The Intracranial Outcomes of 1L Selpercatinib in Advance RET Fusion positive (RET+) NSCLC: LIBRETTO-431 Study

Selpercatinib, a highly selective, CNS active RET inhibitor is approved for treatment of advanced RET+NSCLC. LIBRETTO-431 is the first study comparing intracranial (IC) efficacy of a targeted therapy to chemo/immunotherapy (IO) in patients with NSCLC.

LIBRETTO-431 (NCT04194944) is a randomized, phase 3 trial comparing 1L selpercatinib vs chemotherapy (cisplatin/carboplatin+pemetrexed)+/- pembrolizumab. Primary endpoint of PFS by blinded independent central review (BICR) at the pre-planned interim analysis was met. IC analyses included CNS and non-CNS PD, IC PFS and IC responses by BICR per RECIST 1.1 in eligible patients. Adverse events were evaluated in the CNS safety population.

Of 261 patients, 192 were CNS-evaluable (selpercatinib:120, control:72). Baseline characteristics showed the selpercatinib arm having a slightly lower proportion of patients with BICR-assessed baseline brain mets (21% vs 25%) and prior CNS radiotherapy (RT:6% vs 10%) compared to the control arm. Selpercatinib delayed CNS PD as evidenced by a lower 12-month cumulative incidence rate (CIR) for CNS PD, as well as delaying non-CNS PD compared to control in patients with and without brain mets. In patients with measurable brain mets at baseline (n=29), median time to IC response was similar between selpercatinib and control (1.4 vs 1.6 months); previously reported IC response rates were higher (82% vs 58%) and more durable (12-month DOR rate 76% vs 63%) with selpercatinib vs control (Zhou et al. NEJM 2023). IC responses to selpercatinib were more common in patients without (93%) than with (50%) prior CNS RT.

Selpercatinib delayed IC progression in advanced RET+NSCLC with/without baseline brain mets and achieved higher IC response vs chemotherapy+pembrolizumab. LIBRETTO-431 demonstrated IC efficacy improvement of a targeted therapy vs chemo/IO in a biomarker-selected NSCLC population. These data further support selpercatinib as the preferred 1L regimen in patients with advanced RET+NSCLC.

Previously presented at ASCO 2024.

Publication History

Article published online:
18 March 2025