LIBRETTO-531: Selpercatinib vs standard of care in patients (pts) with multikinase inhibitor-naïve advanced or metastatic RET-mutant (mut) medullary thyroid cancer (MTC)

#3273

Introduction: Multikinase inhibitors (MKI) are approved for MTC; however, their efficacy in RETmut MTC is limited due to incomplete RET inhibition and significant toxicity. Selpercatinib (LOXO-292), a highly selective and potent FDA approved inhibitor of RET alterations including M918T, MKI resistance-associated V804M, and others, showed robust, durable clinical activity with a tolerable profile in pts with RETmut MTC in the Phase 1/2 LIBRETTO-001 study.

Aim(s): -

Materials and methods: This is a multicenter, open-label, Phase 3 trial comparing selpercatinib to investigator’s choice of cabozantinib or vandetanib in pts with MKI-naïve, RETmut MTC (NCT04211337). Pts (n=400) will be randomized 2:1 to Arm A: selpercatinib 160 mg BID or Arm B: investigator’s choice of cabozantinib 140 mg QD or vandetanib 300 mg QD. Stratification factors are: RETmut (M918T vs other) and intended treatment (Tx) if randomized to Arm B (cabozantinib vs vandetanib). For Arm B pts with progression by BICR, crossover to selpercatinib is allowed. Tx will continue until progression, unacceptable toxicity, withdrawal of consent or death. Key eligibility criteria are age ≥12 years; unresectable locally advanced or metastatic MTC; RET alteration in germline DNA, tumor or blood; no prior MKI Tx; progressive, measurable disease by RECIST 1.1 within 14 months; ECOG PS 0-2; adequate organ function; no other known oncogenic drivers; absence of symptomatic CNS metastases. Tx failure free survival by BICR, the primary endpoint, includes radiographic progressive disease, unacceptable toxicity (predefined by protocol) or death. PFS by BICR is the key type I error controlled secondary endpoint. Investigator assessed PFS, ORR/DOR, OS, PFS2, ORR by RETmut status and safety are also secondary endpoints.

Conference: 18th Annual ENETS Concerence (2021)

Presenting Author:

Authors: Leboulleux S, Robinson B, Hoff A, Brose M, Wirth L,

Keywords: RET alteration, medullary thyroid cancer (MTC), phase 3 trial, selpercatinib,