The SWOG S2302 Pragmatica-Lung trial has delivered definitive results showing that a combination of ramucirumab (Cyramza) and pembrolizumab (Keytruda) failed to significantly improve overall survival in patients with advanced non-small cell lung cancer (NSCLC), while simultaneously establishing a revolutionary model for streamlined clinical trial design and execution.
The phase 3 study, which enrolled 838 patients with stage IV or recurrent NSCLC previously treated with immunotherapy and chemotherapy, aimed to validate promising results from the earlier phase 2 S1800A Lung-MAP sub-study. However, an interim analysis conducted in April 2025 revealed no statistical difference between treatment arms, with a hazard ratio of 0.99 (95% CI: 0.81-1.22, p=0.46).
Primary Efficacy Results Show No Survival Advantage
The trial's Data and Safety Monitoring Committee (DSMC) recommended public release of results after 370 deaths were reported among participants. Median overall survival was 10.1 months for patients receiving the ramucirumab plus pembrolizumab combination compared to 9.3 months for those treated with physician's choice of standard therapies.
"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," said study chair Karen L. Reckamp, MD, MS, of Cedars-Sinai Cancer.
Exploratory subgroup analyses revealed differential trends across histological subtypes. In patients with squamous cell carcinoma, representing 29% of the cohort, the hazard ratio was 0.82 (95% CI: 0.56-1.22, p=0.17), suggesting a non-significant trend toward benefit. Conversely, non-squamous patients showed a hazard ratio of 1.09 (95% CI: 0.85-1.39, p=0.75).
Breakthrough in Trial Design and Patient Representation
The Pragmatica-Lung trial distinguished itself through unprecedented inclusivity and operational efficiency. The study successfully enrolled a demographically diverse population that mirrors the broader U.S. population affected by advanced NSCLC, with 22% non-White individuals, 13% Black patients, and 15% from rural areas.
This broad representation was achieved through deliberately simplified eligibility criteria and reduced data collection burden, addressing historical gaps in clinical research participation. The approach ensured that findings would be broadly applicable across real-world patient populations.
Accelerated Timeline Sets New Industry Standard
From concept to completion, the trial demonstrated remarkable efficiency. Protocol development required just 200 days from initial concept review to study activation—approximately 100 days faster than typical benchmarks for comparable phase 3 studies. The study opened in March 2023, completed enrollment by December 2024, and delivered initial results by April 2025.
"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," said Jhanelle E. Gray, MD, of Moffitt Cancer Center and chair of the SWOG lung committee.
Clinical Implications and Safety Profile
Despite the lack of survival benefit, the DSMC reported no new or concerning safety signals throughout the trial. Lead biostatistician Mary W. Redman, PhD, noted that "overall survival appears comparable across arms, so the investigational combination may offer patients a non-chemotherapy-based regimen that's as effective as traditional chemo but that may be less toxic."
Patients who appeared to benefit clinically from the investigational combination were permitted to continue treatment per protocol, reflecting the study's commitment to balancing scientific rigor with compassionate care.
Collaborative Framework Enables Success
The trial's success resulted from strategic partnerships between multiple stakeholders, including the U.S. Food and Drug Administration's Oncology Center of Excellence, the National Cancer Institute's Division of Cancer Treatment and Diagnosis, Friends of Cancer Research, and the Alliance for Clinical Trials in Oncology.
This collaborative approach exemplifies modern cooperative oncology research, where regulatory bodies, advocacy organizations, and research networks work together to design patient-centric trials that provide timely, impactful answers.
Future Impact on Oncology Research
The Pragmatica-Lung model addresses critical challenges in cancer clinical research by demonstrating that trials can maintain scientific integrity while achieving rapid enrollment and reduced operational burden. The approach could accelerate therapeutic development, reduce trial costs, and improve patient and site engagement across the oncology research landscape.
Results from the S2302 Pragmatica-Lung trial will be presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago by study co-chair Konstantin Dragnev, MD, of Dartmouth Cancer Center, where the methodology and clinical findings are expected to generate significant discussion about the future direction of cancer clinical trials.
