S2302 Pragmatica-Lung Trial: Reaching more representative groups of patients with exciting clinical trials

S2302 Pragmatica-Lung is a federally-funded, streamlined clinical trial examining a new combination of agents in patients with advanced non-small cell lung cancer (NSCLC). Like most studies, it is focused on improving outcomes for patients with cancer—but it is also poised to simplify and transform the entire clinical trials model as we know it. 

S2302 Pragmatica-Lung is an inclusive real-world clinical trial for patients whose NSCLC has advanced after immunotherapy and chemotherapy. The phase III trial will evaluate the effectiveness of ramucirumab and pembrolizumab compared to standard of care treatments.

It starts with a “pragmatic trial” design, which means it is planned to inform decision-makers about the comparative balance of the benefits, burdens, and risks of a health intervention. Rather than solely determining efficacy, which may overestimate benefits and underestimate harm, pragmatic trials pivot to measure the real-world effectiveness of treatments in more diverse patient populations, highly representative of patients seen in oncology clinics.

The design of the S2302 Pragmatica-Lung trial looks to the pragmatic end of the spectrum across each of the key elements below:

• Eligibility: will enroll patients like those seen in most community oncology clinics, with minimal exclusion criteria
• Recruitment: will recruit a representative group of patients with NSCLC
• Setting: trial sites will cover the full gamut of clinical settings, including the NCI National Clinical Trials Network’s (NCTN’s) more than 2,000 academic and community sites
• Organization: minimal changes to clinical delivery and resources
• Follow-up: follow-up requires minimal data collection
• Primary outcome: primary outcome is simple, easy to measure and important to patients with lung cancer (overall survival)

[adapted from PRECIS-2 tool, Loudon et al. 2015]

S2302 Pragmatica-Lung has a simple design, aimed at rapid enrollment and easing the burden of data collection and monitoring on research sites. Its eligibility criteria have been cut to a minimum to make enrollment more inclusive. The more representative the patient population in the study, the more generalizable the study results.

SWOG Cancer Research Network and the NCI’s NCTN have conducted practical studies in the past. But one of the groundbreaking differences of this trial is it is a Food and Drug Administration (FDA) registration trial—the agency has agreed to consider data from a simplified pragmatic trial for registration intent in considering a new indication, despite the more limited information collected.

In addition to being a product of Lung-MAP, a unique public–private partnership across SWOG, the NCI, the Foundation for the NIH, and Friends of Cancer Research, the phase II S1800A study that gave us the signal being tested in S2302 Pragmatica-Lung evaluated two drugs that were previously FDA-approved and commonly used across multiple tumor types. 

We already had a full set of outcomes and safety data across various malignancies, making investigators and sites more comfortable conducting a follow-on study with a single trial objective and minimal adverse event collection. This allowed us to forego the collection of specific data for RECIST, a modestly cumbersome system of response assessment, and to focus on overall survival as the endpoint that matters most to patients. 

Right time, right protocol, right team

Lung cancer is, by far, the leading cause of cancer deaths. Yet, there are limited FDA-approved regimens in the second-line setting following first-line immune checkpoint blockade plus or minus chemotherapy. S2302 Pragmatica-Lung represents an area of unmet need and will help us address a key question in a timely way. It is a way to innovate, reduce barriers and be intentional in addressing key meaningful questions—in this case, can we improve overall survival?

Previous work has demonstrated 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) was safe and had provided a signal of efficacy in a phase I trial across tumor types, including lung cancer, that was led by Roy Herbst, MD, PhD, and colleagues. 

The premise that ramucirumab as a VEGFR2 antibody could overcome immune modulation and restore benefit to anti-programmed death 1 (PD1) therapy, such as pembrolizumab, was the hypothesis of our phase II S1800A trial. 

Given the promising results of this phase II trial, which showed improved overall survival with ramucirumab and pembrolizumab in the acquired resistance setting, with a hazard ratio of 0.69 (80% CI: 0.51-0.92), we moved to bring the combination to a pragmatic phase III study as S2302 Pragmatica-Lung to confirm this result. 

Although the protocol has not yet received ultimate approval, it is very close to final form. The condensed, simplified format requires minimal data reporting compared to a typical phase III trial:

• No tissue specimens
• No protocol-required laboratory tests
• No protocol-required disease assessments (no imaging requirements or use of RECIST)
• No reporting of other medications being taken (concomitant medications) 
• No patient-reported outcome instruments to complete
• Very limited adverse event reporting
• No cycle-specific treatment reporting

The data collection requirements for the trial have been trimmed to the bare minimum, compared to those in a standard NCTN clinical trial, particularly relative to other trials with registrational intent. This includes reductions in the time points at which data must be submitted, the number of data forms to be submitted, and the number of data elements.

Eligibility criteria are extremely broad, to ensure the trial population represents the full population of patients with NSCLC. They mimic the package inserts as closely as possible:

• Histologically or cytologically confirmed stage 4 or recurrent NSCLC
• Simple restrictions on prior therapy:
  • Acquired resistance to prior immunotherapy
  • Prior receipt of platinum-based chemotherapy
• Fewer clinical/laboratory criteria:
  • Age 18 or older
  • Zubrod Performance Status of 0-2 (most studies do not allow PS=2)
  • Ability to safely take the investigational drugs per FDA instructions and institutional guidelines

The control arm is non-restrictive, allowing physicians to use any accepted treatment for these disease conditions. 

Although SWOG is the NCTN group coordinating the study, no large NCTN trial succeeds without extensive cross-group collaboration, and S2302 Pragmatica-Lung is no exception. The trial is co-chaired by an Alliance investigator (Dr. Konstantin Dragnev, who also co-chaired the S1800A Lung-MAP sub-study), and Dr. Wade Iams is ECOG-ACRIN study champion.

Condensing requirements, protocol, and timeline

It took a massive effort from many groups to simplify the protocol and informed consent document while answering key questions and remaining compliant with good clinical practice and regulations. After discussions with the NCI, the SWOG operations team moved the purely administrative and instructional parts of the protocol to an appendix. This allowed reviewers from the NCI, FDA, and the Central Institutional Review Board (CIRB)—and will allow site reviewers—to focus on the scientific content and practical application of the study in the main document. 

Data collection will be done using the Medidata RAVE system, as is standard for all trials conducted within the NCTN. Using a subset of the standard SWOG trial forms, the study team modified the content to include only those data elements needed to address the study objectives. The information collected at baseline was reduced to only that needed to adequately describe the study population. 

The study’s informed consent document is now 11 pages, written at a seventh-grade reading level. Lung cancer study consent forms are typically twice as long.

While a patient is on treatment, sites’ only regular submission requirement is vital status information and information on adverse events that are Grade 5 or that are Grade 3 or 4 if they are treatment-related, serious, and unexpected. To address the primary objective, if a patient dies, sites need to report only the date and primary cause of death. 

In addition to limiting data collection and adverse event reporting, other regulatory components were also streamlined for Pragmatica-Lung, given the outcome and safety data already available on the two drugs. Most trials developed for a registration intent include significant monitoring with extensive verification of data, often performed on-site on a frequent basis. 

For S2302 Pragmatica-Lung, with its simplified pragmatic design, the NCTN’s standard site auditing program will be used for review and verification of collected data in addition to SWOG’s standard QA/QC methods for trial conduct. This approach will significantly lessen operational burdens on the sites participating in this clinical trial.

The rigor of executing major trials in the modern era has increased in intensity to the point where we frequently require tissue submission, measurable disease, and collection of data on all adverse events, concomitant medications, and more. 

While this may be appropriate for some trials, with this trial, we aim to reduce the burden associated with conducting a study and to answer the key clinical question of overall survival. A significant fraction of “standard” requirements have been intentionally removed from the protocol to make it more practical, which, in turn, allows it by design to open at more sites and reach more patients.

We anticipate opening the trial in mid-January, which is one of the quickest-ever NCTN activations. This took a tremendous amount of communication to integrate feedback from all stakeholders into the protocol and informed consent. The collective desire to reduce the burden on sites and reach more patients was a huge motivator.

The study’s informed consent document is now 11 pages, written at a seventh-grade reading level. Lung cancer study consent forms are typically twice as long. The consent form for S1800A, the phase II study that led to S2302 Pragmatica-Lung, was 24 pages.

Many clinical sites, and clinical researchers as a whole, have struggled post-COVID. There have been multiple challenges for both academic and community sites. In an era of significant research staff turnover, as well as training and onboarding challenges, the simplicity of S2302 Pragmatica-Lung makes it the ideal NCTN trial for onboarding new staff.

Recruiting more diverse trial participants

The NCI has charged cancer centers with creating diversity, equity and inclusion (DEI) plans to enhance health equity. S2302 Pragmatica-Lung will improve access to clinical trials for patients with lung cancer while maintaining scientific rigor and clinical relevance and significance within the field. Whether the trial is positive or negative, the findings will have an impact. 

Pragmatic trials by nature lend themselves to enrolling a representative population, but this study contains many extra elements to ensure vigorous recruitment and a participant sample that reflects the full diversity of the population of patients with advanced NSCLC—a more diverse patient population than we have historically seen on randomized phase III trials in lung cancer. 

Enrollment goals by race, ethnicity, gender, and age categories are based on real-world national data from patients with NSCLC, as drawn from NCI’s Surveillance, Epidemiology and End Results (SEER) program.

S2302 Pragmatica-Lung should ease the burden on sites wishing to conduct clinical research in NSCLC. As we look to continually optimize the design of other pragmatic trials, we remain steadfast in improving outcomes for patients with lung cancer and ushering in new treatment paradigms.

Incorporating both the NCTN and NCORP networks, S2302 Pragmatica-Lung will use validated data from geographical information systems and the U.S. Census Bureau for purposeful outreach to a diverse set of sites that serve a high percentage of patients from underrepresented groups. Site enrollment rates will be monitored monthly. SWOG Operations will communicate regularly with sites, providing start-up and accrual or additional support as needed. 

We are developing a community engagement package for sites, that includes outreach strategies, advertising materials, a patient-friendly PowerPoint targeting underrepresented populations and evaluation tools. We aim to provide support to selected sites for local advertising and to host community engagement educational events in underserved communities. All patient education material will also be made available in Spanish.

SWOG’s Lung Committee already has a dedicated DEI champion (Lucy Gansauer) and a community engagement subcommittee (represented by Drs. Paul Hesketh and Dan Carrizosa) working with the group’s patient advocate (Judy Johnson) and SWOG’s community advocates, to direct community outreach. 

SWOG also has a dedicated DEI monitoring committee that tracks the diversity of trial enrollment. These efforts are augmented by a custom training program in improving trial diversity that all SWOG leadership and study teams complete, and all of these efforts will be directed toward ensuring representative enrollment for S2302 Pragmatica-Lung.

Patient needs are paramount in S2302. In addition to disseminating patient education materials via advocacy organizations and social media outreach, targeted search result ads will direct visitors looking for a clinical trial in NSCLC to CIRB-reviewed patient education content. 

SWOG is also working to secure funding to help cover some of the costs of participation that patients face, such as travel costs for trial-related clinic visits. A recent report found that the average patient on a clinical trial travels 67 miles for each visit. At standard IRS-allowed mileage reimbursement rates, this comes out to about $84 per clinic visit.

S2302 Pragmatica-Lung should ease the burden on sites wishing to conduct clinical research in NSCLC. As we look to continually optimize the design of other pragmatic trials, we remain steadfast in improving outcomes for patients with lung cancer and ushering in new treatment paradigms.