NEW END POINTS MUST BE ADOPTED FOR IMMUNOTHERPY

September 9, 2010 — Axel Hoos, MD, PhD, who was part of the team at Bristol-Myers Squibb that developed ipilimumab for metastatic melanoma, and a number of other researchers have drawn on their experience to propose an entirely new approach to end points for cancer immunotherapy trials.

Their review was published online September 8 in Journal of the National Cancer Institute.

The question of appropriate end points arose during the regulatory review of ipilimumab, which was eventually fast-tracked by the US Food and Drug Administration. At that time, questions were raised about the appropriateness of response criteria developed for cancer chemotherapy trials, such as the Response Evaluation Criteria in Solid Tumors (RECIST) for immunologic agents.

Dr. Hoos and coauthors point out that cancer immunotherapies affect the immune system and "demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival," and that these effects might occur in an entirely different timeframe than those typically observed with cytotoxic chemotherapy.

They propose 3 changes.

First, cellular immune-response assays need to be standardized and validated as reproducible biomarkers that can be correlated with clinical outcomes. Second, new immune-related response criteria (irRC), which are able to capture more complex response patterns, should replace the RECIST criteria. Third, statistical models "describing hazard ratios as a function of time and recognizing differences before and after the separation of (Kaplan–Meier) curves should be used to design phase 3 trials.

With regard to the first change, the authors note that response to immunotherapy can appear after a period of "stable disease" in which there is no tumor shrinkage, after tumor growth, or after the appearance of new lesions. The delay in radiographically apparent clinical activity "may reflect the dynamics of the immune system — the time required for T-cell expansion followed by infiltration of the tumor — and a subsequent measurable antitumor effect," the authors write.

About the second change, the authors say that irRC assess tumor burden as a continuous variable that considers index lesions identified at baseline and new lesions that occur after the beginning of treatment, based on bidimensional measurements of each lesion. "Percentage changes in tumor burden between assessment time points describe the size and growth kinetics of total tumor burden over time," the authors write.

Response categories are irCR, immune-related partial response (irPR), immune-related stable disease (irSD), and immune-related progressive disease (irPD). The appearance of new lesions alone would not be considered progressive disease unless they add to the tumor burden by at least 25%.

"Importantly, early increase in the size of lesions, which may be attributable to the infiltration of lymphocytes, does not preclude an irCR, irPR, or irSD from being obtained at the next consecutive time point. If a patient is classified as having irPD, confirmation by a second scan in the absence of rapid clinical deterioration is required," the authors write. They warn that "awaiting a response after tumor burden increase may not be appropriate for patients with rapid symptomatic progression accompanied by a decline in performance status."

The third proposed change — recommendations for measuring immunotherapy survival kinetics, which are commonly assessed in chemotherapy trials by the separation of Kaplan–Meier curves – is likely to be more controversial.

The authors propose basing computation of the required events (for clinical trials design) "on a plausible specification of the timing of the delayed separation, the desired statistical power, use of the log-rank statistic, and the understanding that the trial will be overpowered if delayed separation is not observed or is less than specified."

However, the underlying assumption about delayed survival effects with immunotherapy was challenged in an accompanying editorial by Donald A. Berry, PhD, from the Department of Biostatistics at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Berry says that the assumption that immunotherapies have kinetics different from cytotoxic agents "is quite plausible," but that the examples presented by Hoos et al "do not persuade me that the delayed benefit is real."

"The 2 curves are not unlike some survival curves showing benefit of cytotoxic chemotherapy," Dr. Berry writes. He does, however "wholeheartedly concur" with the suggestion that assignment in phase 2 immunotherapy trials be randomized.

Clinical trials with ipilimumab immunotherapy were sponsored by Bristol-Myers Squibb. Dr. Hoos and some of his coauthors are employees of Bristol-Myers Squibb, as detailed in the paper. Coauthor Jedd Wolchok, MD, PhD, from the Memorial Sloan-Kettering Cancer Center in New York City, reports being an ad hoc Advisory Board member (compensated) for Bristol-Myers Squibb. Coauthor F. Stephen Hodi, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reports receiving research support and serving as a consultant for Bristol-Myers Squibb. Dr. Berry is part owner of Berry Consultants, specialists in adaptive Bayesian designs, with clients that include Bristol-Myers Squibb and BioVest International.

J Natl Cancer Inst. Published online September 8, 2010.