Host Dr. John Sweetenham and guests Dr. Karen Reckamp and Dr. Harpreet Singh discuss the S2302 Pragmatica-Lung trial, a streamlined, real-world clinical trial that is poised to simplify and transform the entire clinical trials model as we know it. TRANSCRIPT Dr. John Sweetenham: Hello, I’m Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast.  Today, we are going to be discussing a streamlined, real-world clinical trial from the Southwest Oncology Group (SWOG), which is S2302, also known as the Pragmatica-Lung trial. This study is poised to simplify and transform the entire clinical trials model as we know it. Joining me for this discussion is the trial’s lead investigator, Dr. Karen Reckamp. Dr. Reckamp is a clinical professor, director of the Division of Medical Oncology, and associate director for clinical research at Cedars-Sinai Samuel Oschin Cancer Center. I’m also delighted to welcome Dr. Harpreet Singh, the director of 1 of 3 divisions of oncology at the U.S. Food and Drug Administration. She will discuss the FDA’s views on streamlining clinical trials to reach more representative groups of patients and will also more broadly address some of the key questions that regulators consider when deciding on whether real-world data can substitute for randomized controlled trials. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod. Dr. Reckamp and Dr. Singh, it’s a great pleasure to have you on the podcast today. Dr. Karen Reckamp: Thank you for having us. Dr. John Sweetenham: Dr. Reckamp, I’m going to start with you if I may and ask if you could give us some background on S2302, the Pragmatica-Lung trial for non-small cell lung cancer. Dr. Karen Reckamp: Sure. The Pragmatica-Lung trial really started with the sub-study from Lung-MAP, which was called S1800A, and it was a randomized phase 2 trial that evaluated pembrolizumab and ramucirumab versus standard of care for patients who had previously received chemotherapy and immunotherapy with advanced non-small cell lung cancer and had had disease progression. And in this phase 2 trial, we found that there was an improvement in overall survival with a hazard ratio of 0.69% and survival of 14.5 months for pembrolizumab and ramucirumab, and 11.6 months for standard of care. And with that, we had again a randomized phase 2 trial, but the study was small. And so, trying to think about how to move this to the next level to get phase 3 data, we started thinking about how to do this in a way that would reduce the timelines and potentially move this treatment to patients more quickly than standard registrational, randomized phase 3 trials. And that’s kind of where S2302 and Pragmatica-Lung started. Dr. John Sweetenham: So, can you tell us in a little more detail how the dramatically streamlined pragmatic design of this trial is going to hopefully simplify trial design and trial conduct in the future beyond non-small cell lung cancer?  Dr. Karen Reckamp: I think the important piece of this—and we have Dr. Singh here to speak to the FDA part—but this has been a partnership with the FDA and CTEP [NCI’s Cancer Therapy Evaluation Program]. Really, our goal was to try and find a way to run trials in a more streamlined way. One of our colleagues at CTEP during this process said, “If this is not making you uncomfortable, then you're not doing it right.” So, the first thing we did was kind of lean into the discomfort because for those of us who have been writing trials and putting trials together for the last 20-plus years, this is dramatically different. And we’re really looking at one question, and that is overall survival. We’re trying to validate the overall survival we saw in S1800A. And with that, we stripped away all the unnecess