Randomized Phase 3 Study of First-line Selpercatinib vs Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC: LIBRETTO-431

Randomized Phase 3 Study of First-line Selpercatinib versus Chemotherapy and Pembrolizumab in RET Fusion-positive NSCLC

Background

• Combination chemotherapy + pembrolizumab is 1L SOC for patients without an EGFR or ALK alteration
• RET gene fusions are targetable alterations for some patients with NSCLC
• Selpercatinib is a highly selective RET kinase inhibitor with CNS penetration and compelling activity in a phase 1/2 clinical trial

Study Design

• LIBRETTO-431 is phase 3 study comparing 1L selpercatinib to combination chemotherapy + pembrolizumab in patients with unresectable stage IIIB, IIIC, or IV nonsquamous NSCLC with RET fusion
  • Patients were treatment-naïve for advanced disease, ECOG PS 0-2, and stratified by geography, brain metastases, and choice of chemotherapy
  • Randomization occurred 2:1 to selpercatinib or chemotherapy + pembrolizumab with optional crossover to selpercatinib upon BICR-confirmed PD
• Gated primary endpoint was PFS by BICR in ITT-pembrolizumab and ITT populations
• Gated secondary endpoints were OS, ORR, DoR, CNS ORR, CNS DoR, CNS TTP, safety, and PROs

Results

• Selpercatinib showed superior efficacy vs chemotherapy with or without pembrolizumab in 1L RET fusion-positive NSCLC (study met its primary endpoint of PFS by BICR with statistically significant and clinically meaningful benefit in mPFS)
• Selpercatinib improved intracranial response rate and delay in CNS progression compared to chemotherapy with or without pembrolizumab
• AEs observed with selpercatinib were generally consistent with those previously reported and largely managed with dose adjustments
• In PROs, selpercatinib delayed time to deterioration of pulmonary symptoms and overall physical function
• Selpercatinib should be considered a 1L SOC in RET fusion-positive advanced NSCLC