With the race to develop cancer immunotherapies escalating and new agents appearing in the clinic, oncologists’ decision-making toolbox will need to evolve.
“As immunotherapeutics become increasingly available to patients, clinicians face a major challenge in the evaluation of these novel drugs – the accurate determination of clinical efficacy,” physician-scientists recently wrote in a commentary published online in the Journal of Clinical Oncology.
Dr. Gideon Blumenthal
Response evaluation criteria in solid tumors (RECIST) have typically driven oncologists’ decision making. Patients undergo scans and radiographic measurements to determine the extent of change in tumor size. Scan, treat, repeat is a mantra for advanced cancer patients, so much so some patients have sought to trademark the phrase for T-shirts. And significant tumor growth has traditionally signaled treatment failure.
But although some patients have responded to immune-targeted treatment with tumor shrinkage or stable disease that would be consistent with existing RECIST criteria, distinct immune-related patterns of response are also emerging, including pseudoprogression, said Dr. Victoria L. Chiou and Dr. Mauricio Burotto, both medical oncology fellows at the National Cancer Institute, in their commentary (Jour Clin Onc. 2015 Aug 10. doi: 10.1200/JCO.2015.61.6870).
Investigators first addressed this issue by proposing immune response criteria in 2009, based on data from ipilimumab phase II trials in patients with advanced melanoma. Dr. Jedd D. Wolchok of Memorial Sloan Kettering Cancer Center, New York, and his associates expanded on RECIST by adding two additional patterns of response: response after an increase in total tumor burden and response in the presence of new lesions. All patterns of response were associated with favorable survival, Dr. Wolchok and associates said (Clin Cancer Res 2009 Dec 1. doi: 10.1158/1078-0432.CCR-09-1624).
Subsequent trials in patients with advanced melanoma have confirmed that a subset of patients who are responders using immune response criteria would have been misclassified using RECIST alone.
In a study of patients with metastatic melanoma treated with nivolumab, 10% experienced distinct immune-related responses, according to Dr. Chiou and Dr. Burotto. In another study of patients with advanced melanoma, this one evaluating anti–PD-1 monoclonal antibody pembrolizumab, 6.7% of patients of the patients experienced pseudoprogression, and overall, 12% of patients were classified as responders or as having stable disease by immune response criteria but would have been classified as having progressive disease by RECIST.
It is time to expand on those first immune response criteria, Dr. Chiou and Dr. Burotto conclude. “Five years after the introduction of the immune response criteria, it is necessary to fully characterize the patterns of immune-related phenomena, to understand these patterns across multiple solid tumor types, and to evaluate how these guidelines are used in current clinical practice,” they wrote.
The Food and Drug Administration agrees. Though guidelines for industry were published in 2011 regarding cancer vaccines, there is no specific guidance on approval criteria for other cancer immunotherapies such as checkpoint inhibitors, Dr. Gideon Blumenthal, team leader in the FDA’s Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, said in an interview.
“However, the FDA is actively looking at other metrics of response beyond conventional RECIST criteria, both to help industry in early ‘go/no-go’ decision making, as well as for helping in the design of later stages of trial design and to help inform approval decisions,” he said.
The FDA is interested in investigating internal data sets of immunotherapy trials, and in collaborating with external stakeholders to determine what the optimal endpoints for cancer immunotherapies will be. Median PFS and PFS hazard ratios do not appear to capture the overall survival benefit that patients derive from immunotherapies, particularly in early lung cancer trials with which he is most familiar, Dr. Blumenthal said.
“Overall survival remains the gold standard endpoint in oncology as it is a direct measure of clinical benefit and less subject to bias, but as more effective therapies come on line and patients live longer, overall survival will become more challenging to detect,” he said.
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