Cancer immunotherapies have a mechanism of action that requires a re-think of clinical trial endpoints to evaluate their efficacy. This in turn has prompted the revision of immunotherapy clinical trial designs. No “universal” criteria to measure immunotherapy response have been adopted for research or clinical care, and the EMA and FDA still hold survival as a gold standard for cancer treatment. Both pembrolizumab and nivolumab were initially approved based on small, single-arm trials that utilized surrogate endpoints such as Overall Response Rate (ORR) and Duration of Response (DOR). Looking back, traditional chemotherapy patient response assessment drove the development of Response Evaluation Criteria in Solid Tumors (RECIST) and modified World Health Organization (WHO) criteria, which rely on a reduction in tumor burden. RECIST uses straightforward one-dimensional measures, such as the sum of the longest diameter of the tumors. Immunotherapies are not well served by these criteria in that patients’ responses may not immediately result in tumor burden reduction. Rather, they may experience pseudo disease progression (flare effect) before regression or stabilization. For example, an immune response such as T-cell infiltration can increase a lesion size that without a biopsy may appear as tumor cell proliferation.
 
Accelerated approval regulations, introduced by FDA in 1992, allow approval for products intended to treat life-threatening diseases based on surrogate endpoints considered reasonably likely to predict clinical benefit. As part of the ipilimumab phase II melanoma clinical trial program, investigators proposed four immune-related response criteria (irRC), noting all were associated with favorable survival: “(a) shrinkage in baseline lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions.”[i]irRC, which quantifies response in two dimensions and then calculates their products and their sums, helps reinforce that disease progression is not equivalent to drug failure, and that longer times, even months, may be needed for therapeutic effect and evaluation. 
 
To address limitations of RECIST and irRC, new criteria, irRECIST, were introduced in 2014. Created as an adaptation of irRC, irRECIST is designed “to allow for treatment evaluations and assessments that better meets both investigators’ and patients’ needs and with that better reflects sponsors’ demands for more reliable and reproducible study data analyses.”[ii] irRECIST also contains guidance for ambiguous cases. Like RECIST, irRECIST is unidimensional and enables high reproducibility of results, and its design produces results that highly correlate to irRC. However, the clinical relevance of irRECIST needs confirmation. The authors intended that irRECIST would reduce ambiguity in assessments and promote harmonization between trial sites and central or independent data reviewers, so that all would use the same criteria specifically designed for immunotherapies. When using tumor response as an endpoint in a non-blinded study, blinded centralized radiological review is an important design feature to provide objective evidence in support of efficacy.
 
Quality of Life
Quality of life (QoL) is also an important endpoint to consider, especially as immunotherapy treatment extends survival. Successful treatments may create new challenges (e.g., GI symptoms and skin reactions) that may not be tolerable long term. QoL data may also be instrumental when negotiating reimbursement, and to differentiate a treatment for standard of care.  Since 2006, numerous guidance documents published by FDA and EMA contain recommendations for the inclusion of patient-reported outcome (PRO) endpoints. FDA and EMA both have approved numerous products with PRO endpoints in labeling. 
 
What the Future Holds
While many immunotherapy trials continue to use objective response and progression-free survival as endpoints, the scientific community is still working toward endpoints we are comfortable using for drug approvals. Many trials of immunotherapies report little effect on progression-free survival, but significant improvements in overall survival are observed. For many oncology indications, years of follow-up are required to achieve definitive overall survival results, and this is generally considered an unacceptable obstacle for introducing new and potentially life-saving or life-extending treatments. Another promising and active area of research involves the study of cancer biomarkers and their potential as surrogate markers for overall survival. The burden to establish that a biomarker predicts and captures treatment effect on overall survival remains a significant challenge. While this research continues, overall survival will likely remain the gold standard endpoint for approval for the foreseeable future.

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References: [1]Wolchok JD, Hoos, A., O’Day, S., et al: Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009, 15:7412-20
[1]Bohnsack, O., Hoos, A., Ludajic, K., “Adaptation of the immune related response criteria: irRECIST,” Poster 1070P, ESMO 2014, Sept. 14, 2014.  Published Annals of Oncology (2014) 25 (suppl_4): iv361-iv372. 10.1093/annonc/mdu342.  http://oncologypro.esmo.org/Meeting-Resources/ESMO-2014/Immunotherapy-of-Cancer/Adaptation-of-the-immune-related-response-criteria-irRECIST