PRAGMATICA-LUNG (SWOG S2302): A prospective, randomized study of ramucirumab plus pembrolizumab versus standard of care for participants previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer.

Abstract

LBA8671 Background: Effective therapy after frontline immune checkpoint inhibitor (ICI)-based treatment for advanced NSCLC is needed as limited options are available. Lung-MAP S1800A was a phase II randomized study of RP versus SoC for pts with NSCLC previously treated with ICI that showed benefit in overall survival (OS) with an improved toxicity profile over SOC. S2302 Pragmatica-Lung was designed to evaluate the impact on OS while reducing the barriers and burdens of trial participation. Methods: S2302 is a registration-intent randomized phase III trial for pts with advanced NSCLC who previously received ICI for at least 84 days and platinum-based therapy, randomized to SOC or RP, stratified by immediate prior therapy including ICI (yes/no) and PS (0/1 v. 2). The pragmatic design led to eligibility focus on stage, prior therapy and safety to enroll pts. Laboratory assessment and imaging were not required. Data collection was developed to minimize the burden with fewer number of forms, data elements and time points for data submitted. Only related and unexpected grade 3/4 and all grade 5 adverse events were collected. Two interim analyses (at 40% and 60% of expected deaths) were planned. The criteria for early reporting were a fixed sample p-value from a stratified log-rank test ≥ 0.3156 for futility and ≤ 0.0054 for efficacy. Results: S2302 enrolled 838 pts in 21 months (mos) from March 2023 to December 2024 (419/arm), averaging >50 pts/month in the final 6 mos. Median age (range) was 68 (34-88), 22% non-white /13% Black, 15% rural, 29% squamous cell carcinoma (SCC), 63% adenocarcinoma, 81% had ICI as the most recent treatment, 13% had PS2. The study met futility criteria for early reporting at the second interim analysis (April 2025). With 370 deaths reported and median of follow-up for alive pts of 5.2 mos (0.2-22.1 mos), OS is not different between the arms: HR (95% CI): 0.99 (0.81-1.22), p=0.46; median OS of 10.1 mos for RP and 9.3 for SOC. Within histologic subgroups, the HR (95% CI) for 242 pts with SCC is 0.82 (0.56-1.22), p=0.17 and for 596 with non-SCC is 1.09 (0.85-1.39), p=0.75. Conclusions: Accrual was rapid, and participant representativeness enhanced in this study with pragmatic design features. Often understudied groups were better represented; the study represents a contrast with the usual better prognosis of trial populations. While RP did not improve OS, RP was not worse than SOC overall, may benefit some with SCC, and is chemotherapy-free. There is some evidence of subgroups benefiting with delayed curve separation. Longer follow-up and reported events will provide more clarity on these hypotheses. Support: NIH/NCI/NCTN grants U10CA180888 and U10CA180819; and in part by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eli Lilly and Company. Clinical trial information: NCT05633602 .