Event-free survival with adjuvant selpercatinib in stage IB-IIIA <i>RET</i> fusion-positive NSCLC: Primary results of the phase 3 LIBRETTO-432 trial.

Abstract

LBA3 Background: Selpercatinib, a highly selective, potent and brain-penetrant RET inhibitor, is approved for RET fusion-positive ( RET+ ) advanced/metastatic non-small cell lung cancer (NSCLC). RET-directed therapy has yet to be examined in patients (pts) with stage IB-IIIA RET+ NSCLC, where recurrence rates after definitive therapy remain high, and no adjuvant targeted therapy is approved. Here, we report the efficacy and safety of selpercatinib vs placebo in this population. Methods: LIBRETTO-432 (NCT04819100) is a placebo-controlled, double-blind, phase 3 randomized (1:1) trial of selpercatinib 160mg BID vs placebo for up to 3 years in pts with stage IB-IIIA RET+ NSCLC after definitive locoregional treatment. Primary endpoint was investigator-assessed event-free survival (EFS) in stage II-IIIA pts. Secondary endpoints were investigator-assessed EFS in all randomized pts (overall population, stage IB-IIIA), EFS by blinded independent central review (BICR), overall survival and safety. Crossover from placebo to selpercatinib was allowed upon disease recurrence. Results: In total, 151 pts were randomized (selpercatinib n=75; placebo n=76) and baseline characteristics were balanced across treatment arms. Median follow-up was 24 months for selpercatinib and 27 months for placebo. At the preplanned efficacy analysis, selpercatinib demonstrated significantly improved EFS in pts with stage II-IIIA disease (n=109), HR 0.172 (95% CI: 0.058, 0.509; p=0.0003). The median EFS was not reached for selpercatinib vs 31.8 months for placebo (4 vs 19 EFS events, respectively). EFS by BICR, HR=0.125 (95% CI: 0.028, 0.552; p=0.0011), was consistent with investigator-assessed EFS. The 2-year EFS rate was 91.5% for selpercatinib vs 61.1% for placebo. In the overall population (n=151), error-controlled EFS HR was 0.165 (95% CI: 0.056, 0.485; p=0.0002), and median EFS was not reached on either treatment arm. Adverse events (AEs) with selpercatinib were comparable to those reported in metastatic RET + NSCLC. The most common AEs were increased ALT/AST. Only 3 deaths were observed, all occurred in the placebo arm due to the study disease. No pts died during assigned study treatment. Conclusions: Selpercatinib achieved a statistically significant and clinically meaningful improvement in event-free survival compared to placebo in patients with early-stage RET+ NSCLC. These data add to the body of evidence for targeted therapy, including EGFR and ALK inhibitors, in the adjuvant NSCLC setting and underscore the importance of comprehensive genomic testing at diagnosis of NSCLC across disease stages to inform optimal therapeutic decision-making. Clinical trial information: NCT04819100 .