A clinical trial that breaks new ground with its dramatically streamlined design and unusually broad eligibility criteria is now opening and available to patients with stage 4 or recurrent non-small cell lung cancer at cancer treatment clinics all across the United States. 

The S2302 Pragmatica-Lung trial, developed and led by the SWOG Cancer Research Network, a clinical trials group funded by the National Cancer Institute (NCI), is designed to be easier for institutions to open and run and with few limits on eligibility, making it available to a larger group of patients with advanced non-small cell lung cancer.

“From the ground up, this study was designed to be inclusive, to enroll the full range of patients with this disease, and to be easy to conduct at all sites that treat the disease,” said Charles D. Blanke, MD, chair of the SWOG Cancer Research Network and professor at Oregon Health and Science University.  

An FDA registration trial with a difference
The trial is structured to quickly answer one question: does a combination of the drugs ramucirumab (Cyramza) and pembrolizumab (Keytruda) help patients with stage 4 or recurrent non-small cell lung cancer previously treated with immunotherapy and chemotherapy live longer than the usual treatments?

If trial results suggest the answer is “yes,” those results are likely to be used in an application for U.S. Food and Drug Administration (FDA) review of the drug combination for treating these patients. 

Clinical trials that aim to generate evidence for an FDA approval, also known as registration trials, typically collect large amounts of information about many aspects of treatment and how patients respond to it. Such trials usually record extensive details on each patient’s medical status and reports of all adverse events (side effects) patients experience, serious or not, whether they resulted from the investigational treatment or not. 

S2302 Pragmatica-Lung differs in part by collecting much less data. For example, because safety information on these drugs exists from previous studies, sites will report adverse events to trial researchers only if they are serious, unexpected, and thought to be caused by the experimental arm drugs. 

The trial’s lead biostatistician, Mary W. Redman, PhD, of the SWOG Statistics and Data Management Center and the Fred Hutchinson Cancer Center, estimates that these criteria will reduce the number of such reports to less than 10 percent of what sites would typically need to collect. Similar reductions have been made in many common reporting requirements. 

“It starts with a quantitative difference in data collection,” Redman said, “but these quantitative changes compound and have significant qualitative impact,” in reducing the overall workload at every stage and increasing the speed with which the trial can be conducted, the data reviewed and analyzed, and the results published so they can improve patient care. 

The workload at treatment sites is further decreased because the study does not require them to collect tissue or blood specimens, CT or MRI scans, records of patients’ other medications, or patient-reported outcome questionnaires. The result is a trial that is easier to open and conduct even for small, community clinics, where many patients with cancer receive treatment.

Project Pragmatica
This is the first trial designed to follow the precepts of the FDA’s recently launched Project Pragmatica, a program to make trials more functionally efficient and patient-centric. The approach uses pragmatic trial design elements to more fully integrate trials into real-world routine clinical practice. 

A pragmatic trial is intended to inform clinical decisions about the comparative benefits and burdens of a health intervention. It asks whether a treatment works under usual conditions.

The FDA anticipates that benefits from this approach will include a more diverse group of participants enrolled, faster trial enrollment and completion, and cost savings.

More inclusive enrollment
A key distinguishing feature of the S2302 Pragmatica-Lung trial – and of most pragmatic trials – is fewer limits on who can enroll. 

For example, clinical trials often exclude patients whose disease and its treatment have limited the patient’s ability to work or to carry out some of the standard activities of daily living. A significant fraction of people with recurrent or stage 4 non-small cell lung cancer fall into this group, and S2302 Pragmatica-Lung does not exclude these patients. 

Enrolling a group that more closely represents the real-world population of patients with the disease means results of the trial should be more applicable to all patients with advanced non-small cell lung cancer. 

“This is a first-in-kind, registration-intent study that, by design, will increase the representativeness of the group of patients studied, and thus we hope will yield broader interpretability of the findings,” said Jhanelle E. Gray, MD, chair of the SWOG lung committee and chair of the Department of Thoracic Oncology at Moffitt Cancer Center.

Rapid development
The vision of a paradigm-changing registration trial instilled a sense of urgency that drove development of S2302 Pragmatica-Lung at an unusually rapid pace. This urgency, coupled with the simplified nature of the study, meant the writing of the trial protocol was completed in roughly six months. Often, phase III trials with FDA registrational intent can take as long as one to two years to reach the point of enrolling patients. 

“The stripped down nature of the trial certainly accelerated development, but the breakneck speed was also the result of heroic efforts by everyone involved,” Blanke said. “This was the clinical trial development process at its finest.”

Broad collaboration
The study was designed with extensive input from scientific leadership of the NCI’s Division of Cancer Treatment and Diagnosis and its Cancer Therapy Evaluation Program and in close consultation with the FDA’s Oncology Center of Excellence.

Collaborators include the Alliance for Clinical Trials in Oncology, and the pharmaceutical companies Merck (known as MSD outside the U.S. and Canada) and Eli Lilly and Company, each of which is providing one of the study drugs and additional trial funding. The study will be conducted with participation of the four U.S. NCI National Clinical Trials Network (NCTN) groups that focus primarily on cancer in adults – SWOG, the Alliance, ECOG-ACRIN Cancer Research Group, and NRG Oncology. Together, these groups represent more than 1,600 cancer treatment institutions throughout the U.S. 

Confirming phase II results from Lung-MAP S1800A 
S2302 Pragmatica-Lung aims to enroll 700 patients to confirm whether a survival benefit that was seen in the smaller, phase 2 S1800A study holds in a larger, more diverse group of patients.

Findings from S1800A were first reported at the 2022 annual meeting of the American Society of Clinical Oncology and were simultaneously published in the Journal of Clinical Oncology. That trial found that patients receiving the pembrolizumab plus ramucirumab combination lived significantly longer than those who received standard treatments. 

S1800A was conducted as part of the Lung-MAP master protocol – a SWOG-led portfolio of trials under a single genetic screening protocol. The product of a unique public–private partnership, Lung-MAP was the first lung cancer precision medicine trial supported by the NCI.

“It’s wonderful to have had the opportunity to shepherd this regimen through from a phase 1 trial to a groundbreaking, positive Lung-MAP trial, and now to breakthrough designation with the FDA," said Roy S. Herbst, MD, PhD, deputy director and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital and founding chair of the Lung-MAP trial. "This combination is a perfect option for this new pragmatic clinical trial design to make sure clinical trials are easily available to all patients in their communities.”

The partnership underlying Lung-MAP, which includes the Foundation for the National Institutes of Health and the advocacy organization Friends of Cancer Research, also played a significant role in driving the priorities that allowed Project Pragmatica’s vision to rapidly come to life in the development and launch of the S2302 Pragmatica-Lung trial.

“This trial will answer a truly important question to guide the future of lung cancer treatment,” said Ellen Sigal, chair and founder of Friends of Cancer Research. “Importantly, it will also provide a model for future clinical trials – ones that are simplified, more straightforward, and easier for patients and clinicians to participate in.”

To learn more
The study is now enrolling people with stage 4 or recurrent non-small cell lung cancer who have previously been treated with immunotherapy and chemotherapy. 

Those interested in learning more should ask their health care team about the Pragmatica-Lung trial (also known as S2302). They can also get more information from the NCI’s Cancer Information Service at 1-800-4-CANCER or on the NCI website. They can visit the NCI website for a list of sites that have the trial open, or can learn more at clinicaltrials.gov (NCT05633602).

The S2302 Pragmatica-Lung study is supported by the NCI, part of the National Institutes of Health (NIH), led by SWOG, and conducted by the NIH-funded NCTN and NCI Community Oncology Research Program (NCORP). 

The trial is funded through NIH/NCI grants CA180888 and CA180819, and is supported in part by Eli Lilly and Company, and by Merck & Co., Inc., Rahway, NJ, USA, including through Cooperative Research and Development Agreements between NCI, SWOG, and Lilly and between NCI, SWOG, and Merck.

The core S2302 Pragmatica-Lung study team includes study chair Karen L. Reckamp, MD, of Cedars-Sinai Cancer; study co-chair Konstantin Dragnev, MD, of Dartmouth-Hitchcock Norris Cotton Cancer Center and Alliance for Clinical Trials in Oncology; lead biostatistician Mary W. Redman, PhD, of SWOG Statistics and Data Management Center and Fred Hutchinson Cancer Center; SWOG lung committee patient advocate Judy Johnson, MBA; ECOG-ACRIN study champion Wade T. Iams, MD, of Vanderbilt University Medical Center; and biostatisticians Jieling Miao, MD, and James Moon, MS, both of SWOG Statistics and Data Management Center and Fred Hutchinson Cancer Center.

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