Adjuvant Selpercatinib Significantly Improves EFS in Early-Stage RET Fusion–Positive NSCLC

Selpercatinib (Retevmo) led to an 83% reduction in the risk of disease recurrence or death vs placebo when used in the adjuvant treatment of patients with stage II to IIIA, RET fusion–positive non–small cell lung cancer (NSCLC), according to primary data from the phase 3 LIBRETTO-432 study (NCT04819100) shared during a press briefing at the 2026 ASCO Annual Meeting.¹

The event-free survival (EFS) improvement with selpercatinib was determined to be statistically significant, and the primary end point of the study was met. The 24-month EFS with selpercatinib was 91.5% (95% CI, 75.4%-97.2%) vs 61.1% (95% CI, 44.2%-74.3%) with placebo (HR, 0.172; 95% CI, 0.058-0.509; P = .0003).

“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,” Jonathan Goldman, MD, said in the presentation of the data. “Adjuvant selpercatinib should be considered as a new standard of care in early-stage RET fusion–positive lung cancer.”

Goldman is a professor of medicine in the Hematology/Oncology Division at UCLA. He is the director of Clinical Trials in Thoracic Oncology and the associate director of Early Drug Development; he is also the chair of University of California Lung Cancer Consortium.

What inspired the launch of the LIBRETTO-432 trial?

For early-stage lung cancers that are driven by EGFR and ALK gene changes, the standard of care is surgery followed by targeted therapeutics, and this approach has resulted in significant reductions in the risk of cancer recurrence.

Previously, selpercatinib significantly prolonged progression-free survival (PFS) vs platinum-based chemotherapy with or without pembrolizumab (Keytruda) in patients with advanced RET fusion–positive NSCLC, according to data from the phase 3 LIBRETTO-431 study (NCT04194944).² The median PFS with selpercatinib was 24.8 months (95% CI, 16.9-not estimable) vs 11.2 months (95% CI, 8.8-16.8) with the control (HR, 0.46; 95% CI, 0.31-0.70; P < .001). Moreover, the objective response rates in the respective arms were 84% (95% CI, 76%-90%) and 65% (95% CI, 54%-75%), respectively.

In May 2020, the FDA granted accelerated approval to selpercatinib for use in patients with RET alteration–positive NSCLC, medullary thyroid cancer, and other thyroid cancers.³ In September 2022, accelerated approval was again granted to the drug for adult patients with locally advanced or metastatic solid tumors harboring a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.⁴ In September 2024, the regulatory agency granted traditional approval to selpercatinib for adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer with a RET mutation who require systemic therapy.⁵

What is the design of LIBRETTO-432 with selpercatinib?

“One of the major challenges for patients with early-stage lung cancer is that, despite potentially curative surgery or radiation, many remain at high risk of cancer recurrence over the following 5 years,” Goldman said in the briefing.¹ “We designed this study to see whether an oral agent could lower that risk.”

LIBRETTO-432 is a multicenter, global, double-blind, randomized, placebo-controlled, phase 3 trial that enrolled patients with histologically confirmed RET fusion–positive NSCLC who had received definitive therapy in the form of surgery or radiotherapy plus or minus systemic adjuvant chemotherapy. Patients could not have evidence of disease recurrence or progression after definitive therapy.

Study participants (n = 151) were randomized 1:1 to receive selpercatinib at 160 mg or 120 mg twice daily based on weight (≥ 50 kg and < 50 kg, respectively) or placebo twice daily. Patients were stratified by disease stage (IB vs II to IIIA) and definitive treatment (surgery vs radiotherapy). They continued to receive treatment for up to 3 years or until disease recurrence, progression, or death. Those in the placebo arm had the option to crossover at the time of disease progression.

In addition to the primary end point of the study being EFS by investigator assessment in the primary analysis population of patients with stage II to IIIA disease, secondary end points included EFS by blinded independent central review (BICR) in the primary analysis population, EFS by investigator and BICR assessment in the overall population of patients with stage IB to IIIA disease, safety, and overall survival.

Of the overall 151 patients who were randomized, 75 patients with stage IB to IIIA disease received selpercatinib and 76 patients with stage IB to IIIA disease; of these patients, 54 and 55, respectively, had stage II to IIIA disease and comprised the primary analysis populations. In the selpercatinib arm, 30 patients were still on treatment at the time of the data cutoff date of January 2026, and 24 had discontinued; the most common reasons for discontinuation were toxicity (n = 9) and treatment completion (n = 9). In the placebo arm, 24 patients were still on treatment, and 31 had discontinued; the most common reason for discontinuation was disease relapse (n = 17).

“The key point here is that this was a large global effort...This was also during the pandemic, and this really demonstrates the rarity of RET, but also the need to screen patients to identify these important mutations,” Goldman.

What were the baseline characteristics of the primary analysis population?

Within the primary analysis population, the median patient age was 59.5 years (range, 41.0-84.0) for those in the selpercatinib arm (n = 54) vs 61.0 years (range, 26.0-78.0) in the placebo arm (n = 55). In the respective arms, more than half of patients were female (63.0%; 54.5%), Asian (61.1%; 58.2%), from East Asia (57.4%; 56.4%), were never smokers (68.5% vs 69.1%), and had an ECOG performance status of 0 (55.6%; 65.5%).

Regarding PD-L1 status, in the selpercatinib arm, 20.4% were PD-L1 negative and 46.3% were positive; this information was unknown for 31.5% of patients. In the placebo arm, these respective rates were 29.1%, 50.9%, and 20.0%. All patients in the selpercatinib arm had undergone surgery, 3.7% had prior radiotherapy, and 92.6% received prior systemic therapy; in the placebo arm, 98.2% had a prior surgical procedure, 10.9% had prior radiotherapy, and 90.9% had prior systemic treatment.

“The two arms were generally well balanced,” Goldman said.

What was the safety profile of selpercatinib in LIBRETTO-432?

Goldman noted that the toxicity profile of the drug was consistent with what is seen in the metastatic setting.

All patients who received selpercatinib experienced at least 1 treatment-emergent adverse effect (TEAE), and 66.7% of these effects were grade 3 or higher. The most common TEAEs reported with selpercatinib were increased alanine aminotransferase level (any grade, 62.7%; grade ≥ 3, 17.3%), increased aspartate aminotransferase level (60.0%; 18.7%), diarrhea (38.7%; 4.0%), dry mouth (40.0%; 0%), cough (26.7%; 0%), increased blood bilirubin (26.7%; 0%), hypertension (30.7%; 10.7%), constipation (22.7%; 0%), and hyperuricemia (20.0%; 0%).

AEs were generally manageable with dose modifications, Goldman said, adding that discontinuations were mostly because of low-grade events in the selpercatinib arm. TEAEs led to discontinuation in 17.3% of patients in the selpercatinib arm vs 1.3% of those in the placebo arm. No deaths occurred on the investigative arm.

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. J Clin Oncol. 2026;44(suppl 17):LBA3. doi:10.1200/JCO.2026.44.17_suppl.LBA3
2. Zhou C, Solomon B, Loong HH, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion–positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. doi:10.1056/NEJMoa2309457
3. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. FDA. May 8, 2020. Accessed May 30, 2026. https://www.prnewswire.com/news-releases/fda-approves-first-therapy-for-patients-with-lung-and-thyroid-cancers-with-a-certain-genetic-mutation-or-fusion-301056045.html
4. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. News release. FDA. September 21, 2022. Accessed May 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-solid-tumors
5. FDA approves selpercatinib for RET fusion-positive medullary thyroid cancer. FDA. September 27, 2024. Accessed May 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-ret-fusion-positive-medullary-thyroid-cancer