The new iRECIST guideline—developed in consultation with academics, drug companies, and regulatory authorities—provides a standardized approach to assessing whether patients' disease improves, stays the same, or worsens in trials of immunotherapeutics, agents that can trigger different response patterns from other kinds of drugs.

The singular patterns of tumor responses to immunotherapies compared with other drugs demand a singular set of rules for assessing changes in tumor burden in clinical trials of these agents, according to the world's leading authority on response evaluation criteria.

In a new report, a team led by Lesley Seymour, MD, PhD, an oncologist at the Canadian Cancer Trials Group based at Queen's University in Kingston, Ontario, outlined a series of modifications to the Response Evaluation Criteria in Solid Tumors (RECIST) that account for the apparent tumor growth that sometimes occurs before tumor load begins decreasing—a phenomenon known as pseudoprogression (Lancet Oncol 2017;18:e143–52). These responses occur in a small but consequential fraction of patients receiving checkpoint inhibitors and other immune-modulating agents.

The new consensus guideline is the first developed with input from pharmaceutical companies—Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, and Servier—as well as regulatory authorities in the United States and Europe. “It builds on the earlier exploratory work to provide a consistent, agreed-upon approach to evaluating response in clinical trials of immunotherapeutics,” says Seymour, who co-chairs the RECIST Working Group and led the subcommittee that crafted the new guideline.

With RECIST, any tumor growth or the appearance of new lesions on a CT scan counts as progression. To account for delayed responses after pseudoprogression, separate teams led by Daniel Chen, MD, PhD, global head of cancer immunotherapy development at Genentech, and Axel Hoos, MD, PhD, senior vice president of oncology R&D at GlaxoSmithKline, created their own immune-related adaptions of RECIST, which required confirmation of progression at a second timepoint. However, the details differed slightly and there were no commonly agreed-upon criteria that could be applied to all immunotherapies.

Enter iRECIST, the guideline laid out by the RECIST Working Group. Although similar to previous approaches, it requires additional imaging showing continued tumor growth 4 to 8 weeks after initial evidence of mounting tumor burden in order for the disease to be deemed as progressing. (Stable disease does not count as disease progression.) Only then, Seymour says, can oncologists confidently say that the initial tumor growth was true disease progression, not simply the consequence of immune-cell infiltration, which can temporarily increase tumor volume.

“It makes sense for the field to coalesce around a certain set of guidelines, and this committee involved some of the leaders in the immunotherapy field as well as leading experts on radiologic endpoints in cancer,” says Elad Sharon, MD, a senior investigator with the NCI's Cancer Therapy Evaluation Program in Bethesda, MD, who was not involved in developing iRECIST.

Seymour emphasizes that iRECIST is designed to provide a common rubric for data collection in trials, not to guide routine clinical decision-making.

To validate the new guideline, Seymour is calling on stakeholders to share results of immuno-oncology trials in a massive database. “The goal,” she says, “is to formally test which is the better surrogate of benefit: RECIST as it is, or iRECIST, or perhaps some other criteria.” Currently, most late-stage trials use classic RECIST-based metrics.

Hoos, who was not involved in formulating the new criteria, applauds the effort to create a common yardstick for the community, but notes that iRECIST needs to prove its worth. “Data ultimately drives the story,” says Hoos, “and as we learn and see more patients being treated, we'll fine-tune this based on the commonalities of responses that we see.” –Elie Dolgin

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