Outcomes of Patients with RET Fusion-Positive Non-Small Cell Lung Cancer Treated with First-Line Non-Molecularly Targeted Therapies: A Real-World Benchmark in Europe from the RECALIB-RET Study

INTRODUCTION: The single-arm phase 1/2 LIBRETTO-001 trial demonstrated durable efficacy and a favorable safety profile with the selective RET inhibitor (RETi) selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC), regardless of prior non-RET-selective treatment. The aim of this study (RECALIB-RET), comparison of outcomes with first-line (1L) non-RET-selective therapy in a real-world external control arm to the LIBRETTO-001 selpercatinib-treated population, was precluded by a small real-world sample size. Therefore, we report European benchmark data, reflecting physician's choice of 1L therapy and treatment availability in routine clinical practice. METHODS: The study population comprised data from adult patients with RET fusion-positive, locally advanced/metastatic NSCLC who received ≥ 1 prior line of systemic non-RET-selective therapy, pooled across chart reviews from four European countries. Patient characteristics, biomarker testing and treatment patterns, clinical outcomes, and safety events during 1L therapy are reported. RESULTS: Patients in the RW benchmark population (n = 24) had a median age at 1L therapy initiation of 61.0 years (interquartile range 56.0-71.5); 58.3% were male and 41.7% were female, 95.8% had adenocarcinoma, and 91.7% had advanced-stage disease at diagnosis. Overall response and disease-control rates to 1L non-RET-selective therapy were 37.5% (95% confidence interval [CI] 18.8-59.4) and 58.3% (95% CI 36.6-77.9), respectively. Median progression-free survival was 5.4 months (95% CI 2.1-8.0). Median time between advanced disease diagnosis and biomarker testing (n = 21, 87.5%) was 17 days, with a median turnaround time for the results of 25 days; 70.8% (n = 17) initiated 1L treatment before receiving test results. Of 125 adverse events reported, 20 (16.0%) were grade ≥ 3. CONCLUSION: Outcomes observed in the RECALIB-RET RW benchmark population reflect the limitations of non-selective RETi therapies in RET fusion-positive NSCLC, and reinforce the rationale for early use of targeted agents such as selpercatinib. Optimizing biomarker testing practices may enable earlier access to these therapies.