Selpercatinib (LOXO-292) is a highly selective and potent small-molecule RET kinase inhibitor. Patients with advanced solid tumors, including RET fusion–positive solid tumors, medullary thyroid cancer (MTC), and other tumors with RET activation, were enrolled in the phase 1/2 LIBRETTO-001 trial, a global, multicenter trial evaluating the safety and efficacy of selpercatinib. An update on the efficacy and safety of selpercatinib in patients with RET-mutant MTC was presented at the 2020 ASCO Annual Meeting.
Following a phase 1 dose escalation, enrolled patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary end point of the study was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included duration of response (DOR) and safety. The primary analysis set was defined as the first 55 consecutively enrolled patients who had previously been treated with the multikinase inhibitors cabozantinib and/or vandetanib. Patients who were naïve to cabozantinib and vandetanib treatment were analyzed separately. Analyses were based on a data cutoff date of December 16, 2019.
In the primary analysis set of 55 patients with MTC who had been previously treated with cabozantinib and/or vandetanib, the ORR by independent review was 69% (95% confidence interval [CI], 55%-81%). Despite a median follow-up of 14 months, the median DOR was not reached (95% CI, 19 months-not estimable [NE]). In the 88 patients with MTC who had not received prior treatment with cabozantinib and/or vandetanib, the ORR by independent review was 73% (95% CI, 62%-82%). Among 19 patients with previously treated RET fusion–positive thyroid cancer, the ORR was 79% (95% CI, 54%-94%), with a median DOR of 18 months (95% CI, 8 months-NE).
Among the safety analysis set consisting of all 531 patients receiving selpercatinib, the most frequent treatment-related adverse events occurring in ≥15% of patients were dry mouth (33%), increased aspartate aminotransferase (26%), increased alanine aminotransferase (25%), hypertension (24%), diarrhea (22%), fatigue (18%), and peripheral edema (15%). Of all patients treated with selpercatinib, 2% discontinued treatment due to treatment-related adverse events.
Treatment with selpercatinib was associated with marked and durable antitumor activity in patients with RET-mutant MTC. This was demonstrated both in patients previously treated with cabozantinib and/or vandetanib and in cabozantinib/vandetanib-naïve patients, with the majority of responses ongoing in both groups. Treatment with selpercatinib was well-tolerated. Selpercatinib recently received approval for the treatment of RET-mutant MTC and RET fusion–positive thyroid cancers based on the results of the LIBRETTO-001 phase 1/2 trial.
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