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Adjuvant selpercatinib improves event-free survival (EFS) in patients with early-stage, RET fusion-positive non-small cell lung cancer (NSCLC) who have undergone definitive surgery or radiation, based on results of the first phase 3 trial to use a RET inhibitor as adjuvant therapy.

Among patients with stage II-IIIA disease, specifically, the addition of the selective, brain-penetrant RET inhibitor slashed the risk for recurrence, progression, or death by more than 80%.

Selpercatinib significantly improved event-free survival (EFS), and the only deaths in the trial occurred in the placebo group, reported lead author Jonathan W. Goldman, MD, during a press conference at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

Goldman, of the University of California, Los Angeles, called the results “striking.” He emphasized that they “highlight the importance of testing for specific gene changes at the time of diagnosis,” so that patients with NSCLC can start the most appropriate therapy from the outset.

The results of the LIBRETTO-432 Trial are scheduled to be presented today during the plenary session (abstract LBA3) at the meeting.

A Gap in Adjuvant Care

RET fusions drive about 1%-2% of NSCLC cases and occur more often in younger patients with little or no smoking history, Goldman said. 

Selpercatinib is approved for advanced RET fusion-positive disease. Until now, however, it has been untested as an adjuvant treatment for early-stage lung tumors.

This is a critical gap, Goldman said, because up to two thirds of patients with early-stage NSCLC relapse despite surgery or radiation and adjuvant therapy, and many “may ultimately die from metastatic disease.” 

Trial Design

LIBRETTO-432 involved 151 patients from 22 countries who had stage IB-IIIA RET fusion-positive NSCLC. Following definitive surgery or radiation, participants were randomized in a 1:1 ratio to receive selpercatinib 160 mg twice daily or placebo for up to 3 years. Patients in the placebo group who experienced recurrence could cross over to selpercatinib.

Patients were median age 60 years, roughly 60% were women, and about 70% had never smoked.

The primary endpoint was EFS in the 109 patients with stage II-IIIA disease. Secondary endpoints included EFS in the overall population, EFS on blinded independent review, and overall survival. 

For the presented data, median follow-up was 24 months for selpercatinib and 27 months for placebo. The study is ongoing.

Event-Free Survival and Safety

Selpercatinib reduced the risk of an event by approximately 83% (hazard ratio, 0.17; P = .0003) in those with stage II-IIIA disease. Median EFS was not reached in the selpercatinib group vs 31.8 months for placebo. Four events occurred in the selpercatinib arm compared with 19 in the placebo group.

The 2-year EFS rate was 91.5% with selpercatinib vs 61.1% with placebo. These results were similar in a blinded independent review and in the overall stage IB-IIIA population.

Goldman reported that selpercatinib reduced recurrence at all sites of relapse, including the central nervous system, where there was 1 recurrence with selpercatinib vs 3 with placebo.

Adverse events (AEs) were consistent with selpercatinib’s known profile in metastatic disease. The most common AEs were elevations in liver enzymes, which were generally mild and managed with dose modifications.

Three deaths occurred during the study, and all were in the placebo group.

A New Standard, With Open Questions

David R. Spigel, MD, of the Sarah Cannon Research Institute in Nashville, who was not involved in the trial, called the results “immediately practice-changing,” and suggested that they “establish a new standard of care for a rare subset of lung cancer.” 

Speaking at the press conference, Spigel suggested that selpercatinib should be considered analogous to the EGFR and ALK inhibitors that have become standard care in their subsets. 

These new data underscore the need for comprehensive biomarker testing across all stages of NSCLC, Spigel said. From a research standpoint, he said the data support more urgent evaluation of proven advanced-line agents in earlier treatment settings.

In a real-world analysis of patients with newly diagnosed stage IB-IIIA NSCLC, only half underwent next-generation sequencing, and roughly 1 in 6 received no molecular testing at all, according to the MYLUNG Consortium. 

Through continued follow-up, Goldman and colleagues will be assessing overall survival and examining outcomes in key subgroups, such as patients with stage IB disease, according to an ASCO press release.

In the meantime, Spigel said he will be applying these new data in the clinic as soon as possible: “If I have a patient in my clinic tomorrow who has early-stage disease that has a RET alteration, I absolutely would offer them [selpercatinib] therapy.”

LIBRETTO-432 was funded by Eli Lilly and Company. Goldman disclosed relationships with Eli Lilly, AstraZeneca, Genentech, and others; several co-authors are employees of Eli Lilly. Spigel reported relationships with Eli Lilly, AstraZeneca, Genentech/Roche, and others.