With multiple negative phase III studies and limited FDA-approved options after progression on immunotherapy and chemotherapy, there is a pressing need for effective therapies for advanced non-small cell lung cancer (NSCLC).

In the randomized phase II Lung-MAP (S1800A) study, the combination of ramucirumab with pembrolizumab demonstrated an improvement in overall survival (OS), with a median OS of 14.5 months compared to 11.6 months for the standard of care (SoC) in the second-line setting, after disease progression on platinum-based chemotherapy and immunotherapy.
Additionally, patients receiving the combination therapy experienced fewer treatment-related adverse events (TRAEs) of grade 3 or higher: 42% in the ramucirumab-pembrolizumab group versus 60% in the SoC group.
Building on Lung-MAP, the phase III Pragmatica-Lung (SWOG S2302) trial was designed to evaluate the efficacy of ramucirumab plus pembrolizumab versus SoC chemotherapy in patients with previously treated stage IV or recurrent NSCLC.
“This was a simple trial with a primary objective to look at OS in the two arms and a secondary objective to summarize serious and unexpected adverse events (AEs) in patients on the two arms,” said Karen L. Reckamp, MD, MS, during a presentation at the 2025 American Society of Clinical Oncology (ASCO) annual meeting.

The trial confirmed that the ramucirumab-pembrolizumab combination yielded similar survival results to SoC treatment (median OS: 10.1 months vs. 9.3 months with SoC) and a more favorable safety profile, with 41 participants discontinuing treatment due to AEs in the SoC arm versus 29 in the ramucirumab-pembrolizumab arm.
Additionally, OS appeared to improve among patients with squamous cell carcinoma who were treated with the ramucirumab-pembrolizumab combination (median OS: 10.8 months vs. 8.2 months with SoC; hazard ratio [HR]: 0.82). Patients with non-squamous cell carcinoma reported similar outcomes in both arms (median OS: 9.7 months vs. 9.4 months with SoC; HR: 1.09).
Despite these results, we await evaluation for follow up. Ultimately, the real story of the Pragmatica-Lung trial is its design, which sets it apart from most conventional clinical studies. The trial used a pragmatic approach aimed at increasing enrollment, reducing barriers to participation, and streamlining data collection. The trial showcased how such a design could improve clinical trial efficiency, boost participant accrual, and better reflect real-world populations in lung cancer.
About Pragmatica-Lung
Unlike conventional clinical trials, Pragmatica-Lung opted for a simplified, real-world approach compared with stricter protocols that typically limit patient eligibility.
The trial’s pragmatic elements focused on expediting protocol development, decreasing administrative burdens, and improving participant diversity. These strategies contributed to faster protocol development and activation while reducing strains on clinical staff.
“The pragmatic design allowed us to decrease barriers to enrollment for a more real-world population,” Dr. Reckamp, Director of the Division of Medical Oncology at Cedars-Sinai Medical Center, said. “We incorporated very limited eligibility criteria that allowed for treatments as would be done in a standard practice.”
Entry criteria focused on stage, treatment history, and safety, with stratification based on the most recent line of therapy and performance status (PS) of 0 to 1 versus 2.
“We developed a recruitment plan that provided outreach to sites with populations generally less represented in standard trials, with help from our patient advocates and community engagement representatives,” said Dr. Reckamp.
Only 1% of patients failed to meet the eligibility requirements, which is significantly lower than the typical 10% observed in traditional trials. The simplified eligibility criteria allowed for broader demographic inclusion and faster enrollment, resulting in the accrual of 838 patients in 21 months.
“We were able to enroll a more representative population. Thirteen percent of the patients in this trial were Black—which mirrors the expected general US population. This is uncommon in most phase III trials,” said Dr. Reckamp.
The trial surpassed its target accrual goal of 29 patients per month, ultimately enrolling more than 50 patients per month during its final 6 months.
“The participant demographics reflect the typical patient with lung cancer that we see in the clinic,” said Konstantin H. Dragnev, MD, Dartmouth Cancer Center, who presented the phase III findings during the Lung Cancer Rapid Oral session at ASCO 2025. “Around 22% of the participants were nonwhite, 81% had received immunotherapies as the immediate prior line of treatment, 13% had a PS of 2, and nearly 40% of patients received protocol therapy in the third-line setting and beyond.”
Another key point of success of the trial design is evidenced by its reduced administrative and data collection burden. By minimizing unnecessary data reporting and eliminating traditional data requirements, the trial scaled back on the time- and labor-intensive procedures typically featured in conventional clinical trials.
The investigators observed a 45% reduction in the number of forms and a 66% reduction in the number of data elements at 1 year by cutting back on:
- Protocol-required disease assessments and lab tests
- Specimen collection
- AE reporting
- Concomitant medications (conmed) collection
Limiting data collection facilitated a quicker trial launch, with rapid protocol development, which was completed in 200 days from concept to activation in this case. Additionally, the protocol itself was streamlined to only 47 pages, and the informed consent form totaled 11 pages.
A New Model for Future Trials
Designing clinical trials that align with real-world practice helps improve enrollment, increases patient diversity, and enhances overall efficiency.
“Overall, this trial was pragmatic in its design, which led to a rapid accrual of historically understudied participants, improved study staff burden with reduction in data collection, and had a more representative real-world population,” Dr. Reckamp said. “The clinical research we know should be embedded in clinical care every day. And pragmatic designs may promote this approach and increase access for our patients.”
The success of the trial proves that effective research with FDA-approved agents can be conducted without excessive data collection or narrow eligibility criteria. As the field of oncology works to reduce disparities and improve trial efficiency, it’s important to consider how adopting a more pragmatic approach can benefit both patients and researchers, she said.
“Pragmatica-Lung sets a paradigm-shifting example in trial conduct that should be applied to future large, randomized trials, including those with registrational intent,” said Dr. Dragnev.