EFS Improves With Selpercatinib in RET+ NSCLC Trial

Event-free survival (EFS) significantly improved among patients with stage II-IIIA RET fusion-positive non-small cell lung cancer (NSCLC) who received adjuvant selpercatinib (Retevmo) vs placebo, according to findings from the phase 3 LIBRETTO-432 trial (NCT04819100) highlighted in a press briefing at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

The median EFS was not reached with selpercatinib versus 31.8 months with placebo, translating to an 83% in the risk of disease recurrence or death (HR, 0.172; 95% CI, 0.058-0.509; P = .0003). The 24-month EFS rate was 91.5% (95% CI, 75.4-97.2) with selpercatinib versus 61.1% (95% CI, 44.2-74.3) with placebo, at a median follow-up of 22.1 months in the selpercatinib arm and 22.4 months in the placebo arm. The EFS benefit was consistent across patient subgroups and confirmed by blinded independent central review (BICR).

The low number of events in the selpercatinib arm—only 4 recurrences or deaths among 54 patients at the time of analysis—reflects the degree of disease control achieved with targeted RET inhibition in the adjuvant setting. In the placebo arm, 17 of 55 patients in the primary analysis population discontinued due to disease relapse, compared with only 3 in the selpercatinib arm, further underscoring the magnitude of benefit.

“The benefits with selpercatinib were consistent across patient subgroups and confirmed by independent review. Adjuvant selpercatinib should be considered as a new standard of care in early-stage RET fusion–positive lung cancer,” said lead study author Jonathan Goldman, MD, University of California, Los Angeles. “These results highlight the importance of testing for specific gene changes at the time of diagnosis of lung cancer to guide the best treatment choices,” added Goldman.

Safety Profile of Selpercatinib

The safety profile of selpercatinib was consistent with its established profile from prior studies in the advanced disease setting.1 In the overall population (N = 151), all 75 patients (100%) in the selpercatinib arm experienced at least one treatment-emergent adverse event (TEAE) of any grade, compared with 74 of 76 patients (97.4%) in the placebo arm. Grade 3 or higher TEAEs occurred in 50 patients (66.7%) receiving selpercatinib versus 18 patients (23.7%) receiving placebo.

The most common TEAEs of any grade with selpercatinib included ALT increase (62.7%), AST increase (60.0%), dry mouth (40.0%), diarrhea (38.7%), hypertension (30.7%), cough (26.7%), blood bilirubin increase (26.7%), constipation (22.7%), and hyperuricemia (20.0%). Grade 3 or higher events of note included ALT increase (17.3%), AST increase (18.7%), and hypertension (10.7%). These were manageable with dose modifications.

Treatment discontinuation due to TEAEs occurred in 13 patients (17.3%) in the selpercatinib arm versus 1 patient (1.3%) in the placebo arm; however, discontinuations in the selpercatinib arm were predominantly driven by low-grade events rather than severe toxicity. No TEAEs leading to death occurred in either arm during study treatment. Notably, no deaths were reported in the selpercatinib arm at data cutoff, while 3 deaths occurred in the placebo arm.

LIBRETTO-432 Study Design

LIBRETTO-432 is a global, multicenter, phase 3, double-blind, randomized, placebo-controlled trial (NCT04819100).1 Eligible patients had histologically confirmed RET fusion-positive NSCLC of stage IB, II, or IIIA and had received definitive therapy — surgery or radiotherapy, with or without adjuvant chemotherapy — with no evidence of disease recurrence or progression at enrollment. Patients were randomized 1:1 to selpercatinib (160 mg twice daily orally for patients ≥50 kg, or 120 mg twice daily for patients <50 kg) or placebo for up to 3 years, or until disease recurrence, progression, or death. Patients in the placebo arm had the option to cross over to selpercatinib upon disease progression. Randomization was stratified by disease stage (IB or II-IIIA) and type of definitive treatment (surgery or radiotherapy). The primary endpoint was investigator-assessed EFS in the primary analysis population (stage II-IIIA). Secondary endpoints included EFS by BICR in the primary analysis population, EFS by investigator and BICR assessment in the overall population (stage IB-IIIA), safety, and overall survival.

A total of 3446 patients were assessed for eligibility; the most common reason for exclusion was absence of a RET fusion (n = 3149), reflecting the relative rarity of this molecular subtype. A total of 151 patients across 65 sites in 22 countries were enrolled between January 2022 and March 2025, with a database cutoff of January 2026.

Patient Characteristics

Baseline characteristics were well-balanced between arms in both the primary analysis population (n = 109) and the overall population (N = 151). In the primary analysis population, median age was 59.5 years (range, 41.0-84.0) in the selpercatinib arm and 61.0 years (range, 26.0-78.0) in the placebo arm. The majority of patients were female (63.0% selpercatinib, 54.5% placebo) and never-smokers (68.5% vs 69.1%, respectively). Asian patients comprised approximately 61% of both arms, with East Asian patients making up 57.4% and 56.4% of the selpercatinib and placebo arms, respectively.

ECOG performance status was 0 in 55.6% of selpercatinib patients and 65.5% of placebo patients. The most common RET fusion partner was KIF5B::RET, present in 61.1% of selpercatinib patients and 61.8% of placebo patients, followed by CCDC6::RET in 25.9% and 20.0%, respectively. PD-L1 status was positive in 46.3% of selpercatinib patients and 50.9% of placebo patients. Virtually all patients had undergone surgery (100% selpercatinib, 98.2% placebo), and approximately 92% in each arm had received prior systemic therapy, predominantly adjuvant chemotherapy.

At the data cutoff, 43 (57.3%) of 75 selpercatinib patients and 38 (50.0%) of 76 placebo patients in the overall population remained on treatment. In the primary analysis population, 30 (55.6%) of 54 selpercatinib patients and 24 (43.6%) of 55 placebo patients were still on treatment.

Expert Insight on Clinical Implications

David R. Spigel, MD, FASCO, president and chief medical officer at Sarah Cannon Research Institute and an ASCO Expert in lung cancer, shared his insight on the LIBRETTO-432 findings at a press conference during the ASCO meeting:

“We know these targeted drugs are very effective in advanced cancer, so they should be tested and proven that they work in early-stage disease. We know that this has been true for EGFR alterations and ALK rearrangements, where now it is the standard of care to offer EGFR-directed and ALK-directed therapies in patients with early-stage resected cancer to try to cure them. And so this study, which was remarkably done across the world in 4 years’ time in a mutation (RET) that is seen in 1% to 2% of the population, it really is groundbreaking. The EFS data is quite compelling, and for me this is a new standard of care. If I have a patient in my clinic tomorrow who has early-stage disease that has a RET alteration. I absolutely would offer this therapy.”

Is currently approved in the NSCLC setting for patients with advanced or metastatic NSCLC with a RET gene fusion.²

References

1. Goldman J, Yang XN, Hochmair M, et al. Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: primary results of the phase 3 LIBRETTO-432 trial. J Clin Oncol. 2026;44(suppl 17):LBA3. doi:10.1200/JCO.2026.44.17_suppl.LBA3
2. Retevmo (selpercatinib) [prescribing information]. Indianapolis, IN: Loxo Oncology, Inc. (Eli Lilly and Company); September 2024. Accessed May 30, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213246s011s013lbl.pdf