RET fusion-positive lung cancer accounts for approximately 2% of all non-small cell lung cancer (NSCLC) diagnoses. Before targeted therapies were introduced for this specific subtype, treatment relied largely on conventional approaches, including chemotherapy and radiation.1
The treatment landscape for RET fusion-positive NSCLC shifted in 2020 with the US Food and Drug Administration’s approval of selpercatinib, an oral selective RET inhibitor. By specifically targeting RET alterations that drive tumor growth, selpercatinib provided a targeted therapeutic option for patients with metastatic RET fusion-positive NSCLC.1
Recently, the placebo-controlled, double-blind, randomized phase 3 LIBRETTO-432 trial evaluated selpercatinib in patients with stage IB-IIIA RET fusion-positive NSCLC—a population with no approved targeted therapies in the adjuvant setting and persistently high recurrence rates following definitive treatment.2
For Alexander E. Drilon, MD, a coauthor of the LIBRETTO-432 study, the key takeaway is the potential benefit of moving selpercatinib into earlier-stage disease. “This study demonstrated that adjuvant selpercatinib can improve outcomes in early-stage RET fusion-positive lung cancers,” Dr. Drilon said.
The study included 151 patients across 22 countries who were randomly assigned to receive selpercatinib or placebo.3 The primary end point was investigator-assessed event-free survival (EFS) among patients with stage II-IIIA disease. Secondary end points included investigator-assessed EFS among all randomized patients, EFS by blinded independent central review, overall survival, and safety.2
In the primary analysis population, selpercatinib significantly improved EFS compared with placebo. Median EFS was not reached in the selpercatinib group compared with 31.8 months in the placebo group (HR, 0.172; 95% CI [0.058, 0.509]; P = .0003).3
The benefit was also observed in the overall stage IB-IIIA population. At 24 months, EFS rates were 91.5% with selpercatinib compared with 61.1% with placebo.
Grade 3 or higher treatment-emergent adverse events occurred in 66.7% of patients receiving selpercatinib and 23.7% receiving placebo. The most common adverse events were increased alanine aminotransferase/aspartate aminotransferase levels. Only three deaths occurred, all in the placebo arm due to the disease. No patients died during assigned study treatment. According to investigators, adverse events were generally consistent with the drug’s known safety profile.3
“Selpercatinib was well-tolerated overall,” Dr. Drilon said. The results also reinforce the potential importance of identifying RET fusions earlier in the course of disease, he said. Investigators highlighted the need for comprehensive genomic testing across all stages of NSCLC, particularly as targeted therapies traditionally used in advanced disease are evaluated in earlier-stage disease.3
“The study confirms a paradigm we’ve observed in other oncogene-driven cancers such as EGFR and ALK,” Dr. Drilon said. “Adjuvant TKI therapy can help prevent cancer recurrence after definitive therapy for early-stage oncogene-driven lung cancers.”
References
1. Patel T. Breaking ground: the most successful treatment options for RET-positive lung cancer. The Happy Lungs Project. Published January 27, 2025.
2. 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. ASCO. 2026;44(17):suppl. doi:10.1200/JCO.2026.44.17_suppl.LBA3
3. LIBRETTO-432: selpercatinib improves clinical outcomes in early-stage NSCLC with RET fusions. ASCO Daily News. Published May 31, 2026.
