling and acquired resistance mechanisms that would limit the effectiveness of this approach.


RET mutations drive tumor proliferation and growth and are particularly common in NSCLC and MTC. However, no singularly targeted agents are currently approved for patients with RET mutation–specific tumors, according to Alexander Drilon, MD, clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York. “It’s a substantial population,” he said. “RET fusions are found [commonly] in NSCLC, papillary thyroid cancers, and other tumors; RET point mutations are enriched in medullary thyroid cancers.”

Unlike multikinase inhibitors that are approved for NSCLC or MTC, LOXO- 292 is a highly selective potent RET inhibitor that has very few inhibitory effects on other targets. It is also potent in vitro and in vivo against diverse RET fusions and mutations, including the V804M gatekeeper mutation.1


The phase I open-label LIBRETTO-001 clinical trial (NCT03157128) is currently testing LOXO-292 in these patient populations to determine the safety and recommended dosage of the drug. The investigators are seeking to enroll approximately 180 participants for this dose-escalation and -expansion study. The primary endpoints are to determine the maximum tolerated dose and the recommended dose for LOXO-292, with secondary endpoints of overall response rate and duration of response.


Patients who are eligible for the trial must be 12 years or older, with an ECOG performance status of 0 to 2. They must have locally advanced or metastatic solid tumors that are refractory or intolerant to standard therapy or that would be unlikely to respond to standard therapy. Most important, they must have a RET alteration.
Drilon AE, Subbiah V, Oxnard GR, et al. LIBRETTO-001: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol. 2018;36(suppl; abstr 102).

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