During the past decades, the treatment of non-small cell lung cancer (NSCLC) has been transformed by the recognition that many tumors are driven by specific oncogenic alterations. These alterations can be effectively targeted with oral agents, resulting in major improvements in response rates, progression‑free survival (PFS), and often quality of life, compared to chemotherapy or chemo‑immunotherapy in the advanced disease setting.
RET fusions are one such actionable driver mutation. They occur in approximately 1% to 2% of NSCLC, often in younger patients with little or no history of smoking; however, their rarity should not be mistaken for marginal importance.
RET-directed therapy has yet to be explored in patients with stage IB-IIIA RET fusion-positive NSCLC, a population with high recurrence rates and no approved adjuvant targeted therapies currently available. However, selpercatinib, a highly selective, potent, and brain-penetrant RET inhibitor, offers the potential to deliver comparable benefits in this patient population.
“Selpercatinib is a highly effective, central nervous system (CNS)‑penetrant, oral RET inhibitor with substantial systemic and intracranial activity in advanced disease,” said Jonathan W. Goldman, MD. “This sets the stage for another seismic shift in thoracic oncology: moving effective targeted therapies from the metastatic setting into earlier‑stage disease, now a proven approach for EGFR‑mutated and ALK fusion-positive NSCLC.”
LIBRETTO-432 (NCT04819100) is the first randomized phase III trial conducted in a RET fusion-positive population. The trial evaluated selpercatinib versus placebo for up to 3 years in patients with stage IB to IIIA RET fusion-positive NSCLC following definitive locoregional treatment.
“This study demonstrated that adjuvant selpercatinib improved event‑free survival (EFS) in early‑stage RET fusion-positive NSCLC,” Dr. Goldman said. “The safety profile was consistent with prior experience with selpercatinib, and the results support comprehensive biomarker testing, even in patients with early‑stage disease.”
Dr. Goldman reported the results of the placebo-controlled, double-blind study at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
“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 recurrence over the following 5 years,” Dr. Goldman said. “We designed this study to see whether an oral targeted therapy could lower that risk.”
Study Design
A total of 151 patients were enrolled in the LIBRETTO-432 trial. Eligible patients had histologically confirmed RET fusion-positive NSCLC, stages IB to IIIA. All patients had undergone surgery or radiation therapy with curative intent.
Adjuvant chemotherapy was allowed but not required. Patients were then randomly assigned to receive selpercatinib (n = 75) or placebo (n = 76) for up to 3 years. Twenty‑one patients with stage IB disease per arm were not included in the primary analysis population, resulting in 54 patients in the selpercatinib arm and 55 in the placebo arm.
Baseline characteristics were generally well balanced between the treatment arms. The median age was approximately 60 years. Around 60% of the patients were women, and 70% had never smoked. The population was geographically diverse.
Crossover to selpercatinib was permitted for patients initially assigned to placebo who developed disease recurrence or progression. Although patients with stage IB disease were enrolled, the primary endpoint was investigator‑assessed EFS in patients with stage II or IIIA disease.
Secondary endpoints included investigator-assessed EFS in all randomized patients (overall population, stage IB-IIIA), EFS assessed by blinded independent central review (BICR), overall survival (OS), and safety.
Safety Profile
The safety profile of selpercatinib was consistent with its known adverse event (AE) profile. Treatment‑emergent adverse events (TEAEs) occurred in nearly all patients in both arms (100% with selpercatinib vs. 97.4% with placebo). Grade 3 or higher events were more common in the selpercatinib group, occurring in 67% of patients compared to 24% in the placebo group.
Treatment discontinuation due to TEAEs occurred in 17% of patients receiving selpercatinib and 1% of those on placebo. These events were primarily due to lower‑grade liver function test (LFT) abnormalities, according to Dr. Goldman.
Disease relapse led to treatment discontinuation in three patients receiving selpercatinib, compared to 17 patients in the placebo group.
No TEAEs resulted in death. Dose modifications were common with selpercatinib; however, even grade 3 or higher AEs were generally manageable through dose adjustments, Dr. Goldman noted. Two events of interstitial lung disease occurred in patients receiving selpercatinib, which were resolved after drug discontinuation.
The most common AEs were ALT and AST elevations. Other common events included grade 1 to 2 diarrhea in 39% of patients and hypertension in 31%. Only three deaths were reported, all in the placebo arm and none in the selpercatinib group.
LIBRETTO-432 Results
The median follow-up was 24 months for selpercatinib and 27 months for placebo. At the preplanned efficacy analysis, selpercatinib demonstrated a significantly improved EFS in patients with stage II to IIIA disease.
Median EFS was not reached for selpercatinib versus 31.8 months for placebo (4 EFS events with selpercatinib vs. 19 EFS events with the placebo, respectively). EFS by BICR was consistent with investigator-assessed EFS. The 2-year EFS rate was 91.5% for selpercatinib versus 61.1% for placebo.
In the overall population (n = 151), the error-controlled EFS hazard ratio (HR) was 0.165, and the median EFS was not reached in either treatment arm. Selpercatinib significantly improved investigator‑assessed EFS compared with placebo, with an HR of 0.17 and a p‑value < 0.001.
Subgroup analysis also demonstrated a consistent benefit across clinically relevant subgroups, although some subgroup sample sizes were relatively small.
The study also analyzed the sites of progression by treatment, showing that local, regional, and CNS relapses were all less frequent in the selpercatinib arm. With a median follow‑up of just over 2 years on each arm, OS remain immature.
Sixteen patients crossed over from placebo to selpercatinib following disease recurrence, and 12 of these patients remained on selpercatinib at the data cutoff. The three reported deaths in the placebo group occurred at least 1 year after the start of the crossover. These early data suggest that delaying RET inhibition until recurrence may not fully recapture the benefits of early treatment.
Future Directions
Taken together, these findings support adjuvant selpercatinib as a new standard of care for patients with early‑stage RET fusion-positive NSCLC, Dr. Goldman noted. However, OS data remain immature, and longer-term follow-up will be necessary to understand the durability of benefit, patterns of recurrence, the extent of CNS protection, and the impact of crossover.
“The magnitude of benefit with selpercatinib is consistent with what we have come to expect from effective targeted therapy in oncogene‑driven lung cancer,” Dr. Goldman said. “The HR of 0.17 in the stage II to IIIA population is similar in magnitude to the effects seen in major adjuvant‑therapy trials that have changed practice in EGFR‑ and ALK‑positive disease.”
