The SWOG S2302 Pragmatica-Lung trial, which broke new ground with its streamlined pragmatic design, unusually broad eligibility criteria, and reduced data collection, has quickly answered its primary question, finding that the investigational combination it tested did not significantly extend overall survival compared to standard of care treatments.
Importantly, the phase 3 trial’s rapid development and implementation, coupled with its successful enrollment of a group of patients broadly representative of the larger U.S. population, establish Pragmatica-Lung as a paradigm-shifting model for the design and conduct of future large randomized studies.
Results will be presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago on June 2nd by study co-chair Konstantin Dragnev, MD, of Dartmouth Cancer Center (Abstract LBA8671).
Pragmatica-Lung compared treatment with an immune checkpoint inhibitor-based combination of ramucirumab (Cyramza) and pembrolizumab (Keytruda) to physician’s choice of standard treatment in patients with stage 4 or recurrent non-small cell lung cancer (NSCLC) that had been previously treated with immunotherapy and chemotherapy. The study’s primary objective was to evaluate whether a survival benefit that had been seen with this regimen in the smaller, phase 2 S1800A trial (a Lung-MAP sub-study) would be validated in a larger, more representative population of patients.
“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, of Cedars-Sinai Cancer.
A planned second interim analysis of Pragmatica-Lung data in April found that it was unlikely the investigational combination would lengthen overall survival compared to standard of care. Based on the analysis, the trial’s Data and Safety Monitoring Committee (DSMC) recommended that results be publicly released.
The DSMC also reported that no safety concerns had been identified, and that patients clinically benefitting from treatment with the combination could continue the protocol treatment. Model letters summarizing the findings and the DSMC recommendations were sent to participating clinical sites for use in notifying clinicians and enrolled patients.
The April interim analysis found that, with 370 patient deaths reported, overall survival was not significantly different between the study arms, with a hazard ratio (HR; 95% CI) of 0.99 (0.81-1.22), with p = 0.46. Median overall survival was 10.1 months on the investigational arm and 9.3 months on the standard-of-care arm.
Pre-specified subset analyses evaluated treatment effects within squamous cell and non-squamous histologic subgroups. Among the 29 percent of enrolled patients who had squamous cell carcinoma, the HR (95% CI) was 0.82 (0.56-1.22), with p = 0.17. Among those with non-squamous histology, the HR (95% CI) was 1.09 (0.85-1.39), with p = 0.75. Longer-term follow-up data are needed to determine whether this difference represents a benefit for patients with squamous cell histology.
“For patients enrolled to Pragmatica-Lung, 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,” said the study’s lead biostatistician Mary W. Redman, PhD, of the SWOG Statistics and Data Management Center and the Fred Hutch Cancer Center.
The S2302 Pragmatica-Lung trial is led by the SWOG Cancer Research Network, supported by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and conducted within the NCI’s National Clinical Trials Network (NCTN).
The study was meant to serve as a prototype for large pragmatic trials that would reduce the burden of participation for both clinical sites and patients, would promote enrollment of all patients with the disease, and could be developed and conducted more efficiently, giving us earlier answers. It was developed in consultation with the U.S. Food and Drug Administration’s (FDA’s) Oncology Center of Excellence and with collaborative input from the NCI’s Division of Cancer Treatment and Diagnosis, the advocacy organization Friends of Cancer Research, and the NCTN’s Alliance for Clinical Trials in Oncology.
To make the trial accessible to the widest possible range of patients, at as many treatment sites as possible, Pragmatica-Lung was designed with relatively few restrictions on which patients with advanced NSCLC would be eligible to enroll. The group that ultimately did enroll looks much like the U.S. population overall, with strong representation of several demographic groups that are often understudied in clinical trials. Of the 838 enrolled patients, 22 percent were non-White, 13 percent were Black, and 15 percent lived in rural locations. This broad representation helps ensure the trial’s results are generalizable across the U.S. population. (See ASCO Abstract 11016 for additional details on increasing representation in this trial.)
With its swift enrollment and reduced burden of data collection, the trial was able to answer its primary question in just over two years, much more quickly than the typical phase 3 study. It opened in March 2023, completed enrollment by December 2024, and notified participating sites of initial results in April 2025.
The trial’s design stage was also unusually brief – study protocol development, from review of the initial concept to study activation, was completed in just 200 days, cutting about 100 days off of what would typically be considered an efficient timeline for building a phase 3 study of this sort. Of note is that this rapid timeline was achieved in a study with registrational intent – designed so that results could be used, if needed, in an application for FDA review of the treatment.
“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.
The S2302 Pragmatica-Lung study is funded through NCI/NIH grants to the SWOG Cancer Research Network U10CA180888 and U10CA180819, and is supported in part by Eli Lilly and Company and Merck (known as MSD outside of the US and Canada), including through Cooperative Research and Development Agreements between NCI, SWOG, and Lilly and between NCI, SWOG, and Merck.
In addition to Dragnev, Redman, and Reckamp, co-authors on the ASCO abstract include Maya Khalil, MD, The University of Alabama, Birmingham; Brian S. Henick, MD, Columbia University/Herbert Irving Comprehensive Cancer Center; James Moon, MS, SWOG Statistics and Data Management Center and Fred Hutch Cancer Center; Pasarlai Ahmadzai, SWOG Statistics and Data Management Center and Fred Hutch Cancer Center; Michael LeBlanc, PhD, SWOG Statistics and Data Management Center and Fred Hutch Cancer Center; Daniel R. Carrizosa, MD, MS, Levine Cancer Institute/Wake Forest Baptist Comprehensive Cancer Center; Paul J. Hesketh, MD, Lahey Hospital and Medical Center; Ellen V. Sigal, PhD, Friends of Cancer Research; Jeff Allen, PhD, Friends of Cancer Research; Andreas N. Saltos, MD, Moffitt Cancer Center; Bryan A. Faller, MD, Heartland NCORP/Missouri Baptist Medical Center; Roy S. Herbst, MD, PhD, Yale University; Charles D. Blanke, MD, SWOG Network Operations Center and Oregon Health & Science University; and Jhanelle E. Gray, MD, Moffitt Cancer Center.
SWOG Cancer Research Network is part of the National Cancer Institute's National Clinical Trials Network and the NCI Community Oncology Research Program and is part of the oldest and largest publicly funded cancer research network in the nation. SWOG has more than 20,000 members in 46 states and eight other countries who design and conduct clinical trials to improve the lives of people with cancer. SWOG trials have directly led to FDA approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 3 million years of human life. Learn more at swog.org.
CYRAMZA® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or its affiliates. KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
References:
Abstract LBA8671: Dragnev KH, Redman M, Reckamp KL, et al. “Pragmatica-Lung (SWOG S2302): A prospective pragmatic 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.” https://meetings.asco.org/abstracts-presentations/253426
Abstract 11016: Reckamp K, Redman M, Dragnev K, et al. “SWOG S2302, PRAGMATICA-LUNG: A pragmatic trial designed to increase participant representation.” https://meetings.asco.org/abstracts-presentations/247054
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