Although the SWOG S2302 Pragmatica-Lung trial did not achieve its primary endpoint of improved overall survival with the combination of ramucirumab and pembrolizumab compared with standard-of-care treatments for patients with stage IV or recurrent non–small cell lung cancer (NSCLC) who previously received immunotherapy, the study was still considered significant—and potentially paradigm-shifting.
The trial was notable for its pragmatic design, broad eligibility criteria, and reduced data collection, which allowed for a faster and easier study process while reducing some of the barriers and burdens of trial participation. The study authors hope the study design could act as a model for other large future studies.
“Although the answer to the trial’s primary question is negative, the trial itself—in its speed, its broad and highly representative enrollment, and the reduced burden for clinic staff and participants alike—has been hugely positive in demonstrating the viability of a model for large, pragmatic clinical trials that are lean, inclusive, and quick, even with FDA registrational intent,” said study chair Karen L. Reckamp, MD, MS, Director of the Division of Medical Oncology, Cedars-Sinai Cancer.
Findings from the study and insights into its design were presented during the 2025 ASCO Annual Meeting (Abstract LBA8671 and Abstract 11016).
About the Study
Previous positive results had been seen with the combination of ramucirumab and pembrolizumab compared with standard of care in patients with advanced NSCLC in the phase II Lung-MAP S1800A study.
The SWOG S2302 Pragmatica-Lung trial is a registration-intent randomized phase III study that included 838 patients with advanced NSCLC who had previously received an immune checkpoint inhibitor for at least 84 days as well as platinum-based therapy. Participants were randomly assigned to either receive ramucirumab and pembrolizumab or physician’s choice of standard-of-care treatments, and they were stratified by prior immunotherapy receipt and performance status.
Laboratory assessment and imaging were not required for study enrollment. Data collection was minimized in the form of fewer forms, data elements, and time points for data submissions. Safety was monitored focused on related and unexpected grade 3 or 4 adverse events as well as all grade 5 events. Two interim analyses were planned at 40% and 60% of expected deaths.
Designing the study took only 200 days. The study was opened in March 2023 and completed patient enrollment within 21 months, with an average of more than 50 patients enrolled per month in the final 6 months. Initial results were released to participating sites by April 2025.
Few restrictions were placed on eligibility criteria, which led to a patient population that was more representative of the overall U.S. population, including several groups that are often understudied in clinical trials. The median age was 68 years (range = 34–88), 22% of enrollees were non-White, 15% were from rural areas, and 13% had a performance status of 2.
“Designing trials so they test new treatments in settings that reflect everyday, real-world practice removes barriers to participation and speeds trial enrollment and completion. Pragmatica-Lung offers a paradigm-shifting example in trial conduct that should be applied to future large randomized studies, including studies with FDA registrational intent,” said Jhanelle E. Gray, MD, of Moffitt Cancer Center, and chair of the SWOG lung committee.
Study Results
The study met futility criteria for early reporting at the second interim analysis with a median follow-up of 5.2 months. The Data and Safety Monitoring Committee recommended that the results be publicly released at this time.
Overall survival was not significantly different between the two treatment arms, at 10.1 months with ramucirumab and pembrolizumab compared with 9.3 months for the standard of care (hazard ratio [HR] = 0.99; 95% confidence interval [CI] = 0.81–1.22; P = .46).
Patients with squamous cell carcinoma demonstrated a greater benefit (HR = 0.82; 95% CI = 0.56–1.22; P = .17) compared with patients with nonsquamous cell carcinoma (HR = 1.09; 95% CI = 0.85–1.39; P = .75). Some other subgroups also showed benefit in terms of delayed curve separation.
“For patients enrolled to Pragmatica-Lung, overall survival appears comparable across arms, so the investigational combination may offer patients a nonchemotherapy-based regimen that’s as effective as traditional chemotherapy but that may be less toxic,” said the study’s lead biostatistician Mary W. Redman, PhD, of the SWOG Statistics and Data Management Center and the Fred Hutch Cancer Center.
Disclosure: Funding for the study was provided by National Institutes of Health/National Cancer Institute grants as well as by Merck Sharp & Dohme LLC and Eli Lilly and Company. For full disclosures of the study authors, visit coi.asco.org.
