Lung-MAP: A five-year recap on the first master protocol trial in cancer research

When the Lung-MAP trial was launched in June 2014, the goal was simple: Make drug development faster and more collaborative—and do it for lung cancer, the leading cause of cancer death in the United States.

This is a formidable challenge. Cancer trials were, and remain, notoriously time-consuming to launch, expensive to run, and difficult to enroll patients to. A deeper understanding of cancer biology and the genomics revolution in medicine have changed how we approach clinical research.When the Lung-MAP trial was launched in June 2014, the goal was simple: Make drug development faster and more collaborative—and do it for lung cancer, the leading cause of cancer death in the United States.

We now have the ability to sequence a patient’s tumor tissue, determine which proteins or DNA sequences are associated with their cancer, then select a drug designed to attack that type of abnormality in order to create precision, or personalized, treatments. Great news for patients, but tough for researchers.

Once clinical trials incorporate genomic biomarkers, the patient pool splinters. For example, EGFR mutations are observed in 10% to 15% of non-small cell lung cancer patients in the U.S. The ALK gene rearrangement occurs in fewer than 7% of patients, and ROS1 rearrangements are found in only 1% to 2%. In the era of personalized medicine, we are required to sort through a much bigger haystack in order to find much smaller needles.

To address these challenges, the scientific leadership of Lung-MAP adopted an emerging trial design called a “master protocol”—making us one of the first to adopt this model in cancer research and the first to do so with drug registration intent.

Master protocols, while complex, are based on the illusion of simplicity—many drugs or patient populations, but only one protocol. No need to open and close the whole trial every time you want to test a new agent or bring on a new group of patients. You simply use the master platform and “plug and play” independent sub-studies to incorporate promising new treatments.

After an expansion last year, Lung-MAP is open to the vast majority of patients with NSCLC. It’s a biomarker-driven protocol that tests several drugs at the same time, a so-called “umbrella” design. The trial is streamlined, with uniform genomic screening, highly harmonized eligibility requirements, coordinated treatment plans, and consistent endpoints. The sub-studies are also designed to get answers to safety and effectiveness questions quickly and, particularly, to pave the way to regulatory approval.

Finally, because biomarker trials require screening large patient populations, we tapped into the NCI’s National Clinical Trials Network. By working within the NCTN, we get access to tens of thousands of lung cancer patients who get their care in more than 2,200 affiliated cancer centers, academic medical centers, and community hospitals and clinics worldwide.

So, here we are, five years after the Lung-MAP launch. What have we accomplished?

Quite a bit. The first NCI-backed precision medicine trial has a track record of accelerating drug discovery and development and fostering innovation in cancer research. We have strong scientific partnerships and a robust drug pipeline. Currently, Lung-MAP has five sub-studies open. In 2020, one more is targeted for activation—with seven others under discussion with pharmaceutical partners. It’s our largest pool of potential trial drugs yet.

Lung-MAP’s primary mission is to create efficiency and operate collaboratively—all to benefit patients. We’ve succeeded on those counts.

Phase II/III trials testing a drug against a biomarker at one or just a few clinical sites historically face slow accrual, especially if the prevalence of the biomarker is low. Similarly, patients with rare molecular biomarkers may have difficulties accessing precision trials due to a lack of comprehensive genomic screening and geographic distance from enrolling sites.

Lung-MAP has opened and completed eight drug-centered sub-studies testing 12 novel therapies since activating in June 2014. That’s 12 new therapies tested in five years. While no comparative studies have been conducted to show how much time master protocols and other innovative trial designs save, we can credibly claim a much faster track record than a typical single drug, single biomarker cancer trial.

We’ve also tested a model that was, and remains, a unique public-private partnership. Lung-MAP is a result of years of work by the NCI, NIH, FDA, Friends of Cancer Research, the Foundation for the NIH, SWOG Cancer Research Network and many other research institutions, patient advocacy groups, and industry partners.

This ongoing partnership has been instrumental to fostering innovation and creating a strong value proposition for industry participation. Many Lung-MAP innovations are built into the trial design.

Under Lung-MAP, clinicians have the ability to pre-screen patients while they are on a prior therapy, a feature that shortens the time needed to move a patient into the trial once they progress on front-line therapy. Another innovation: patients who don’t qualify for biomarker-driven sub-studies are offered a “non-match” option. In non-match sub-studies, Lung-MAP patients receive an immunotherapy or another investigational drug expected to work on a range of molecular sub-types.

Additionally, as novel immunotherapies were approved by FDA and quickly became the standard of care in NSCLC, we changed the design in 2015 to allow evaluation of molecularly-targeted compounds to continue in immunotherapy-naïve patients, and also provided these cutting-edge drugs as our non-match sub-study for those who were eligible. In 2019, we further revised the trial to allow the addition of sub-studies that evaluate treatment combinations in immunotherapy-resistant patients—an unmet medical need that is increasing as more patients are exposed to immunotherapies.

More achievements that have come out of Lung-MAP:

Pioneering the use of next-generation sequencing and the Foundation Medicine platform in a large-scale cancer clinical trial.

Lung-MAP was one of the first trials to partner with Foundation Medicine to use its DNA next-generation sequencing platform, FoundationOne®CDx (F1CDx), now an industry standard for comprehensive genomic screening of all patients.

F1CDx detects gene substitutions, insertions and deletion alterations, and copy number alterations in 324 genes and select gene rearrangements and can evaluate complex molecular targets (e.g., DNA repair deficiency, microsatellite instability, tumor mutational burden, and loss of heterozygosity.

This broad range of molecular signatures defined from F1CDx are used as the molecular biomarkers for Lung-MAP sub-studies, allowing numerous therapies to be evaluated in a biomarker-driven manner and providing historical and real-time information on molecular target prevalence in study populations useful in future Lung-MAP studies—as well as other drug discovery and development efforts. The short turnaround time established for generating screening results from tissue submission to results reporting—16 days or less, with an average of 12 days—is critical to the success of Lung-MAP.

Beyond Lung-MAP, F1CDx-derived molecular signatures are now serving as companion diagnostics for 19 drugs, and F1CDx and other NGS platforms are widely used in establishing genomic profiles and diagnostic signatures in clinical research and practice settings. Even with all this success, Foundation Medicine remains a valuable partner and continuously works with us to adapt their platform for new biomarker-driven sub-studies and provide critical insights on developments in the field.

Increasing the amount of genomic screening data available on lung cancer patients, advancing medicine and science.

As of Feb. 6, 2020, Lung-MAP had screened 2,813 patients and paired 799 patients to some type of trial therapy. Data from these patients are being shared to stimulate research that will further our understanding of common NSCLC mutations and to discover future treatment targets.

Influencing the design of other master protocols within and outside of cancer research.

The Lung-MAP design was a pioneer that paved the way for a dozen master protocol trials to launch in recent years, including the landmark NCI-MATCH and Pediatric MATCH cancer trials.

It has also influenced master protocol designs for other diseases, including infectious diseases and Alzheimer’s disease. Benefits of the Lung-MAP design were highlighted in an October 2018 FDA draft guidance, “Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics.”

Establishing a site coordinators committee to provide fast, critical feedback and insights on trial conduct.

Site staff are linchpins to patients when it comes to trial enrollment and management, and we hold their perspectives in high regard when it comes to Lung-MAP conduct.

We selected 12 coordinators based on geography and site-type diversity (e.g. cancer center, community clinic, etc.) to advise us on all aspects of the master protocol to ensure that both patients and staff needs are considered. This committee helps us streamline processes to minimize complexity of the trial.

Providing access to biomarker-targeted drugs and immunotherapies to hundreds of patients, with some success of extending and improving lives.

This broad access is a product of the study design.

As we described above, Lung-MAP patients whose tumor doesn’t include a biomarker that matches a trial drug, or who don’t otherwise qualify for a biomarker sub-study, still have an option to enroll in a non-match sub-study. These test a novel immunotherapy or other drug expected to have activity across multiple molecular subtypes. Although the squamous NSCLC sub-studies did not lead to the approval of new therapies, it is clear that some patients have benefited from Lung-MAP participation.

For example, about 450 Lung-MAP patients have gotten access to immunotherapies to date. One is Carol “Annie” Burke, an artist from Savannah, GA, who enrolled on Lung-MAP when she was diagnosed with stage IV squamous cell lung cancer at age 56. After chemotherapy failed to stop her cancer from spreading, she was eligible for a non-match immunotherapy sub-study. The cancer in her lungs, and brain, was gone. “The Lung-MAP treatment saved my life,” she said.

In addition, trial partner SWOG Cancer Research Network has a unique outreach program with U.S. Department of Veterans Affairs medical centers, which is aimed at getting more military veterans enrolled onto cancer clinical trials. The partnership has given Lung-MAP access to hundreds of veterans, who are at higher risk for lung cancer.

Exploring new, less invasive methods for pairing patients with the best treatments.

With the latest revision of Lung-MAP, the team is collecting blood from patients that consent both during patient screening and while they are being treated on study to allow for retrospective circulating tumor DNA.

These results can eventually be compared to the NGS results and build the appropriate evidence for the eventual use of the less invasive ctDNA testing for clinical placement of patient who are not able to provide a suitable biopsy for participation in the trial, as well as potentially lead to the discovery of blood-based biomarkers of response.

The future of Lung-MAP

If Lung-MAP has taught us anything these last five years, it’s that even with a master protocol, you can’t stand still. The science moves too fast, always changing the drug development and treatment landscape. This is particularly true of the immunotherapies and targeted drugs we test.

Last year, we expanded Lung-MAP eligibility from squamous cell lung cancer patients to patients with all types of NSCLC—making investigational drugs available to thousands more eligible people and expanding our patient pool exponentially. That decision to expand has, in part, revived the trial, which is surpassing accrual goals and boasting a pipeline of exciting new drugs, including cutting-edge, promising targeted therapies and the already noted treatments for immunotherapy-refractory patients.

Another reason behind the renewed energy is a change in management structure. There are now eight Lung-MAP study chairs—two each from SWOG, the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, and NRG Oncology. This new format of equal representation of all four adult cancer clinical trial groups in the NCI-supported NCTN allowed us to bring in new leaders with broader knowledge of emerging NSCLC therapies, expand access to companies whose drugs are ideal candidates for the trial, and invigorate a broader NCTN commitment to enrolling patients onto the trial.

While no Lung-MAP sub-study has led to full registration of a drug, the trial has successfully evaluated drugs within specific patient populations and very quickly established for companies whether or not their drug is an appropriate treatment for that population. This precision and speed are the main purposes and strengths of Lung-MAP. The trial team has strong hopes that currently accruing sub-studies and those in development will net Lung-MAP’s first drug registration.

The success of Lung-MAP to date, and its future success, relies heavily on the commitment of hundreds of sites across the country, the commitment of not only the physician-scientists, but the nurses, navigators, and administrators who all support and promote this trial, and spend precious time learning the nuances of a complex and rapidly evolving area of oncology. The on-going sub-studies, the banked tissue and blood, and the comprehensive genomic profiles generated for registered patients will provide a rich resource for both prospective and retrospective studies to advance treatment of lung cancers.

As we look ahead, we envision Lung-MAP as a resource for development of biomarker assays (e.g., ctDNA, TMB, PD-L1, specific molecular signatures, etc.), better understanding of the biological and geographical landscapes of lung cancer, and, most importantly, establishing a pathway for accelerating drug development to benefit patients.