Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians Choice of Cabozantinib or Vandetanib in Patients with Progressive, Advanced, Kinase Inhibitor Naïve, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531)

This is a global, multicenter, randomized (2:1), open-label, Phase 3 study comparing
selpercatinib (treatment Arm A) to physician’s choice of cabozantinib or vandetanib (treatment
Arm B) in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant MTC.
CONFIDENTIAL Protocol J2G-MC-JZJB(d)
LY3527723 13
Patients will be stratified based on:
RET mutation: M918T vs. other
Intended treatment if randomized to control arm: cabozantinib vs. vandetanib.
Patients with histologically confirmed, unresectable, locally advanced, or metastatic MTC who
have not received previous treatment with a kinase inhibitor are eligible. Patients are required to
have radiologic progressive disease per RECIST 1.1 at screening compared with an image
obtained within the prior 14 months and to have a documented RET mutation in tumor or
germline DNA. Both radiographic progression and RET mutation must be confirmed by the
sponsor prior to patient randomization.
Patients will be randomized in a 2:1 ratio to receive selpercatinib (treatment Arm A) or
physician’s choice of cabozantinib (treatment Arm B1) or vandetanib (treatment Arm B2).
Patients assigned to the control arm cannot switch from cabozantinib to vandetanib or from
vandetanib to cabozantinib during the study. Treatment will continue until disease progression,
unacceptable toxicity, or death.
Patients randomized to Arm B who discontinue treatment and who have radiographic disease
progression that is confirmed by blinded independent central review (BICR) may be eligible for
crossover to selpercatinib if they meet the eligibility criteria for crossover