In its continuing efforts to help ensure that patients receive the best treatments in the safest and fastest way possible, the Friends of Cancer Research (FOCR) announced a new pilot project called ctMoniTR at its annual meeting, held in Washington, D.C. The pilot project aims to harmonize the use of circulating tumor DNA (ctDNA)—genetic material shed from cancer cells that can be measured in blood—to monitor patients’ response to cancer treatment. The pilot project will also test the feasibility of data comparison from different clinical studies.
FOCR President and CEO Jeff Allen, PhD, said the pilot project will seek to answer this question: “Do changes in circulating tumor DNA levels accurately reflect the therapeutic effect of cancer treatments?” The project’s hypothesis is that broad changes in ctDNA can detect whether a cancerous tumor is responding to a given therapy.
Allen said the project will consist of two steps: 1) using previously collected trial data from a subset of lung cancer trials to study the feasibility of ctDNA as a monitoring tool; and 2) building on step one to prospectively investigate the ability of ctDNA to detect early tumor response to treatment in clinical trials for different cancer types and treatments.
In other news from the annual meeting, the FOCR released three white papers, each designed to improve and streamline the cancer clinical trials process. And, in a keynote presentation, Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence, described Project Orbis, the FDA’s first international collaboration on concurrent review of new cancer therapies.
Under Project Orbis, the FDA, the Australian Therapeutic Goods Administration, and Health Canada recently collaboratively reviewed applications for two oncology drugs, lenvatinib in combination with pembrolizumab, for patients with advanced endometrial cancer that is not microsatellite instability-high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. The goal of concurrent international reviews under Project Orbis is to make safe and effective new therapies available globally as quickly as possible.
Discussing External Controls
A panel discussion addressed the first FOCR white paper, which focused on the methodology and implementation of external controls (sometimes referred to as synthetic controls) in clinical trials for formal regulatory use. The white paper notes that, in drug development, randomized controlled trials (RCTs) are the gold standard for evaluating safety and efficacy. But oncology drug development increasingly relies on single-arm clinical trials, “especially in certain settings where there are ethical or feasibility challenges with deploying a concurrent control arm,” states the paper. External controls traditionally rely on historical data from prior clinical trials, but the ability to aggregate real-world data from electronic medical records, claims data, and other sources is opening the door to new opportunities using these new data, notes the paper.
The use of external controls is most common in orphan diseases, where it can be difficult to accrue patients, especially for an RCT. Put simply, when an investigational agent is considered to be much more effective than standard-of-care therapy, patients don’t want to risk not getting the investigational therapy by enrolling in an RCT. “This option is helpful when patients find a control arm unacceptable,” said Ruthie Davi, PhD, a contributor to the white paper and a statistician and Vice President at Acorn AI.
External control arms can be used now for accelerated approval, but confirmatory clinical trials still have to be done, panel moderator and white paper contributor Gary Rosner, PhD, the Eli Kennerly Marshall Jr. Professor of Oncology at Johns Hopkins School of Medicine, told Oncology Times. The white paper cites the 2017 accelerated approval of avelumab for merkel cell carcinoma, which was based on an 88-patient single-arm phase II trial. Real-world evidence contributed by external data from a registry was used as supportive evidence, although the regulatory approval was based primarily on data from the phase II trial.
The white paper discussed at the FOCR annual meeting presented a case study of relapsed/refractory multiple myeloma, and demonstrated that it is possible to use specially designed methodology to produce an external control arm from historical clinical trial data that is well-matched with the investigational arm at baseline. Davi noted that an external control arm could be useful in a hybrid clinical trial design, where a small number of patients are still randomized, but that group is supplemented with the external controls. “To me, that is the best of both worlds,” she said.
The second white paper, also discussed in a panel session, addressed immuno-oncology drug development for patients with disease progression after initial treatment with anti-PD-L1 therapy; these patients have limited treatment options. The FOCR white paper posed this question: “Will the patient’s disease be able to respond to the challenge by either the same PD-L1 inhibitor or a similar in-class inhibitor when used in combination with another drug or biologic?” Panelists discussed several studies attempting to answer this question, including the phase II HUDSON study and the phase II Platform study.
It is becoming more and more common to combine checkpoint inhibitors with other therapies, said panel moderator and white paper contributor Ryan Sullivan, MD, Associate Director of the Melanoma Program at the Massachusetts General Hospital Cancer Center and a member of the Termeer Center for Targeted Therapy. But, he noted, many patients don’t receive benefits from checkpoint inhibitors, due either to de novo or acquired resistance. Sullivan stressed the need for further research on the basic mechanisms of drug resistance. The white paper notes that there can be advantages to the use of external data for the assessment of combination immuno-oncology therapies, stating, “It is important to explore the use of external data to complement clinical trial data and further confirm the benefit of the combination regimen.”
This white paper posed the following questions for further investigation, among others: What preclinical models or clinical translational data would be helpful to identify combinations most likely to be effective in patients who have progressed on PD-L1 therapies? What is the role of biomarkers in better understanding the drug combinations most likely to be effective in patients who have progressed on PD-L1 therapies? What are some statistical considerations or approaches to evaluate early efficacy or early futility in these combination trials? Is there a role for non-invasive monitoring of treatment response in the adjuvant setting (by ctDNA, for example) to identify patients who respond to treatment versus those who never achieved a benefit?
Finally, the third FOCR white paper focused on review considerations for use of a companion diagnostic test for a class of oncology therapeutic products, rather than one or more specific products within that class. This white paper constructs a framework for that review with the aim of providing a benefit to patients by simplifying information for them and enabling access to therapies. The white paper notes, “The benefits of multiple therapeutic options offered by approvals of same-in-class therapeutic products, such as the EGFR and PARP inhibitors, may in part be compounded by added complexity in CDx [companion diagnostic] development as well as clinical testing workflows and practice, inadvertently introducing obstacles to access.”
In December 2018, the FDA released draft guidance for the development and labeling of companion diagnostic tests for a class of specific therapeutic oncology products; final guidance is pending, and so far this approach has not been used, said speakers.
Sometimes it seems that developing a companion diagnostic is more difficult than developing the drug, said white paper contributor David Hyman, MD, Chief of the Early Drug Development Service and Co-Chair of the Center of Mechanism Based Therapy at Memorial Sloan Kettering Cancer Center. “I think it’s affecting the patient’s ability to enroll in a clinical trial.” He noted that having a companion diagnostic test for a class of oncology drugs could speed up enrollment in cancer clinical trials, thus speeding up patients’ time to treatment.
There are clear reasons for interest in using a companion diagnostic test for a class of drugs, said Preeti Narayan, MD, a Medical Officer on the breast cancer team in the Division of Oncology 1 in FDA’s Center for Drug Evaluation and Research. But, she noted, “From a regulatory perspective we have to be cautious.” What needs to be asked is: Does the diagnostic test for a class of drugs really represent the mechanism of each drug in the class?
The FOCR white paper considers case studies for three biomarkers, EGFR, ALK and BCRA/HRD, in order to 1) define categories of biomarkers based on biological and technical complexity, 2) explore how FDA’s draft guidance could be implemented for simple or moderately technical biomarkers, and 3) begin to develop a common solution on how to establish a shared definition and evidentiary standard for high-complexity biomarkers.
The white paper notes that the formulation of a scientific evidentiary standard for a companion diagnostic device for a class of oncology therapeutic products could be helpful to industry, the FDA, physicians, and patients. Such a standard will allow the communication of “information about new and exciting targeted therapies to physicians using ‘simplicity in labeling.’ This will be of enormous help to them as they manage their patients.” Such a standard will also aid patients who “seek streamlined and efficient access to both innovative life-changing therapies and to high-quality diagnostic tests that are critical in directing their safe and effective use,” as the white paper puts it.
The FOCR recently announced some of its priorities, including implementing the necessary quality assurances for diagnostic test oversight; developing a framework for cutting-edge individualized technologies such as cell and gene therapies; ensuring the accuracy of drug labels over time; and setting the groundwork for the upcoming reauthorization of FDA user fees programs.