Lilly’s Retevmo Reduces Recurrence Risk by 83% in RET-Positive NSCLC

Eli Lilly reported positive Phase 3 results from the LIBRETTO‑432 trial, showing that adjuvant Retevmo (selpercatinib) significantly reduced the risk of disease recurrence or death in patients with early‑stage RET fusion‑positive non‑small cell lung cancer (NSCLC).

The study met its primary endpoint, lowering recurrence or death risk by 83% compared with placebo following surgery or definitive radiotherapy. The findings were selected for presentation during the Plenary Session at the 2026 ASCO Annual Meeting and were simultaneously published in The New England Journal of Medicine.

RET fusions occur in a small but clinically important subset of NSCLC and act as potent oncogenic drivers. While targeted therapies have transformed outcomes in advanced RET‑positive disease, no adjuvant targeted therapy had previously demonstrated benefit in early‑stage NSCLC.

The LIBRETTO‑432 results place RET fusions alongside EGFR mutations and ALK rearrangements as validated biomarkers associated with substantial benefit from targeted therapy in the curative‑intent setting, reinforcing the importance of comprehensive genomic testing at diagnosis across all stages of lung cancer.

LIBRETTO‑432 Delivers Strong Event‑Free Survival Benefit

LIBRETTO‑432 (NCT04819100) is the first randomized Phase 3 trial evaluating a selective RET inhibitor as adjuvant therapy in RET fusion‑positive NSCLC. The study enrolled 151 patients with stage IB–IIIA disease who were randomized to receive selpercatinib 160 mg twice daily or placebo for up to three years after surgery or definitive radiotherapy, with or without adjuvant chemotherapy.

At a median follow‑up of 24 months, selpercatinib reduced recurrence or death risk by 83% versus placebo in stage II–IIIA disease (HR 0.17; p<0.001). The 24‑month event‑free survival (EFS) rate reached 92% with selpercatinib compared with 61% for placebo. Across the overall IB–IIIA population, rates were 94% versus 70%. Median EFS was not reached in the selpercatinib arm, while placebo patients experienced a median EFS of 31.8 months. Overall survival data favored selpercatinib, though the analysis remains immature due to limited events a factor regulator will weigh, but the magnitude of EFS benefit is compelling.

Manageable Safety Profile Supports Long‑Term Use

The safety profile was consistent with prior selpercatinib studies. The most common grade ≥3 adverse events were elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), occurring more frequently with selpercatinib than placebo. These events were manageable through dose modifications, and no new safety signals were identified, supporting the feasibility of long‑term adjuvant therapy.

Clinical and Strategic Implications

Investigators emphasized that the magnitude of benefit observed in LIBRETTO‑432 could reshape treatment for patients with early‑stage RET‑positive NSCLC and strengthen the case for routine genomic profiling at diagnosis. The results extend the role of precision oncology beyond advanced disease and support earlier use of biomarker‑directed therapies when the opportunity for cure is greatest.

For Lilly, the study expands selpercatinib’s reach beyond metastatic disease and reinforces the growing importance of molecularly defined treatment strategies across the lung cancer continuum. The trial positions RET fusions alongside EGFR and ALK as biomarkers with established adjuvant benefit, echoing precedent‑setting approvals of osimertinib and alectinib in early‑stage NSCLC.

Potential Impact on Clinical Practice

Lilly plans to submit the LIBRETTO‑432 results to global regulatory authorities. If approved, selpercatinib would become the first targeted adjuvant therapy specifically indicated for RET fusion‑positive NSCLC, extending the precision oncology model into another biomarker‑defined population.

The findings could establish a new treatment standard for patients with early‑stage RET‑positive NSCLC while accelerating adoption of comprehensive biomarker testing at diagnosis to identify eligible patients earlier in their treatment journey.

Reference

Lilly’s Retevmo (selpercatinib) demonstrated an 83% reduction in the risk of disease recurrence or death as adjuvant therapy for people with early-stage RET fusion-positive lung cancer | Eli Lilly and Company