One of the major challenges to implementing personalized medicine is the lack of information about the risks and benefits of targeted drugs that are used off-label to treat patients whose tumor harbors a genomic abnormality.
—Richard L. Schilsky, MD, FACP, FASCO
Response rate is not just a surrogate measure, it is a real-world clinical tool for patient assessment. Significant and prolonged reduction of tumor burden is clinically meaningful and could be used for regulatory approval.
—Gideon Blumenthal, MD
Friends of Cancer Research, in conjunction with the Engelberg Center for Health Care Reform at Brookings, recently held the seventh annual Conference on Clinical Cancer Research in Washington, DC. The panels that comprised the daylong meeting discussed a future that has already begun.
The most salient point was that a potential new role is emerging for single-arm trials. Traditionally, large randomized clinical trials, with overall survival as the primary endpoint, have been the best—and often only acceptable—way to conduct new research. They require years of time and millions of dollars but for many years were the only way a new product could get through the U.S. Food and Drug Administration (FDA) for full approval.
Now, mostly because of the advent of molecular therapy and the problems of accruing large numbers of participants, single-arm trials can provide alternative ways of looking at and interpreting evidence. As Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “In the 1970s and 1980s, we tested highly toxic drugs that mostly didn’t work. Now, with these new agents, because response rates are so good, we have to ask two entirely different questions: not whether we should approve a drug but how quickly we can approve it, and does a trial answer a meaningful question for a good reason?”
Off-label use in oncology is more common than ever and is often supported by varying types of evidence: reports in the medical literature as well as information from clinical trials, practice guidelines, and therapeutic standards.
Reasons to go off-label with an agent can be compelling, especially when its use can be applied with great precision. Some patients have tumors with distinct biomarker signatures that do not align with abnormalities found in other cancers of the same histology, and others may have exhausted multiple lines of approved treatment.
An agent that has efficacy in a biomarker-defined population may also have activity in another cancer expressing the same biomarker. If this is proven to be true, it means that off-label use will become more important.
However, off-label use is not without challenges. Data about clinical effectiveness are sometimes limited, and the costs and side effects may be high. In addition, insurers may not reimburse unless the proposed use is in a major drug compendium, and there is no system to capture outcomes data when a drug is prescribed off-label.
Off-label uses with enough supporting evidence to be listed in a major drug compendium are now covered by Medicare and some private payers. Some plans will reimburse when all other treatment options have been exhausted.
Role of Nonrandomized Trials
Deborah Armstrong, MD, Professor of Oncology, Gynecology, and Obstetrics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, noted that randomized controlled trials with overall survival have long been the gold standard, with single-arm trials reserved for accelerated approval.
“The overall response rate of a drug can be easily measured in a single-arm trial because, absent the therapy, it is extremely unusual for a tumor to regress spontaneously,” she said. “But overall survival requires a randomized controlled trial, because only many patients and enough time can provide those data. In view of new types of therapy, it is time to re-evaluate which trials are appropriate for which patients.”
Dr. Armstrong added that several highly effective molecularly targeted agents have shown that certain subsets of patients are most likely to respond, thus obviating the need for as many patients as once might have been required in a single trial. And more often than not, response rate reflects clinical benefit.
“It may also be ethically and logistically challenging to enroll patients in a placebo-controlled or active-controlled randomized trial when they and their physicians are aware of the potential for benefit with the experimental agent. Moreover, because of crossover, [interpretation of overall survival data] has become increasingly difficult.”
Two other situations render a randomized controlled trial inadvisable: if a new drug demonstrates an unprecedented overall response rate when there is no other treatment available, and when an approved molecularly targeted agent is tested in a rare tumor histology expressing the appropriate biomarker.
Josh Sommer, Executive Director of the Chordoma Foundation and a chordoma survivor, added, “For patients with no good standard treatment options, the idea of enrolling in a randomized trial in which they take a risk of not receiving the experimental therapy could be less than appealing.”
The median survival for chordoma is 8 years, he said, so it is difficult to do a trial that measures overall survival. “Though we don’t know the preferences of chordoma patients as a whole, I frequently hear from patients that, if forced to make a choice, they would rather have better quality of life than more years with poor quality of life.”
Role of Single-Arm Trials
Can single-arm trials support FDA approval? This is the big question, and the answer is, in many circumstances, they can—and should.
Mace Rothenberg, MD, Senior Vice President for Clinical Development/Medical Affairs and CMO of Pfizer Oncology, talked about when large effects are seen in early clinical studies or in rare cancers. Since 2003, he said, the FDA has granted traditional approval for a number of agents, notably the 2006 approval of imatinib (Gleevec) for several rare, life-threatening malignancies (chronic myelogenous leukemia and gastrointestinal stromal tumors) that express imatinib-sensitive tyrosine kinases. The 2012 approval of vismodegib (Erivedge) for metastatic and locally advanced basal cell carcinomas was based on a strong mechanistic rationale and the fact that it produced durable tumor responses.
These approvals over the past decade can generate a set of standards to determine whether a single-arm trial is robust enough to support traditional approval:
Translating Tumor Response Into Clinical Benefit
Tumor response rates have been used to assess therapeutic efficacy for more than 50 years and can translate to historic controls in single-armed trials, said Gideon Blumenthal, MD, Clinical Team Leader, FDA Office of Hematology Oncology Products. He described a meta-analysis of 26 randomized controlled trials in ovarian cancer published between 1975 and 1989, which found that large improvements in response rates meant significant improvement in overall survival.
Another meta-analysis, this one in non–small cell lung cancer, found that treatment effect on overall response rate was strongly correlated with treatment effect on progression-free survival but not between overall response rate and overall survival.
“Response rate is not just a surrogate measure, it is a real-world clinical tool for patient assessment. Significant and prolonged reduction of tumor burden is clinically meaningful and could be used for regulatory approval. Using response rate as an endpoint would shorten the time to final analysis compared with progression-free survival or overall survival,” he added.
There are caveats, though. Clinical relevance depends on the nature of the disease, tumor location, and associated symptoms. Moreover, whether a tumor response is clinically meaningful depends on the depth, duration, and type of response. Even more critical is the existence of competing therapies, especially in rare or fast-growing malignancies.
Designing Single-Arm Trials
For a single-arm trial to be acceptable for FDA approval, its outcome has to be clearly superior to that obtainable with currently available treatments, said Richard Simon, DSc, Chief of the Biometric Research Branch at the National Cancer Institute. The following factors should be considered:
Two Pathways to Evidence Development
ASCO has outlined an approach to better evidence through a national “facilitated access program” and study of cancer patients receiving off-label targeted agents. It’s called the Targeted Agent and Profiling Utilization Registry (TAPUR), which will enroll patients with advanced cancer who have been on standard treatment and who have an “actionable” genomic alteration that can be targeted with an FDA-approved drug.
“One of the major challenges to implementing personalized medicine is the lack of information about the risks and benefits of targeted drugs that are used off label to treat patients whose tumor harbors a genomic abnormality,” said Richard L. Schilsky, MD, FACP, FASCO, ASCO Chief Medical Officer. “Other difficulties are lack of access to these agents and interpretation of complex genomic test results. The ASCO-led trial will address both challenges.”
It has two primary objectives: to describe the antitumor activity and toxicity of commercially available targeted cancer drugs used off label for treatment of patients with advanced solid tumors with a known genomic variant and to provide patient access to these drugs.
The primary endpoint is objective tumor response. Data on progression-free survival, overall survival, duration of treatment, and serious adverse events also will be collected.
The prospective, nonrandomized clinical trial will enroll patients who are no longer benefiting from standard treatment or for whom no such treatment is available. Patients will be screened for acceptable performance status and organ function, and a tumor genomic test must identify at least one variant that can be targeted with drugs provided by participating pharmaceutical companies.
The second pathway is proposed by Palmetto GBA, a subsidiary of BlueCross BlueShield of South Carolina. It was described by Dane Dickson, MD, Director of Clinical Science. The company is spearheading an off-label program called Molecular Evidence Development Consortium (MED-C), which allows patients access to off-label oncology products while collecting registry data on care and outcomes.
Newly diagnosed patients will receive standardized molecular testing to identify mutations for which treatments exist in other diseases. They then enter a centrally prescribed treatment pathway, consisting of a number of options for combinations of mutations and disease. Patients with no actionable mutations will receive standard care.
These two pathways are similar in some respects and different in others:
Considerations for Evidence Development
The two programs aim to generate data about the reliability and efficacy of targeted agents, but they and others to follow face significant challenges. To begin with, drugs can be selected in one of two ways: to allow any treatment a physician chooses or from a limited list. Either way, use of an off-label drug must be considered medically viable, and it must have an adequate safety profile.
A program has to decide how to design and operate diagnostic testing, which can be left to the discretion of the oncologist and/or site-specific laboratory or can be predefined through a list of qualified tests. Moreover, a program must decide whether it will require next-generation sequencing or other types of molecular testing, and if so, what criteria will be used to determine test inclusion.
Rigorous reliability of test results must be ensured. The data collected must include many aspects of treatment and be obtainable without being overly burdensome: basic demographics, histologic diagnosis and genomics, prior therapy and best response, comorbidities, drug regimen, clinical outcomes, and how endpoints are assessed.
Payment for off-label use is a critical issue and an important hurdle. Although patients receive drugs at no cost in the two studies, off-label use is not covered for most patients most of the time. Payment for diagnostic testing is also a problem, because there may be no reimbursement when the tests are done in conjunction with use of off-label drugs.
Finally, patients’ active engagement with either a trial or “routine” use of off-label drugs is critical. They need to understand the reasons for and conduct of genetic profiling and accept that out-of-pocket expenses may be a significant part of (and potentially an impediment to) off-label treatment. ■
Disclosure: Drs. Pazdur, Armstrong, Rothenberg, Simon, Blumenthal, Schilsky, and Dickson, and Mr. Sommer reported no potential conflicts of interest.