LIBRETTO-432 establishes the first targeted adjuvant therapy benefit in resected RET fusion-positive NSCLC

RET fusion-positive non-small cell lung cancer (NSCLC) accounts for approximately 1–2% of lung adenocarcinomas and is associated with a distinct molecular profile that can be effectively targeted with selective RET inhibitors. While agents such as selpercatinib have demonstrated substantial benefits in advanced disease, patients with early-stage RET fusion-positive NSCLC remain at significant risk of recurrence. Until recently, no targeted therapy had been shown to improve outcomes in this rare molecular subgroup, highlighting a clear unmet need for more effective postoperative treatment strategies.¹

The Phase III LIBRETTO-432 trial (NCT04819100), presented at the 2026 American Society of Clinical Oncology (ASCO) Meeting, evaluated adjuvant selpercatinib in patients with completely resected stage IB–IIIA RET fusion-positive NSCLC. In this global, double-blind study, patients were randomized 1:1 to receive selpercatinib or placebo for up to three years. The primary endpoint was investigator-assessed event-free survival (EFS) in patients with stage II–IIIA disease, with secondary endpoints including EFS in the overall study population, overall survival (OS), and safety.²

At the prespecified interim analysis, LIBRETTO-432 met its primary endpoint, demonstrating a marked reduction in the risk of recurrence or death with selpercatinib compared with placebo. However, the median EFS was not reached in the selpercatinib arm versus 31.8 months in the placebo arm (HR 0.172, 95% CI: 0.058, 0.509). The 24-month EFS rate was 91.5% and 61.1% in patients receiving selpercatinib and placebo respectively. In the overall population, the EFS benefit was also substantial (HR 0.165, 95% CI: 0.056, 0.485). The safety profile was consistent with previous studies, with hypertension, elevated liver enzymes, and diarrhea among the most common adverse events, and no unexpected toxicities were observed.²

Abdul Rafeh Naqash, MD, University of Oklahoma Health Sciences Center, Oklahoma City, OK, who presented highlights of the year in lung cancer at ASCO, provides his insights into the trial:

“Selpercatinib does show in this setting, which again is practice-changing. And more importantly, this tells us that NGS sequencing is going to become integral in treating patients appropriately with precision medicines to improve outcomes”

LIBRETTO-432 is the first Phase III trial to demonstrate a benefit for a RET-targeted therapy in the adjuvant setting, establishing selpercatinib as a potential new standard of care for patients with resected RET fusion-positive NSCLC. These findings reinforce the importance of comprehensive molecular testing in early-stage disease and signal a continued shift toward precision oncology in the curative setting.