Selpercatinib Meets Primary Endpoint in Phase III Adjuvant NSCLC Trial

Eli Lilly and Company has announced positive topline results from the Phase III LIBRETTO-432 trial, demonstrating a statistically significant and clinically meaningful improvement in event-free survival with Retevmo (selpercatinib) as adjuvant therapy in patients with stage II-IIIA RET fusion-positive non-small cell lung cancer. The study met its primary endpoint, showing that adjuvant selpercatinib significantly reduced the risk of disease recurrence or death compared with placebo following definitive surgery or radiotherapy.

LIBRETTO-432 is a global, Phase III, randomized, double-blind, placebo-controlled trial evaluating adjuvant selpercatinib in patients with RET fusion-positive NSCLC following curative-intent surgery or radiotherapy, with or without prior adjuvant therapy. A total of 151 patients were randomized 1:1 to receive selpercatinib or placebo. The primary endpoint is investigator-assessed event-free survival in patients with stage II-IIIA disease.

While overall survival data remain immature due to a low number of events, results trended in favor of selpercatinib. Key secondary endpoints include overall survival, blinded independent central review-assessed EFS, time to distant CNS recurrence, progression-free survival on subsequent therapy, assay performance metrics for RET testing, and safety outcomes.

The safety profile of selpercatinib in LIBRETTO-432 was generally consistent with prior studies. Known risks include hepatotoxicity, hypertension, QT prolongation, interstitial lung disease, hemorrhage, and hypersensitivity reactions. Liver enzyme elevations and hypertension remain among the most closely monitored toxicities in clinical practice. No new safety signals were reported in this early-stage population.

The executive vice president and president of Lilly Oncology stated that cancer medicines can deliver their greatest impact when administered early in the course of a patient's treatment journey. The LIBRETTO-432 results support this observation, demonstrating an effect size in line with the most striking data for targeted adjuvant therapy in lung cancer. Building on the adoption of targeted therapies for early-stage patients with EGFR- and ALK-driven lung cancer, these results may further accelerate the use of genomic testing for all people diagnosed with early-stage disease.

LIBRETTO-432 is the first and only randomized Phase III study to evaluate the safety and efficacy of a selective RET kinase inhibitor as adjuvant therapy in this population. Approximately 1-2% of NSCLC cases harbor RET fusions. With nearly half of NSCLC patients carrying actionable genomic alterations, the expanding use of molecular testing at diagnosis has become increasingly critical—not only in metastatic disease but now in early-stage settings.

Selpercatinib is a selective RET kinase inhibitor developed by Eli Lilly and Company for cancers driven by RET gene alterations, including RET fusion-positive NSCLC and RET-mutant thyroid cancers. First granted accelerated FDA approval in 2020, its indications have expanded to tumor-agnostic RET fusion-positive solid tumors and pediatric patients. The drug works by blocking abnormal RET signaling and has demonstrated strong systemic and intracranial activity. Selpercatinib is taken orally twice daily and is generally well tolerated, with manageable side effects such as hypertension and elevated liver enzymes requiring routine monitoring.

The LIBRETTO-432 results position selpercatinib as a potential new standard of care for patients with resected stage II-IIIA RET fusion-positive NSCLC, pending full data presentation and regulatory review. If approved in the adjuvant setting, selpercatinib would extend precision oncology deeper into early-stage lung cancer management, reinforcing the importance of comprehensive genomic profiling across all stages of disease.

Full results will be presented at an upcoming medical congress and submitted for peer-reviewed publication. Detailed findings will also be discussed with health authorities globally.