Novel Approach to Accelerate Lung Cancer Research: Lung-MAP and the Potential of Public-Private Partnerships Open Access

Over 230,000 Americans are diagnosed with lung cancer each year and it remains the leading cause of cancer death (1). However, over the past several years, notable progress has been made. Researchers from the NCI recently found that death rates for non–small cell lung cancer (NSCLC), the subtype of lung cancer that comprises approximately three quarters of all lung cancers, have been reduced by over 6% overall in recent years (2). This reduction in mortality has been accompanied by an average increase in overall survival times and largely credited to the therapeutic advancements for the effective treatment of NSCLC. Numerous molecular alterations have been identified in NSCLC that have enabled the development of new drugs capable of targeting these changes and efficiently kill cancerous cells. In addition, new treatments to modulate patients' immune systems have been shown to be effective in stimulating natural immune cells to have an improved anticancer effect (3, 4).

While these types of approaches to treat cancer are providing new options for patients, leadership from the Food and Drug Administration (FDA) recognized that the expansion of targeted therapy in NSCLC presented significant promise, but evaluation of the safety and efficacy of these new drugs would be slowed if new models for conducting clinical studies were not identified. Specifically, the FDA recommended that a comprehensive approach be implemented to identify the patients that are the best candidates for these, and other new treatments based upon the molecular characteristics of their tumors, and more efficiently conduct the clinical studies necessary to evaluate the safety and efficacy of new drugs. To address this growing challenge, leading lung cancer experts and stakeholders across academia, government, industry, and patient advocacy came together to design a clinical research approach that could serve as a sustainable infrastructure for new potential lung cancer treatments called the Lung Cancer Master Protocol (Lung-MAP).

Lung-MAP is an innovative, groundbreaking clinical trial model designed to advance the development of targeted therapies in a manner that is more efficient than if individual clinical trials were conducted for each drug candidate independently of one another. The primary objective of Lung-MAP is to evaluate the overall survival of biomarker-selected patients treated with standard of care versus the experimental targeted therapy. This first-of-its-kind trial model provides broad-based molecular screening to each patient and matches them to various substudies testing new therapies based on their unique tumor profiles. Substudies are regularly completed, and new studies added to keep pace with the rapidly evolving molecular understanding of lung cancers. For patients that do not match an existing biomarker-driven substudy, a “non-match” immunotherapy-based substudy is continuously available. This helps ensure that there is an available substudy for any patient that enrolls in Lung-MAP as part of their care, and creates a new framework for more efficient, collaborative trials.

At the origin of Lung-MAP, leaders from the NCI and the FDA sought to develop a consensus on how to establish a disease-specific standing research network capable of conducting large trials with diverse populations. The Lung Master Protocol Trial Design Proposal was introduced at the 2012 Conference on Clinical Cancer Research, hosted by Friends of Cancer Research and the Brookings Institution, and was further developed in conjunction with government and industry partners over a series of workshops, forums, and working groups (5). Lung-MAP launched in 2014 as a public-private partnership between the FDA, NCI, the Foundation for the NIH, leading academic researchers and institutions, patient advocacy groups, and industry. The initial iteration of Lung-MAP was led by the Southwest Oncology Group (SWOG), one of the four adult cooperative groups that comprise the NCI's National Clinical Trial Network.

While SWOG continues to hold the Investigational New Drug Application for the protocol, Lung-MAP and its operational leadership has since been expanded to include all of the adult cooperative groups and currently operates at over 700 hospitals and clinics across the country (6, 7).

To be successful, clinical trials must be able to evolve with the fast-paced treatment and drug development landscape. Lung-MAP has shown that successful trial design and execution require collaboration between drug companies and clinical researchers, and between different companies as well. Multiple different options for substudies have been designed and implemented over time, which allows for Lung-MAP to be tailored to each new drug and clinical scenario as needed. For some studies, this includes a phase II/III design in which an interim analysis is performed, and successful drugs seamlessly proceed into the latter phase of the study. This introduces efficiencies in terms of trial conduct. In this case, the use of patient data from the earlier phases and alleviation of time gaps in trial initiation is able to reduce the time and total number of patients needed to accrue as compared with the conduct of individual phase II and phase III studies. Pharmaceutical companies have utilized this process and in numerous cases found it to be complementary to their approach as evidenced by the recent Pragmatica lung trial which evolved out of SWOGs 1800a (8).

Implementing and conducting a traditional clinical protocol is resource intensive and requires significant project coordination. This can be a time-consuming process to fulfill and manage procedures set by individual institutions. A protocol that contains multiple substudies and regular modifications can exacerbate the challenges and amplifies the need for cohesive operations and project management. A mutual commitment among all project participants to create a culture for maximizing efficiencies, even when that requires modifying normal processes, is needed to overcome the complexities of a master protocol. Lung-MAP works with advice from the FDA and NCI, as well as an Oversight Committee, Executive Operations Group, and Project Management Office to facilitate trial design and operation. This transparent and strong governance structure has helped to improve the inclusion of a wide variety of expertise and to overcome barriers that can slow typical clinical studies. Strong, cross-sector leadership is needed to identify and implement best practices to maximize efficiency and facilitate a joint commitment to address patient needs. This multistakeholder approach to project leadership has undertaken efforts to reduce overall trial start-up time for new substudies, assisted with the migration to a centralized Institutional Review Board, and often aims to improve efficiencies for long-term sustainability and enrollment in the trial.

Maintaining a pipeline of new drug candidates is essential for the success of any master protocol. Lung-MAP operates with a Drug Selection Committee comprised of leading government and academic experts charged with identifying potential new drug targets and evaluating the applications of candidates as they are submitted. Lung-MAP has held over 30 formal drug selection committee meetings since 2013 assessing over 40 drugs from more than 20 companies (9–15). The selection process included additional ad hoc meetings to discuss pathways and targets, as well as monthly internal drug selection committee meetings. The ideal agents for this trial have been biomarker selected against specific driver targets which have shown activity in other settings and/or have limited activity in lung cancer. Conducting a trial with the molecular targets without the benefit to recruit patients with rare mutations from a large number of sites would be impossible.

While genomic sequencing is used to determine which substudy patients are enrolled in, it also provides a wealth of information that can be used to identify additional genomic alterations as potential drug targets and be a molecular research tool for correlative studies in the future. These data are collected as part of the Lung-MAP database and activities related to their use are overseen by the Translational Medicine Committee. In addition to the baseline genomic sequencing, liquid biopsy collection has been incorporated into Lung-MAP and enabled studies such as an assessment of the concordance between tissue and plasma-based tests to identify mutations. To date, over 20 studies have been completed through the Lung-MAP partnership. Many of the studies have eliminated drug candidates due to futility. While this is an indicator of the continued challenges to successfully treating NSCLC, rapid identification of unviable treatments and a “fail fast” mentality can help clear the queue and enable efficient progression of future candidates into clinical testing. In addition, by establishing a common biorepository, biospecimens from both positive and negative trials are contributing to valuable future molecular research, including analyses to better inform sensitivity to different compounds and mechanisms of treatment resistance.

The most important attribute of Lung-MAP has been the impact on patient access on multiple fronts. At the outset of the project, genomic sequencing was not as readily available as it is today. Sequencing has been performed by Foundation Medicine, Inc. since the beginning of the project, and given the widespread availability of the trial in several hundred research facilities, sequencing, and subsequently the associated targeted therapies, became available to many patients that otherwise may not have access. To date, over 60% of patients that have been enrolled in Lung-MAP have been from community-based centers which has enabled clinical trial access to more patients. Efforts to enable timely access for patients have also been successful. Prescreening procedures are used to help identify potential patients and preregister them to Lung-MAP. Over 4,600 patients have been screened since 2014, nearly half of which were prescreened during their frontline treatment enabling seamless access to a substudy if subsequent treatment was needed.

Lung-MAP has also shown that providing drugs at the point of care in diverse communities can improve trial diversity. An evaluation of the representativeness of patients enrolled found LungMAP improved access for patients of older age, from rural areas, and from neighborhoods with higher social needs compared with other NSCLC trials. The study also found Lung-MAP participants to be younger and less racially and ethnically diverse than patients with NSCLC in the United States, showing there is still work to be done, particularly in Latino populations. To further promote diversity and representativeness in its trials, Lung-MAP has formed a diversity, equity, and inclusion (DEI) subcommittee and is supporting community sites conducting a DEI Gap Analysis and engaging with lung cancer advocacy groups (16).

A recent study through the Lung-MAP partnership showed a significant improvement in overall survival in immune therapy refractory non–small cell lung cancer using the combination of pembrolizumab and ramucirumab as compared with standard of care alone (8). This study provides foundational evidence for what could ultimately advance standard-of-care treatment, and as acknowledgment of the transformative potential, the combination has received Breakthrough Therapy Designation by the FDA. A subsequent phase III study is underway to confirm the initial observations from Lung-MAP but given the already existing experience with both drugs in the combination it offers a subsequent opportunity to optimize the research paradigm. The primary investigators and sponsors, in collaboration with the NCI and FDA, have designed a protocol focused on collecting the core evidence needed to confirm the survival benefit, while minimizing extraneous datapoints that would complicate study conduct and be unnecessary in this situation. This follow-up study is part of the FDA's Project Pragmatica, which aims to identify and help implement studies that reduce the burden of data collection, maximize site and patient participation, and enable efficient research through the use of pragmatic trial designs. This first pilot through Project Pragmatica will inform the design and utilization of pragmatic trials as a future clinical research tool.

Lung-MAP is a unique public-private partnership that has developed a standing infrastructure that new drugs can be rapidly incorporated into for efficient evaluation of their safety and efficacy. It has facilitated genomic sequencing and enabled treatment of more than 1,000 patients on the basis of the molecular profile of their cancer. Master protocols can serve as a more efficient approach, particularly for smaller, molecularly defined patient subsets, than individual trials. Issues regarding patient quality of life and the implications of participation in genomic studies have also been explored (17, 18). However, implementation can be complicated. Oversight, implementation, and project management are more laborious than for a single study, or even the same number of independent studies. Upfront planning and regular communication are critical. A shared goal and creation of a culture toward constant innovation, aggressive timelines, and teamwork are essential. As science continues to evolve, the models for timely research also need to advance to efficiently and successfully meet patients' needs.

R.S. Herbst reports other support from Southwest Oncology Group during the conduct of the study and other support from American Association for Cancer Research, International Association for the Study of Lung Cancer, and Society for Immunotherapy of Cancer, personal fees from Abbvie, Bristol Myers Squibb, Candel Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, LLC, eFFECTOR Therapeutics, EMD Serono, Gilead, HiberCell, I-Mab Biopharma, Immune-Onc Therapeutics, Janssen, Johnson and Johnson, Loxo Oncology, Mirati Therapeutics, Nextcure, Novartis, Ocean Biomedical, Inc., Oncocyte Corp, Oncternal Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revelar Biotherapeutics, Ribbon Therapeutics, Roche, Sanofi, Seattle Genetics, and Xencor, Inc, and personal fees and other support from Immunocore, Junshi Pharmaceuticals, AstraZeneca, Bolt Biotherapeutics, Checkpoint Therapeutics, Eli Lilly and Company, Genentech, Merck and Company, and Normunity outside the submitted work. C.D. Blanke reports grants from NIH during the conduct of the study. E.V. Sigal reports personal fees from EQRx, Grail, and AstraZeneca outside the submitted work. No other disclosures were reported.