Selpercatinib in Early-Stage RET Fusion

Selpercatinib in Early-Stage RET Fusion–Positive Non–Small-Cell Lung Cancer Published May 31, 2026 N Engl J Med 2026;395:660-670 DOI: 10.1056/NEJMoa2602628 Abstract Background Selpercatinib, a highly selective, potent, and central nervous system–penetrant RET inhibitor, is approved for RET fusion–positive advanced or metastatic non–small-cell lung cancer (NSCLC). The efficacy and safety of selpercatinib in early-stage NSCLC are unknown. Methods We conducted a phase 3, double-blind trial involving patients with RET fusion–positive NSCLC who had received definitive therapy with curative intent (surgery or radiotherapy with adjuvant systemic anticancer therapy, if applicable). Patients were randomly assigned to receive adjuvant selpercatinib or placebo for up to 3 years. The primary end point was investigator-assessed event-free survival in patients with stage II or IIIA disease. Secondary end points were investigator-assessed event-free survival in patients with stage IB, II, or IIIA disease; event-free survival as assessed by blinded independent central review; overall survival; and safety. Results A total of 151 patients were assigned to receive selpercatinib (75 patients) or placebo (76 patients). Median follow-up was 24 months and 27 months in the respective groups. Among 109 patients with stage II or IIIA disease, 2-year investigator-assessed event-free survival was 92% with selpercatinib and 61% with placebo (hazard ratio for disease recurrence, progression, or death, 0.17; 95% confidence interval [CI], 0.06 to 0.51; P<0.001). Event-free survival as assessed by blinded independent central review was consistent with investigator-assessed event-free survival. Among the 151 patients with stage IB, II, or IIIA NSCLC, investigator-assessed event-free survival at 2 years was 94% with selpercatinib and 70% with placebo (hazard ratio for disease recurrence, progression, or death, 0.16; 95% CI, 0.06 to 0.48; P<0.001). The most common adverse events during the treatment period were increased levels of alanine aminotransferase and aspartate aminotransferase (grade ≥3 in 17% and 19% of patients, respectively, in the selpercatinib group). Three deaths occurred, all in the placebo group, owing to disease progression. Conclusions Among patients with stage II or IIIA RET fusion–positive NSCLC, event-free survival was significantly longer with adjuvant selpercatinib than with placebo. (Funded by Lilly; LIBRETTO-432 ClinicalTrials.gov number, NCT04819100.) Are you a member of an institution such as a university or hospital?Learn more about Institutional Access Notes This article was published on May 31, 2026, and updated on August 13, 2026, at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. Supported by Lilly. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the trial participants, their families and caregivers, and the site personnel, without whom this work would not have been possible; and the following employees of Lilly: Wambui Gathirua-Mwangi, Valeria Maria Cortesi, and Keerthana Muthiah for their medical writing assistance; Shruti M and Andrew Lithio for critical operational and statistical support; and Collin Churchill and Jim White for critical review. Supplementary Material Information & Authors Information Published In Copyright Copyright © 2026 Massachusetts Medical Society. All rights reserved. For personal use only. Any commercial reuse of NEJM Group content requires permission. History Published online: May 31, 2026 Published in issue: August 13, 2026 Topics Authors Metrics & Citations Metrics Altmetrics Citations Export citation Select the format you want to export the citation of this publication. Cited by - Next-Generation Sequencing Completion and Timeliness Using a Reflex Testing Protocol for Patients with Stage II to IV Nonsquamous Non–Small Cell Lung Cancer, Clinical Lung Cancer, 27, 7, (33-41), (2026).https://doi.org/10.1016/j.cllc.2026.06.012 - UpToDate®, Oncology Times, 48, 8, (6-6), (2026).https://doi.org/10.1097/01.COT.0000000000000452 - Adjuvant immunotherapy in resected non-small cell lung cancer harboring oncogenic driver alterations beyond EGFR and ALK: results from a retrospective analysis, Clinical and Translational Oncology, (2026).https://doi.org/10.1007/s12094-026-04498-z - Adjuvant selpercatinib shows benefit in patients with NSCLC, Nature Reviews Clinical Oncology, 23, 8, (564-564), (2026).https://doi.org/10.1038/s41571-026-01172-9 Loading...