1927TiP LIBRETTO-531: Selpercatinib in patients with treatment (Tx)-naïve RET-mutant medullary thyroid cancer (MTC)

Activating RET gene alterations are common in MTC, yet current RET mutant (mut) MTC Tx options are not ideal for many patients (pts). Despite improvements in progression free survival (PFS) and response rate with multikinase inhibitors (MKI), notable toxicity and tumor resistance may limit their long-term efficacy in RETmut MTC. Selpercatinib (LOXO-292), a selective and potent inhibitor of RET alterations including M918T, MKI resistance-associated V804M, and others, showed evidence of robust antitumor activity [objective response rate (ORR) 73% in phase I/II] and a well-tolerated profile in pts with MKI-naïve, advanced RETmut MTC. This global, open-label, randomized, controlled, phase III trial will compare selpercatinib to physician choice of cabozantinib or vandetanib in pts with MKI-naïve progressive advanced or metastatic RETmut MTC. Pts (n=400) will be randomized 2:1 to Arm A: selpercatinib (160 mg BID) or Arm B: physician choice of cabozantinib (140 mg QD) or vandetanib (300 mg QD). Stratification factors are mutation: M918T vs other and intended Tx if randomized to Arm B: cabozantinib vs vandetanib. For Arm B pts, crossover to selpercatinib is allowed at progression. Tx will continue until progressive disease (PD), unacceptable toxicity, withdrawal of consent or death. Major eligibility criteria are age ≥12 years; unresectable locally advanced or metastatic disease; RETmut identification by PCR or NGS on germline DNA, tumor or blood; sufficient tissue for central analysis of RET mutation; MKI-Tx naive; measurable disease and PD within 14 months by RECIST 1.1; ECOG performance status 0-2; adequate organ function. Exclusion criteria are presence of other oncogenic drivers or symptomatic CNS metastases. Tumor evaluations will be performed every 8 weeks for 24 weeks and then every 12 weeks. Treatment failure free survival, including radiographic PD, unacceptable toxicity (predefined by protocol) or death, is the primary endpoint. The key type I error controlled secondary endpoint is PFS by independent review. Other secondary endpoints are physician assessed PFS, ORR/duration of response, overall survival, PFS2, ORR by RET mutation status, safety profile and pharmacokinetics. NCT04211337. Hannah Davis, PhD, an Eli Lilly and Company employee, provided medical writing support. Eli Lilly and Company. Eli Lilly and Company.