An interim analysis of the phase III LIBRETTO-431 trial has shown significantly improved progression-free survival with first-line selpercatinib vs platinum-based chemotherapy with or without pembrolizumab in patients with RET fusion–positive advanced non–small cell lung cancer (NSCLC). The findings were presented at the European Society for Medical Oncology (ESMO) Congress 2023 (Abstract LBA4) and were reported in The New England Journal of Medicine by Caicun Zhou, MD, PhD, and colleagues.

Caicun Zhou, MD, PhD

Study Details

In the open-label trial, 261 patients (overall intention-to treat [ITT] population) from sites in 23 countries enrolled between March 2020 and August 2022 were randomly assigned 1.6:1 to receive selpercatinib at 160 mg twice daily in continuous 21-day cycles (n = 159) or platinum-based chemotherapy (n = 102) with pemetrexed at 500 mg/m² plus carboplatin at AUC = 5 or cisplatin at 75 mg/m² with or without pembrolizumab at 200 mg every 21 days at investigator's discretion. The ITT-pembrolizumab population consisted of 129 patients in the selpercatinib group vs a total of 83 patients in the control group who received pembrolizumab. Patients from East Asia constituted 54% of the overall ITT population. The primary endpoint was progression-free survival on blinded independent central review in both the ITT-pembrolizumab population and the overall ITT population.

Progression-Free Survival

At the time of interim analysis in the ITT-pembrolizumab population, median progression-free survival was 24.8 months (95% confidence interval [CI] = 16.9 months to not estimable) with selpercatinib and 11.2 months (95% CI = 8.8–16.8 months) with control treatment including pembrolizumab (hazard ratio [HR] = 0.46, 95% CI = 0.31–0.70, P < .001). Objective responses were observed in 84% vs 65% of patients. Median response duration was 24.2 months vs 11.5 months. The cause-specific hazard ratio for time to disease progression affecting the central nervous system was 0.28 (95% CI = 0.12–0.68).

In the overall ITT population, median progression-free survival was 24.8 months (95% CI = 17.3 months to not estimable) in the selpercatinib group vs 11.2 months (95% CI = 8.8–16.8 months) in the control group (HR = 0.48, 95% CI = 0.33–0.70, P < .001). Objective responses were observed in 84% vs 63% of patients. Median response duration was 24.2 vs 12.0 months. 

Adverse Events

Among 158 vs 98 patients in the safety population, grade ≥ 3 adverse events occurred in 70% of the selpercatinib group vs 54% of the control group. The most commonly reported events in the selpercatinib group were alanine aminotransferase increase (22%), hypertension (20%), aspartate aminotransferase increase (12%), and QT prolongation (9%); the most common adverse events in the control group were neutropenia (28%) and anemia (10%). Adverse events led to discontinuation of treatment in 10% vs 2% of patients. Adverse events led to death in seven patients (4.4%) in the selpercatinib group vs none in the control group; death in two patients in the selpercatinib group was considered related to treatment.

The investigators concluded: “Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion–positive NSCLC.”

Dr. Zhou, of the Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, is the corresponding author of The New England Journal of Medicine article.

Disclosure: The study was supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly, and others. For full disclosures of the study authors, visit nejm.org.