The S2302 Pragmatica-Lung trial is poised to transform clinical trial methodology in oncology, representing what researchers call a "dramatically streamlined" phase III study designed to evaluate real-world effectiveness of combination ramucirumab and pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) whose disease has progressed following prior immunotherapy.
This federally-funded trial marks a significant departure from traditional clinical trial design, with the FDA agreeing to consider data from this simplified pragmatic approach for registration intent despite the more limited information collected. The study focuses on patients whose NSCLC has advanced after both immunotherapy and chemotherapy, addressing a critical area of unmet medical need in second-line treatment options.
Revolutionary Trial Design Eliminates Traditional Barriers
The Pragmatica-Lung design represents a fundamental shift toward pragmatic trials that measure real-world effectiveness rather than solely determining efficacy under controlled conditions. The study maximizes eligibility through extremely limited exclusion criteria, minimal laboratory tests, simplified consent procedures, and recruitment across both academic and community oncology clinics.
Data collection has been reduced to only essential elements needed to evaluate overall survival and rates of severe adverse events. Sites are required to report only vital status, date and cause of death, grade 5 adverse events, and grade 3-4 adverse events only if they are treatment-related, serious, and unexpected.
The streamlined approach eliminates numerous traditional requirements including tissue specimens, protocol-required laboratory tests, disease assessments using RECIST criteria, reporting of concomitant medications, patient-reported outcome instruments, and cycle-specific treatment reporting. The informed consent document has been condensed to 11 pages written at a seventh-grade reading level, compared to typical lung cancer study consent forms that are twice as long.
Scientific Foundation Built on Promising Phase II Results
The combination being tested stems from promising results in the phase II S1800A trial, which demonstrated improved overall survival with ramucirumab and pembrolizumab in the acquired resistance setting, achieving a hazard ratio of 0.69 (80% CI: 0.51-0.92). The scientific premise centers on ramucirumab's role as a VEGFR2 antibody that could overcome immune modulation and restore benefit to anti-PD1 therapy such as pembrolizumab.
Previous research has established the role of vascular endothelial growth factor (VEGF) and its receptor in promoting an immunosuppressive tumor microenvironment. The combination of Eli Lilly's ramucirumab (Cyramza) and Merck's pembrolizumab (Keytruda) demonstrated safety and efficacy signals in phase I trials across multiple tumor types, including lung cancer.
Patient-Reported Outcomes Reveal Predictive Potential
Concurrent research from the Lung-MAP (S1400I) substudy has revealed unexpected insights into the predictive value of patient-reported outcomes in NSCLC treatment. Among 158 participants completing quality of life questionnaires, exploratory analyses found that patients reporting high levels of appetite loss and shortness of breath at baseline (20% of the sample) had a 3-fold increased risk of progression (hazard ratio = 3.06, 95% confidence interval = 1.88 to 4.98, P < .001).
Even more striking, patients reporting high baseline appetite loss and work limitations (14% of the sample) demonstrated a 5-fold increased risk of death (hazard ratio = 5.60, 95% confidence interval = 3.27 to 9.57, P < .001). These findings suggest that patient-reported outcomes may serve as noninvasive and inexpensive biomarkers of disease outcomes, with completion rates of 85% at 7 weeks and 68% at 13 weeks exceeding initial estimates.
Enhanced Diversity and Accessibility Focus
The trial incorporates comprehensive diversity, equity, and inclusion initiatives designed to reach more representative patient populations. Enrollment goals are based on real-world national data from SEER program statistics, with validated geographical information systems data used for purposeful outreach to sites serving high percentages of patients from underrepresented groups.
SWOG is developing community engagement packages including outreach strategies, advertising materials, patient-friendly educational content targeting underrepresented populations, and evaluation tools. The organization plans to provide support for local advertising and community engagement events in underserved communities, with all patient education materials available in Spanish.
The study's eligibility criteria mirror package inserts as closely as possible, requiring only histologically or cytologically confirmed stage 4 or recurrent NSCLC, acquired resistance to prior immunotherapy, prior receipt of platinum-based chemotherapy, age 18 or older, Zubrod Performance Status of 0-2, and ability to safely take investigational drugs per FDA instructions.
Implications for Future Clinical Trial Methodology
National oncology leaders have expressed hopes that this design will become "the new normal" for clinical trials. The approach addresses significant challenges facing clinical sites post-COVID, including research staff turnover and training difficulties. The simplified design makes it ideal for onboarding new staff while maintaining scientific rigor.
The trial is expected to open in mid-January, representing one of the quickest-ever NCTN activations. This rapid timeline resulted from extensive stakeholder collaboration and collective desire to reduce site burden while reaching more patients. The study will incorporate both NCTN and NCORP networks, with site enrollment rates monitored monthly and regular communication providing startup and accrual support as needed.
SWOG is also working to secure funding to help cover patient participation costs, including travel expenses for trial-related clinic visits. Research indicates that the average clinical trial patient travels 67 miles per visit, translating to approximately $84 per clinic visit at standard mileage reimbursement rates.
