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.)
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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.
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Copyright © 2026 Massachusetts Medical Society. All rights reserved.
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History
Published online: May 31, 2026
Published in issue: August 13, 2026
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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
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* The trial included 151 patients randomized to receive either selpercatinib (75 patients) or placebo (76 patients).
* Median follow-up times were 24 months for the selpercatinib group and 27 months for the placebo group.
* For stage II or IIIA disease, 2-year investigator-assessed event-free survival was 92% with selpercatinib and 61% with placebo.
* The hazard ratio for disease recurrence, progression, or death in the stage II/IIIA group was 0.17 (95% CI, 0.06 to 0.51).
* For stage IB, II, or IIIA NSCLC, 2-year investigator-assessed event-free survival was 94% with selpercatinib and 70% with placebo.
* The hazard ratio for disease recurrence, progression, or death in the stage IB/II/IIIA group was 0.16 (95% CI, 0.06 to 0.48).
* Increased levels of alanine aminotransferase and aspartate aminotransferase were observed as adverse events in the selpercatinib group.
* Three deaths occurred in the placebo group due to disease progression.

A phase 3, double-blind trial assessed the use of adjuvant selpercatinib versus placebo in patients with RET fusion–positive non-small-cell lung cancer (NSCLC) who had received curative intent therapy. The primary endpoint focused on investigator-assessed event-free survival for patients with stage II or IIIA disease. In the group with stage II or IIIA disease, 2-year investigator-assessed event-free survival was 92% for selpercatinib compared to 61% for placebo, resulting in a hazard ratio of 0.17 (95% CI, 0.06 to 0.51). For patients with stage IB, II, or IIIA NSCLC, the event-free survival at 2 years was 94% for selpercatinib versus 70% for placebo, with a hazard ratio of 0.16 (95% CI, 0.06 to 0.48). The most common adverse events observed were increased alanine aminotransferase and aspartate aminotransferase in the selpercatinib group. Three deaths occurred in the placebo group due to disease progression during the follow-up period.

The finding suggests a substantial benefit in event-free survival for patients with early-stage RET fusion–positive NSCLC receiving adjuvant selpercatinib compared to placebo, indicating that this targeted therapy may add significant value beyond established curative treatments in this setting. The statistical significance observed across different disease stages—hazard ratios of 0.17 and 0.16—suggests a robust association between adjuvant treatment and delayed recurrence or progression. However, the context of comparing outcomes based on investigator assessment requires careful consideration regarding measurement bias; the consistency check using blinded central review aligns these two measures, lending credence to the observed difference in survival estimates. A critical pattern involves the trade-off: while clinical event-free survival improved significantly, the emergence of elevated liver enzymes warrants ongoing surveillance, as this represents a tangible safety cost associated with achieving therapeutic benefit. The implication is that for early-stage disease, systemic intervention offers an advantage in managing long-term outcomes, shifting the focus from acute disease management to durable control. What specific prognostic factors might mediate the difference between stage IB and stage II/IIIA responses, and how do these results inform decisions regarding the intensity of adjuvant therapy for patients with very early-stage disease?

Selpercatinib in Early-Stage RET Fusion

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Executive Summary

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Sentinel — Human

Selpercatinib in Early-Stage RET Fusion

Facts Only

Executive Summary

Full Take

Sentinel — Human