As new discoveries at the molecular level and new data sources from digital technology lead to new treatment approaches for cancer, researchers are considering new ways of bringing promising oncology therapies from bench to bedside. While the randomized controlled clinical trial is the gold standard, many agree the traditional phased paradigm of phase I, II, and III trials is too lengthy, complex, cumbersome, inefficient, and expensive.
Invited speakers and attendees explored different approaches to enhance oncology drug development at a workshop in Washington, D.C., hosted by the National Cancer Policy Forum in collaboration with the Forum on Drug Discovery, Development, and Translation. Components of the National Academies of Sciences, Engineering, and Medicine, the two groups plan a published summary report from the workshop.
The workshop was held shortly before President Obama signed into law the 21st Century Cures Act, landmark legislation designed to accelerate the pace of U.S. biomedical research. As previously reported in Oncology Times (Dec. 25, 2016 issue), the measure provides authority to federal agencies to implement the Cancer Moonshot initiative led by Vice President Biden; that initiative seeks to double the rate of progress toward cures for cancer by achieving 10 years of research advances in just 5 years.
Asked by Oncology Times what he would like to see as a result of the meeting at the National Academy of Sciences, Richard L. Schilsky, MD, workshop planning Committee Chair and Senior Vice President/Chief Medical Officer of ASCO said, "I hope that we can stimulate discussions on a more efficient drug development model. That is the overarching goal."
In his introduction to the workshop, Schilsky said, "the potential for advances in cancer research and drug development to significantly improve patient outcomes provides a compelling rationale to reexamine the scientific and regulatory approach to developing new cancer therapies to ensure that patients ultimately benefit from these advances."
But, Schilsky noted at the meeting that "one of the challenges we face is aligning the culture of drug development with the science of drug development. Typically the science is ahead of the culture." For example, the traditional culture of drug development is not collaborative, but is concentrated in silos that protect intellectual property and do not share data.
Patient-Centered Drug Development
Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research at the FDA, said oncology is leading the way in making progress in patient-centered drug development trials using innovative data sources, such as real-world evidence that takes patient-reported data into account. She said real-world evidence-data gathered from electronic health records, registries, administrative claims, surveys, social media, and mobile health-generated sources-"is a real opportunity" for improving drug development and "has a longer horizon than its opponents think." Woodcock said the FDA recognizes the need for new clinical trial designs, but also recognizes that they come with certain risks.
Woodcock cited the promise of coupling diagnostics with cancer therapies in enhancing drug development. But, she noted, in the development process diagnostics often lag behind therapeutics, and "understanding the performance of various diagnostics with respect to drug therapy remains a challenge."
When it comes to a new oncology drug development paradigm, "there is an urgency," said Ellen V. Sigal, PhD, Chairperson and Founder of the Friends of Cancer Research. She noted that innovative trial designs in drug development are emerging, a promising trend, and cited as an example the Lung Cancer Master Protocol (Lung-MAP), a clinical trial launched in 2014 for patients with advanced squamous cell lung cancer that has not responded to, or has stopped responding to, the current standard of care. Lung-MAP uses genomic profiling to assign patients to either a new investigational treatment or a more standard treatment approach; they are screened for alterations in any of more than 200 cancer-related genes. "I think the idea of these master protocols is evolving," said Sigal.
"The development of knowledge about a drug is a continuum. We're always learning about a drug; we're still learning about digoxin, frankly. We are trying to establish a benefit/risk framework," Woodcock emphasized. So, she said, it is important to have a vision of drug development as a seamless learning process that never really stops.
"The overall development pipeline is a learning machine," commented Steven Piantadosi, MD, PhD, the Phase ONE Foundation Distinguished Chair and Director of the Samuel Oschin Cancer Institute at Cedars-Sinai.
Schilsky agreed, stating that one can think of seamless cancer drug development as a learn/confirm model in which decisions need to be made about what needs to be done when, for example, a drug is approved and when it goes into the post-marketing time frame.
The vision of a continuous, seamless drug development process is important, because "I think we have to recognize that when we bring a drug to market, we can never have full certainty," said Mace Rothenberg, MD, Chief Development Officer for Oncology at Pfizer's Global Product Development Group. A white paper released by the National Academy of Medicine in October 2016 called Real-World Evidence to Guide the Approval and Use of New Treatments affirms the seamless, continuous learning vision in drug development.
"A new model for medical product development may see the blurring of current demarcations between premarket and postmarket evaluation. Continued assessment for effectiveness, not just safety, in the postmarket setting using real-world data will enable continuous reevaluation of risk-benefit profiles and generate labeling changes and new indications... Premarket and postmarket evaluations can form a feedback loop, enabling a rapid learning cycle," the white paper stated.
Innovative Trial Design
In innovative drug development, there are marked benefits to expanding a promising early trial to multiple cohorts because the drug may be effective against different cancer types, said Eric H. Rubin, MD, Vice President for Oncology Clinical Research at Merck. Rubin described leading the development of pembrolizumab, the first anti-PD 1 therapy approved in the U.S. (for melanoma), and then identifying the significant activity of this antibody across several other cancer types. Rubin noted it was an adaptive phase I study-with expanded cohorts-that served as the basis for three FDA approvals.
But Rubin stressed there can be many challenges to an innovative trial design in cancer drug development. These may include the fact that the ultimate study design was not predicted at the study's inception; creation of an operational burden on trial sites due to rapid accrual in multiple separate study cohorts; and the complexity of the trial-multiple amendments generate protocol complexity. While traditionally there has been resistance to single-arm trials, Rubin said the benefit of drug approval based on a single-arm trial is that it allows earlier access for patients with high unmet needs and/or rare tumor types. He also noted it is difficult to randomize patients against the standard of care in a subsequent study when an investigational agent shows remarkable efficacy.
Also describing an innovative path to drug development was Pasi A. Janne, MD, PhD, Professor of Medicine at Harvard Medical School, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, and Scientific Co-Director of the Belfer Institute for Applied Cancer Sciences at Dana-Farber.
Janne, a co-discoverer of epidermal growth factor receptor (EGFR) mutations in lung cancer, is also a co-discoverer of the first-in-class mutant selective EGFR inhibitor (WZ4002) capable of overcoming EGFR T790M-mediated drug resistance. He subsequently led the first-in-human clinical trial of the mutant selective EGFR inhibitor osimertinib, which has received regulatory approval worldwide for patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer who have developed resistance to earlier generations of EGFR inhibitors.
Similar to Rubin's experience with pembrolizumab, Janne found that osimertinib not only has efficacy against lung cancer, but also that it has significant activity against other cancers. Specifically, he discovered that osimertinib has central nervous system activity-against brain metastases, for example. "There are other third generation EGFR inhibitors in development," Janne noted, drugs that are effective against the most common mechanisms of acquired drug resistance as well as being effective inhibitors of EGFR-activating mutations. "This research opens up the possibility of combination therapy."
Combination Therapy
In fact, combination therapy may indeed be the direction of a new paradigm in oncology drug development, said David Feltquate, MD, PhD, Head of Early Clinical Development-Oncology at Bristol-Myers Squibb. "I think the future is going to be complex regimens, not monotherapy," said Feltquate, who was the Development Lead for Ipilimumab/Nivolumab Life Cycle Management, focusing on the development of both compounds in a variety of cancer types. "I think we need to spend a lot of time in thinking about combination regimens."
But, cautioned Piantadosi, "The old designs for single agents don't translate well to combinations. More is not necessarily better." Because conventional dose escalation methods are unlikely to work in combination regimens, Piantadosi recommended using algorithms to determine the dose associated with peak response. He also recommended the FDA and NIH take the lead in constructing innovative precision trial designs for precision drug pipelines.
Schilsky said that in thinking about a new, updated oncology drug development paradigm, researchers must always be mindful of patient safety. "Maybe acceleration per se is not what we need," he said. "There are substantial risks to going too fast."
What is needed in successful oncology drug development, he said, is "the right information at the right time."
Resource Expansion
Studies that rely on adaptive clinical trial designs, expanded sources of data, and combinations of therapies can be resource-intensive, stressed speakers. Therefore, adequate funding for the U.S. cancer research enterprise, the bedrock of progress, has never been more important.
A report from an earlier meeting sponsored by the Forum on Drug Discovery, Development, and Translation called Breakthrough Business Models: Drug Development for Rare and Neglected Diseases and Individualized Therapies, makes the following recommendations on economic ways of facilitating new drug development:
* The academic research community needs to increase investments in technology that can improve target validation and drug safety.
* The FDA needs to be adequately funded so it can partner with drug developers and direct the research being done to answer important regulatory questions. (The American Association for Cancer Research is calling for an FDA budget in fiscal year 2017 of $2.85 billion, which is $120 million above its fiscal year 2016 level.)
* Small business innovation regulations need to be revisited and revised to allow for greater investment.
* New incentives for high-risk investors need to be created, perhaps through tax law.
* Private disease foundations' provision of support to the academic community for discovery and to industry for development "is beneficial and should be embraced."
* Experienced investors need to be brought into the innovation process earlier.
* The pharmaceutical industry and academia need to work together to build a stronger U.S. industry.
Peggy Eastman is a contributing writer.