Adjuvant Selpercatinib Improves EFS in RET Fusion–Positive NSCLC

Adjuvant treatment with selpercatinib (Retevmo) significantly improved event-free survival (EFS) in patients with resected, early-stage RET fusion–positive non–small cell lung cancer (NSCLC), according to topline results from the phase 3 LIBRETTO-432 clinical trial (NCT04819100).¹ The study met its primary end point, demonstrating a statistically significant and clinically meaningful improvement in EFS compared with placebo, marking a potential shift in the standard of care for this molecularly defined patient subset.

Full details will be presented at an upcoming medical meeting and shared with regulatory authorities.

"We have consistently observed 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," said Jacob Van Naarden, executive vice president and president of Lilly Oncology, in a news release.¹ "Building on the adoption of targeted therapies for early-stage patients with EGFR- and ALK-driven lung cancer, we hope these results further accelerate the use of genomic testing for all people diagnosed with early-stage disease."

The LIBRETTO-432 trial is a global, randomized, double-blind study evaluating selpercatinib as an adjuvant therapy following definitive surgery, with or without adjuvant chemotherapy, in patients with stage IB to IIIA NSCLC harboring RET fusions.² Although selpercatinib is currently approved for the treatment of adult patients with metastatic RET fusion-positive NSCLC, these data represent the first evidence of a highly selective RET inhibitor demonstrating efficacy in the curative-intent, early-stage setting.

LIBRETTO-432 Trial Design and Objectives

The primary objective of LIBRETTO-432 was to compare EFS, as assessed by an independent review committee, between the selpercatinib and placebo arms.^1,2 EFS was defined as the time from randomization to the first documentation of disease recurrence, a new primary NSCLC, or death from any cause. Secondary end points include overall survival, which remains immature and will continue to be followed, as well as safety and tolerability.¹

The safety profile of selpercatinib in this trial was consistent with previously reported data across the LIBRETTO clinical program. Common adverse events associated with the drug include hypertension, increased liver enzymes, diarrhea, and edema.¹

Clinical Implications for Precision Oncology

The emergence of positive data in the adjuvant setting underscores the increasing importance of comprehensive biomarker testing at the time of diagnosis, regardless of disease stage. Historically, molecular testing for driver mutations such as EGFR, ALK, and RET was prioritized primarily in the metastatic setting. However, the success of targeted therapies in early-stage disease—similar to the paradigm shift seen with EGFR inhibitors—necessitates a move toward precision surgery and adjuvant management.¹

RET fusions occur in approximately 1% to 2% of NSCLC cases. Patients with these alterations are often younger and have a minimal smoking history. Despite successful surgical resection and standard-of-care chemotherapy, this population remains at high risk for disease recurrence, particularly in the central nervous system, where selpercatinib has previously demonstrated significant activity.

Addressing Unmet Needs in NSCLC

The current standard of care for resectable NSCLC has evolved rapidly with the integration of immunotherapy and targeted agents. However, patients with rare driver fusions such as RET have often been excluded from or underrepresented in large immunotherapy trials, and their response to immune checkpoint inhibitors is typically poor compared with patients with wild-type or high tumor mutational burden.¹

By targeting the oncogenic driver directly in the adjuvant window, selpercatinib aims to eradicate micrometastatic disease and delay or prevent recurrence. The findings from LIBRETTO-432 suggest that for patients with RET-driven lung cancer, a tailored approach may offer superior outcomes compared with the traditional one-size-fits-all adjuvant chemotherapy model.

Future Directions

The confirmation of an EFS benefit in LIBRETTO-432 provides a foundation for regulatory applications to expand the indication of selpercatinib into early-stage disease. Clinicians should anticipate updates to clinical guidelines as these data mature, particularly regarding the mandate for molecular profiling in stage IB to III NSCLC. Further analysis will be required to determine the impact on long-term survival and the optimal duration of adjuvant therapy.

REFERENCES

1. Lilly's Retevmo (selpercatinib) delivers substantial event-free survival benefit as an adjuvant therapy in early-stage RET fusion-positive lung cancer. News release. Eli Lilly and Company. February 16, 2026. Accessed February 16, 2026. https://tinyurl.com/3f8fw953

2. A study of selpercatinib after surgery or radiation in participants with non-small cell lung cancer (NSCLC) (LIBRETTO-432). ClinicalTrials.gov. Updated February 9, 2026. Accessed February 16, 2026. https://clinicaltrials.gov/study/NCT04819100