The patient screening component of the newly launched Lung Cancer Master Protocol trial is expected to translate into significant cost-savings that is making the collaborative, multiple-drug “basket” design attractive to industry.

Lung-MAP, which formally launched June 16, has a multiple arm set-up allowing several drugs to be tested simultaneously across a larger pool of patients who will be screened for a variety of genetic markers at once and assigned to appropriate targeted therapy. The pooled screening should be significantly more efficient than a typical clinical trial looking for patients with a particular marker for a particular drug.

The ability to tap a larger network to find participants is one of the potential cost-saving benefits expected for the pharma participants in the advanced squamous cell lung cancer trial, which include Amgen Inc., Genentech Inc., Pfizer Inc. and AstraZeneca PLC/MedImmune LLC. FDA, the National Cancer Institute, Friends of Cancer Research, Foundation for the National Institutes of Health and SWOG Cancer Research, formerly the Southwest Oncology Group, also are working on the project.

Major cancer settings routinely screen patients for multiple markers to guide treatment, and newer trial designs are harnessing that ability to make drug development more efficient.

The master protocol concept is a “basket” trial design involving multiple different targeted therapies – patients will be screened for the Phase II/III trial and based on the biomarkers they present, will be randomized to the appropriate test drug or standard of care.

Those not showing one of the targeted biomarkers could go to an arm using AstraZeneca subsidiary MedImmune’s MEDI4736, an anti-PD-L1 monoclonal antibody versus standard of care. The PD-1/L1 family is not necessarily being tied to a biomarker in the lung setting, though PD-L1 expression is being studied in various trials across the class. However, it is viewed as an important therapeutic option for lung cancer ([A#00140616011]).

All screened patients will be eligible for the Lung-MAP trial, which is structured to add other candidate drugs continuously. Each arm will be independent and open and close separately Also see "Lung Cancer “Master Protocol” Eyed As Paradigm-Changing Approach To Drug Development" - Pink Sheet, 18 November, 2013..

The concept is similar to the I-SPY 2 trial testing neoadjuvant treatment in women with high-risk breast cancer; patients are assigned to different investigational drug arms and based on the evidence seen, those arms can spawn registrational programs for the candidate drugs Also see "Biomarkers Consortium Launches Adaptive Trial To Test Targeted Breast Cancer Drugs" - Pink Sheet, 19 March, 2010.. Puma Biotechnology Inc.’s neratinib recently matriculated into such a study Also see "Life After I-SPY Graduation: Neratinib Likely To Be Tested With Roche’s Perjeta" - Pink Sheet, 9 April, 2014..

Volume Screened A Major Benefit

Several pharma companies saw the screening process as a prime advantage to the master protocol set-up compared to traditional clinical trials.

The Lung-MAP per patient cost has been estimated at $35,000.

The Lung-MAP per patient cost has been estimated at $35,000. Sponsors did not give specific savings calculations but said an expected time savings from the patient screening could translate to cost savings.

Enrollment is expected to move much faster in the master protocol than through independent trials, in part because of the ability to screen more patients.

The master protocol allows all the sponsors to tap into a much wider network of potential patients with a rare biomarker than likely would be found if they worked alone, according to Mace Rothenberg, Pfizer senior VP for clinical development and medical affairs and Pfizer Oncology chief medical officer.

Pfizer is testing its CDK4/6 kinase inhibitor palbociclib in the trial.

There is still a risk of not finding enough patients for a specific arm of the trial, but that is a risk taken when developing a treatment in a specific niche, he said.

“In order to evaluate a new therapy in a subset of patients, you have to be able to have a large enough network to be able to screen enough patients to find enough patients to put on the trial,” Rothenberg said in a June 19 interview.

“By tapping into the existing cooperative group network, we immediately have hundreds of centers … that are going to be signing on to this trial using an existing infrastructure that allows us to rapidly open these sites, understand and be confident of their experience, their capabilities, the quality of research that they do, and do it in a much faster, more efficient way than if any sponsors [try] to do it by themselves.”

David Reese, Amgen VP of translational science and therapeutic area head of oncology global development, said in a June 18 interview that patients also are much more likely to be enrolled in one of the arms.

“It’s both sides of the equation. You have the ability to screen for a large number of biomarkers, but then from the patient and physician’s perspective, you then have an array of therapies within one study that you can offer as opposed to multiple one-off trials,” Reese said.

Amgen is testing rilotumumab, a hepatocyte growth factor receptor c-MET inhibitor, in the Lung-MAP trial.

Reese also said running multiple tests on one sample is especially important in lung cancer, because tissue is not abundant.

“To do a single broad-based test on that looking at multiple biomarkers makes feasible this sort of approach,” he said. “If we had to serially test biomarkers one after the other, you would very quickly run out of tissue.”

Foundation Medicine Inc.’s clinical assays will be used for the Lung-MAP screening. Results are expected to be returned to physicians in about two weeks.

Controlling the growing cost of clinical trials has been a constant source of tension for industry. The Pharmaceutical Research and Manufacturers of America is working with the National Minority Quality Forum on a campaign to connect more minority patients with clinical trials. It is an attempt to control recruitment costs as well as encourage more diversity in trials Also see "PhRMA’s “I’m In” Campaign Looks To Connect Minorities To Studies" - Pink Sheet, 12 March, 2014..

Improving screening capability and creating larger datasets of patients’ molecular profiles is also a growing need as oncology moves toward layering treatment with combinations of different targeted approaches. At the recent American Society of Clinical Oncology annual meeting, ASCO Chief Medical Officer Richard Schilsky estimated that 154 patients would need to be screened to identify one patient with the right set of mutations for a study pairing multiple tyrosine kinase inhibitors.

The collaborative efforts of the master protocol approaches could be a launch pad in that area.

Approvals Not The Only Goal

Lung-MAP is designed to support registration for the candidate compounds if the results are positive. But several sponsors said approvals are not going to be their only measure of success.

Aiman Shalabi, AstraZeneca development VP of MEDI4736, said the information gained hopefully will aid in the design of new targets and agents.

“Some of the science that’s going to come out of this study is hopefully going to inform future development, and these comprehensive assessments of the tumors will only help us move forward,” Shalabi said during a June 19 interview.

Rothenberg said the trial will help determine the activity for its single agent in squamous cell lung cancer, as well as potentially lay the groundwork for combination therapies.

“We also recognize that even if we don’t see our drug move ahead in that straight line that we’re not reaching a dead end, that this is actually an important first step,” he said.

An important measure of success will also be carrying out the trial, because it will be proof of principle, Reese said.

“Ultimately success is dependent on the drugs working, but if that were not to be the case [and] the trial gave you an answer very quickly that a drug or drugs should not be further pursued, that’s also incredibly important to know so that we can all move on to therapies that may be better,” he said.

Reproducing Trial In Other Diseases Possible, But Difficult

Patient groups and others already seem excited about potentially creating a master protocol in their disease areas, but organizers of the Lung-MAP trial said reproducing the protocol will not be easy.

Even before Lung-MAP launched, there was talk of the possibility of using the master protocol concept in pediatrics.

Reese said this trial will be the first of “a wave of such trials” and that it will be used across different diseases. Talks also are underway to establish a trial similar to Lung-MAP in colon cancer ([A#00140331005]).

However, Ellen Sigal, chair and founder of the Friends of Cancer Research, said during a June 18 webinar on the trial that the approach will not fit all diseases.

Sigal said researchers need the right biomarkers and disease stage and industry needs an incentive to join the effort.

“A substantial amount of money was put in by the NCI, very substantial, but a large portion of this money comes from industry and other sources,” she said. “There has to be some compelling need or economic necessity or some value proposition for all these groups to work together.”

Rothenberg also said Lung-MAP will be difficult to replicate because it will require a number of impactful people to put together. He said Sigal, along with researchers, FDA and others made pivotal contributions.

FDA was particularly interested in the master protocol idea as a way of speeding up development ([A#00130722011]).

Lung-MAP Patient Screening Should Translate To Cost-Savings

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