The phase III LIBRETTO-432 trial of adjuvant therapy with the central nervous system (CNS)–penetrant oral RET inhibitor selpercatinib met its primary endpoint of improved event-free survival in patients with early-stage RET fusion–positive non–small cell lung cancer (NSCLC), based on data presented during the Plenary Session of the 2026 ASCO Annual Meeting.¹ These primary results, which were simultaneously published in The New England Journal of Medicine,² further support the use of comprehensive biomarker testing to characterize tumors at diagnosis and inform therapeutic decision-marking.

“Despite receiving surgery or radiation followed by adjuvant chemotherapy or immunotherapy, up to two-thirds of patients with early-stage NSCLC experience disease recurrence…,” said Jonathan W. Goldman, MD, Professor of Medicine, Hematology and Oncology; Director of Clinical Trials in Thoracic Oncology; and Associate Director of Drug Development at the University of California, Los Angeles, in an ASCO press release.

Although RET fusions are present in just 1% to 2% of lung cancers, Dr. Goldman stressed during a press briefing that “rarity should not be mistaken for marginal importance,” given the high risk of recurrence among affected patients.

“No adjuvant targeted therapy has been approved for the subset of patients whose tumors harbor RET fusions, leaving an important gap in care for this population,” he added. LIBRETTO-432 was thus born to determine whether selpercatinib, which is currently approved by the U.S. Food and Drug Administration for advanced RET fusion–positive NSCLC, may be given earlier to delay or prevent recurrence.

Following the reported 83% reduction in disease recurrence or death vs placebo in patients with stage II to IIIA disease, David R. Spigel, MD, FASCO, President and Chief Medical Officer at Sarah Cannon Research Institute and an ASCO Expert in lung cancer, expressed support for selpercatinib in this setting. “The event-free survival data is quite compelling, and for me, this was a new standard of care as soon as I saw the press release,” he told the press. “If I have a patient in my clinic tomorrow who has early-stage disease and a RET alteration, I absolutely will offer this therapy.”

Study Details

A total of 151 patients with stage IB to IIIA RET fusion–positive NSCLC who had completed curative-intent surgery or radiotherapy, with or without adjuvant chemotherapy, were enrolled at 65 sites across 22 countries and randomly assigned in a 1:1 ratio to receive selpercatinib (≥ 50 kg: 160 mg; < 50 kg: 120 mg) or placebo twice daily for up to 3 years—with randomization stratified by disease stage (IB vs II–IIIA) and definitive locoregional therapy type. Crossover to selpercatinib was allowed for those who experienced disease recurrence or progression with placebo.

Although patients with stage IB disease were enrolled, the primary endpoint—investigator-assessed event-free survival—was evaluated in only those with stage II to IIIA disease (primary analysis population; n = 109). Secondary endpoints included event-free survival by blinded independent central review (BICR) in the primary analysis population; event-free survival by investigator assessment and BICR in the overall population; safety; and overall survival.

Baseline characteristics appeared balanced between the arms. In the primary analysis population, the median age was approximately 60 years, about 60% of patients were women, and roughly 70% had never smoked; the cohort was globally diverse, according to Dr. Goldman. KIF5B was the most common RET fusion partner, followed by CCDC6. Nearly all patients underwent curative-intent surgery (99%), with more than 90% also receiving prior adjuvant systemic therapy, most commonly chemotherapy.

Key Findings

In the primary analysis population, the investigator-assessed event-free survival results were “striking,” Dr. Goldman remarked during a press briefing. A total of 4 and 19 events were reported with selpercatinib and placebo, respectively—an approximate 83% lower risk of disease recurrence or death in the experimental arm (hazard ratio [HR] = 0.172; P = .0003). Median event-free survival was not reached with selpercatinib vs 31.8 months with placebo; at 24 months, 91.5% of patients treated with selpercatinib remained event-free compared with 61.1% of those who received placebo.

With median event-free survival not yet reached in either arm in the overall population, the investigator-assessed benefit remained consistent and statistically significant (HR = 0.165; P = .0002), he added. The findings were also confirmed by BICR in both the primary analysis and overall populations (HR = 0.125 for both).

Within the primary analysis population, selpercatinib demonstrated consistent benefit across clinically relevant subgroups, “although some sample sizes were quite small,” Dr. Goldman explained.

He also highlighted an analysis of sites of disease progression in the primary analysis population, which showed that locoregional and distant recurrences were less frequent among patients treated with selpercatinib. There was one CNS recurrence with selpercatinib compared with three with placebo—“low numbers, but certainly in an encouraging direction,” he told The ASCO Post. Reflecting the lower numbers of recurrence events with selpercatinib, disease relapse resulted in treatment discontinuation in 3 and 17 patients assigned to selpercatinib and placebo, respectively.

With a median follow-up of approximately 2 years in each arm, overall survival data remain immature in the primary analysis population. No deaths were reported with selpercatinib vs three with placebo; however, 16 patients crossed over to selpercatinib after disease recurrence, including all those who died, all of whom survived at least 1 year after crossover.

“These early data raise the possibility that delaying RET inhibition until recurrence may not fully recapture the benefit of early treatment,” Dr. Goldman remarked.

Safety Profile

In the overall population, the safety profile of selpercatinib was found to be generally consistent with what has been described in the metastatic setting. Treatment-emergent adverse events were reported in 100% of the selpercatinib arm and 97.4% of the placebo arm; grade 3 or higher events occurred in 66.7% and 23.7%, respectively, and were manageable with dose modifications (required overall in 88.0% vs 46.1%). Events leading to selpercatinib discontinuation (17.3% [vs 1.3% with placebo]) were mostly lower-grade liver function test abnormalities, Dr. Goldman explained. No treatment-emergent adverse events led to death.

Alanine aminotransferase (any grade, 62.7%) and aspartate aminotransferase (60.0%) increases occurred most frequently with selpercatinib. Other common events included dry mouth (40.0%), diarrhea (38.7%), and hypertension (30.7%). There were two cases of interstitial lung disease with selpercatinib, both of which resolved after discontinuation. Based on prior experience with selpercatinib, adverse events of special interest were monitored; hypersensitivity occurred in 6.7% of patients and QT prolongation in 9.3% (vs 1.3% with placebo; grade ≥ 3: 1.3% in both arms).

Insights and Opportunities

According to Dr. Goldman, the magnitude of event-free survival benefit was similar to that observed in major adjuvant therapy trials that changed practice in EGFR- and ALK-positive disease. He said, “These drugs all demonstrate the same necessary triad of successful adjuvant targeted therapy: a highly effective agent with good CNS penetrance and sufficient tolerability for years of treatment.”

“Nevertheless,” he emphasized, “adverse events are especially relevant in the adjuvant population and should be discussed with patients.”

He further noted that longer-term follow-up is needed to assess the durability of the event-free survival benefit, patterns of recurrence, extent of CNS protection, and impact of crossover, as well as whether the observed benefit ultimately translates into an overall survival advantage.

Taken together, the findings were described by Dr. Spigel in a press release as “immediately practice-changing,” and Dr. Goldman concluded that “adjuvant selpercatinib should be considered as a new standard of care in early-stage RET fusion–positive NSCLC.”

“Comprehensive biomarker testing should be performed at initial diagnosis,” he emphasized as a key takeaway point, “so that patients with actionable oncogenic drivers can be identified early and offered the most appropriate treatment strategy.”

Editor’s Note: Study author and pioneer in thoracic oncology research, Masahiro Tsuboi, MD, PhD, passed away on February 27, 2026, at the age of 65following a diagnosis of urothelial carcinoma. Dr. Tsuboi was Chief and Director of the Department of Thoracic Surgery and Oncology at the National Cancer Center Hospital East in Kashiwa, Japan. He also served as a co–global principal investigator of the ADAURA trial and contributed to the NeoADAURA trial. The ASCO Post honors Dr. Tsuboi’s contributions to the field and joins the oncology community in mourning his loss. 

DISCLOSURE: The study was funded by Eli Lilly and Company. Dr. Goldman has received honoraria from AbbVie, AstraZeneca, Genentech, Lilly, and Summit Therapeutics; has held a consulting or advisory role with AbbVie, AstraZeneca, Genentech, Lilly, and Summit Biomedical; has received institutional research funding from AbbVie, Advaxis, Amgen, Astellas Pharma, AstraZeneca/MedImmune, Bristol Myers Squibb, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen, Lilly, Lyell Immunopharma, Pfizer, Summit Biomedical, and SystImmune; and has received reimbursement for travel expenses from Summit Therapeutics.

REFERENCES

1. Goldman JW, Yang X, 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. 2026 ASCO Annual Meeting. Abstract LBA3. Presented May 31, 2026.

2. Wu Y-L, Hochmair M, Yang Y, et al: Selpercatinib in early-stage RET fusion–positive non–small-cell lung cancer. N Engl J Med. Published online May 31, 2026.

EXPERT POINT OF VIEW

The phase III LIBRETTO-432 trial extends the application of precision oncology in non–small cell lung cancer (NSCLC), with the oral RET tyrosine kinase inhibitor selpercatinib joining the EGFR inhibitor osimertinib and the ALK inhibitor alectinib in the adjuvant setting, according to invited discussant Christine M. Lovly, MD, PhD, FASCO, Division Chief of Thoracic Medical Oncology; Professor in the Department of Medical Oncology & Therapeutics Research; and the Dr. Norman and Mrs. Melinda Payson Professor at City of Hope in Duarte, California.¹ “Three trials, each one reinforcing the same principle,” she said at the 2026 ASCO Annual Meeting, namely that comprehensive genomic profiling at diagnosis is now “evidence- based, not aspirational.”

Yet, she added, “This is certainly a step forward, but important questions still remain.”

Among them are whether adjuvant chemotherapy remains necessary in the era of highly effective targeted agents; how long patients should continue adjuvant therapy; and whether improvements in event-free survival will ultimately translate into an overall survival benefit. Additional questions include the detailed impact on central nervous system metastases and the long-term consequences of treatment-related toxicity, particularly given the frequency of dose reductions observed with selpercatinib (54.7%).

The trial also underscores a challenge at the front end of care: early detection. Approximately 70% of patients enrolled had no smoking history, yet this population would not qualify for lung cancer screening under current U.S. Preventive Services Task Force criteria. “In the real world, to fully realize the benefit of adjuvant targeted therapies, we must identify lung cancer at an early stage in patients with no smoking history,” Dr. Lovly said.

For patients, translating the advances of precision oncology into routine care may require addressing this and other barriers beyond the development of effective drugs. Access to reflexive comprehensive genomic profiling at diagnosis and targeted therapies remains inconsistent, years of adjuvant tyrosine kinase inhibition can impose substantial financial burdens, and toxicity monitoring and survivorship programs must evolve to address the unique needs of patients receiving years-long targeted therapies.

Looking ahead, Dr. Lovly outlined several future directions for the field, including using molecular risk stratification to guide individualized approaches to care, determining whether distinct molecular subgroups require tailored adjuvant targeted therapies, and better understanding how resistance biology may shape future treatment strategies. “Most importantly,” she emphasized, “survivorship and quality of life cannot be an afterthought.”

She concluded by highlighting key priorities for maximizing the impact of these advances, including expanding biomarker testing for early-stage lung cancers, developing risk-stratification models, broadening the reach of lung cancer screening, and strengthening survivorship care. 

DISCLOSURE: Dr. Lovly has received honoraria from AbbVie, Amgen, AnHeart Therapeutics, AstraZeneca, Bayer, Black Diamond Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb/Medarex, Daiichi Sankyo/AstraZeneca, Danaher, Exact Sciences, Foresight Diagnostics, Gilead Sciences, GlaxoSmithKline, Illumina, ImmunityBio, Janssen Oncology, Jazz Pharmaceuticals, Merck, Natera, Nuvalent, Nuvation Bio, Onviv, Pfizer, Regeneron, Summit Pharmaceuticals, and Taiho Oncology; has held a consulting or advisory role with AbbVie, Amgen, AnHeart Therapeutics, AstraZeneca, Bayer, Black Diamond Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb/Medarex, Daiichi Sankyo Nordics, Danaher, Exact Sciences, Foresight Diagnostics, Gilead Sciences, GlaxoSmithKline, Illumina, ImmunityBio, Janssen Oncology, Jazz Pharmaceuticals, Merck, Natera, Nuvalent, Nuvation Bio, Onviv, Pfizer, Regeneron, Summit Pharmaceuticals, and Taiho Oncology; has received reimbursement for travel expenses from AbbVie, Boehringer Ingelheim, and Daiichi Sankyo Europe GmbH; and has an uncompensated relationship with Johnson & Johnson/Janssen.

REFERENCE

1. Goldman JW, Yang X, 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. 2026 ASCO Annual Meeting. Abstract LBA3. Presented May 31, 2026.