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

In Partnership With:

Partner | Cancer Centers | <b>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</b>

Expert oncologist Benjamin Levy, MD, shares data from the LIBRETTO-431 trial comparing selpercatinib to chemotherapy plus pembrolizumab in RET fusion-positive NSCLC following ESMO 2023.

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