Due to the unique biology of immunotherapies, they require, investigators have said, a novel approach to development and evaluation, clinical trial methodology, preclinical evaluation, and a drug review process adapted to their characteristics.
Conventional efficacy measurements used to assess cytotoxic drugs in clinical trials can give rise to misleading results for immunotherapeutic drugs. The effects of novel, less toxic immunotherapeutics may be missed because, unlike chemotherapeutic agents that act directly on tumors, cancer immunotherapies exert their effects on the immune system, initiating a complex series of events.
This indirect effect, designed to use the patient’s immune system to act against their tumor, may delay or change response patterns. Initial tumor burden may increase due to lymphocytic infiltration because of T-cell proliferation, followed by a lymphocyte-induced tumor response. These delayed reactions and other patterns of antitumor response are not part of standard criteria from the World Health Organization (WHO), or the Response Evaluation Criteria in solid Tumors (RECIST).
Clinical trials for cytotoxic anticancer agents’ response endpoints use RECIST based on the premise that “effective” therapy causes tumor destruction, target lesion shrinkage, and prevention of new lesions. But in the immunotherapeutic world, therapies may mediate cytostatic rather than direct cytotoxic effects and may be difficult to quantify with customary RECIST criteria.
Further, significant time may elapse before clinical effects are quantifiable because of complex response pathways. Effective immunotherapy may even mediate transient lesion growth secondary to immune cell infiltration
Clinical trials have long relied on intermediate or surrogate endpoints to predict long-term survival. But immunotherapy, according to scientists, doesn’t “try out” the same way as cytotoxic drugs. “Unconventional responses such as tumor shrinkage [sooner than expected] to immunotherapy are relatively frequent and shouldn’t be ignored,” said Axel Hoos, M.D., Ph.D., vp of oncology, GlaxoSmithKline. “We need to develop immune-related response criteria that incorporate both early and delayed response, as well as tumor volume that increases before it recedes.”
Furthermore, "Considering the time of translation of immunologic responses into clinical activity, the survival of patients may not be affected until some months after treatment started compared with chemotherapy," writes Dr. Hoos in an article in the Journal of the National Cancer Institute in 2008. He adds that the kinetics observed for survival may require new statistical approaches for planning randomized trials.
In an accompanying editorial, Donald A. Berry, M.D., of the University of Texas M.D. Anderson Center, addresses the conundrum of delayed responses often induced by immunotherapies: "Any delayed effect of therapy makes product development harder and more expensive than developing a drug that works by attacking the tumor directly."
Dr. Berry also worried about another potential problem in developing immunotherapies: "To fully investigate the potential of an immunotherapy, clinicians may have to stick with it beyond a patient's progression and thereby delay switching to potentially more effective therapy," he says.
Several initiatives have been undertaken to study and develop a new paradigm for immunotherapy clinical trials. Dr. Hoos and colleagues described the results of a five-year collaborative effort between academia and industry in which clinical observations were translated into new response criteria that more comprehensively capture all observed response patterns. The collaboration resulted in the development of immune-related response criteria, or irRC.
The irRC, generally based on the WHO and RECIST criteria, do not require a substantial departure from standard oncology practice, say the investigators. They looked at design and outcomes of immunotherapy clinical trials as part of several initiatives undertaken by the Cancer Immunotherapy Consortium (CIC) of the Cancer Research Institute (CRI) and partner organizations between 2004 and 2009. The irRC were published in 2009, following a series of large, multinational studies based on the clinical development program with Bristol-Myers Squibb’s ipilimumab, a first-in-class anti-CTLA-4 monoclonal antibody, approved by the FDA in March 2011 for the treatment of unresectable or metastatic melanoma.
Ipilimumab produced extended survival, some durable responses, and manageable toxicities in a large Phase III clinical trial in patients with advanced melanoma. Variable response patterns had been observed, including 1) a response in baseline lesions, 2) a slow, steady decline in tumor burden, 3) a response after an increase in tumor burden, and 4) a response in baseline lesions accompanied by the appearance of new lesions. Although responses 1 and 2 may be captured using standard methods, atypical responses 3 and 4 would be classified as progressive disease using conventional assessments. Patients on ipilimumab may have delayed responses or durable stable disease even after apparent disease progression.
Based on modified WHO criteria and involving the use of bidimensional measurements on radiographic assessment of cancerous lesions (the longest diameter and the longest perpendicular diameter), the irRC differ from conventional response criteria in that they incorporate measurement of both preexisting lesions (index lesions) and new lesions, as opposed to just index lesions, and allow for a confirmatory assessment of progression to detect delayed responses.
“In the past, growth of a tumor has been a sign of drug failure. Here it could be a sign of drug success,” said Dr. Hoos. "The novelty of the irRC lies in the measurement of new lesions, which are included in the overall tumor burden, and the confirmation of progression, allowing for it to be described as a continuous variable."
Clinical trial sponsors can now include a study design provision for nonstandard responses, but researchers have been working toward formalizing these observations with the development of irRC and clinical endpoints that are specific to immunotherapies, which could be used to facilitate and accelerate the development of novel agents.
Dr. Hoos told GEN that a CIC workshop brought together big companies that had pivotal programs in immunotherapy and used the irRC in these programs “to see if there was a class effect.” While he noted that “response rates are of course different among different drugs, the biological phenomena are the same.
He and his team have been working on characterizing these phenomena for a decade and now “we are at a point where endpoints that were exploratory in 2009 are now reproducible, and are truly immunotherapy response criteria. The therapies tested produced some response patterns different from chemotherapies.”
Dr. Hoos further noted that “This is a class effect for immunotherapies that seems to be associated with survival. The FDA seems to be increasingly interested in making use of these response criteria and may make them useful for regulatory purposes. That will help immunotherapy drug development.”
Companies developing novel cancer immunotherapeutics acknowledge that using the irRC is a major step forward.” But Brad Thompson, Ph.D., president and CEO at Oncolytics Biotech, told GEN, that “there’s a ways to go and our colleagues at the FDA are rightfully very obsessive on focusing overall survival (OS) as a registration endpoint.”
Oncolytics develops oncolytic viruses for use as cancer therapeutics. The company’s lead product, REOLYSIN®, a proprietary formulation of the human reovirus, is currently being evaluated in clinical trials either alone or in combination with chemotherapy and radiotherapy for various cancers.
Dr. Thompson would like to see the linkage between OS and tumor shrinkage “go away. Some agents are great at reducing tumors but not at increasing overall survival. OS and tumor shrinkage should be independent endpoints that are important for different reasons.”
He noted that he has seen too many studies with great tumor responses and no difference in OS or no tumor responses and better OS.