Activating RET alterations occur at a high frequency in MTC. Despite benefits in progression free survival (PFS) and overall response rate (ORR) in RET-mutant MTC with multikinase inhibitors (MKI), vandetanib and cabozantinib, the toxicity profile and the appearance of resistant RET mutations may limit their long-term efficacy. Selpercatinib (LOXO-292) is a novel, highly selective and potent FDA approved inhibitor of RET alterations including M918T, MKI resistance-associated V804M, and others. In the registrational LIBRETTO-001 Phase I/II trial, selpercatinib demonstrated robust and durable antitumor activity by independent review and a tolerable safety profile in patients with RET-mutant MTC. In vandetanib and/or cabozantinib pretreated RET-mutant MTC (n=55) ORR was 69% (95% confidence interval [CI]: 55-81%) and in vandetanib and/or cabozantinib naive RET-mutant MTC (n=88) ORR was 73% (95% CI: 62-82%), 1-year PFS rates are currently >80% and >90%, respectively. The most common adverse events of grade ≥3 included hypertension (21%), increased alanine aminotransferase level (11%), increased aspartate aminotransferase level (9%), hyponatremia (8%), and diarrhea (6%). Of the overall cohort of 531 patients who received selpercatinib by 17-June-2019, a total of 2% discontinued due to a drug-related adverse reaction.
LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, Phase III trial comparing selpercatinib to physician’s choice of cabozantinib or vandetanib in patients with locally advanced and/or metastatic RET-mutant MTC.
Patients will be randomly assigned 2:1 to receive selpercatinib 160 mg BID (Arm A) or physician’s choice of cabozantinib 140 mg QD or vandetanib 300 mg QD (Arm B) in 4-week cycles. Patients will be stratified based on RET mutation: M918T vs other and intended treatment if randomized to Arm B: cabozantinib vs vandetanib. Crossover to selpercatinib is permitted for Arm B patients with disease progression by blinded independent central review (BICR). Treatment will discontinue for progressive disease, unacceptable toxicity, withdrawal of consent or death. Participants are eligible to be included if the following criteria apply: age ≥12 years; histologically confirmed, unresectable locally advanced and/or metastatic MTC; RET alteration identified via local NGS or PCR testing on germline DNA, tumor or blood; sufficient tissue for central analysis of RET mutation; received no prior MKI-treatment; radiographic progressive, measurable disease per RECIST 1.1 by BICR within the prior 14 months; ECOG performance status of 0-2; adequate organ function; ability to swallow capsules; absence of symptomatic CNS metastases; no additional validated oncogenic driver in MTC. Tumor evaluations will be performed every 8 weeks following treatment initiation through week 24 and then every 12 weeks thereafter. The primary endpoint is treatment failure free survival, which incorporates radiographic progressive disease, unacceptable toxicity (predefined by protocol) or death. The key type I error controlled secondary endpoint is PFS by BICR. Other key secondary endpoints include PFS by investigator assessment, ORR/duration of response, overall survival, PFS2, ORR by RET mutation status, safety, and tolerability. This study is active and recruiting, with planned enrollment of 400 participants at ~150 sites in 21 countries. In response to the global COVID-19 pandemic, mitigations for patient safety are included in the protocol.