Jeffrey Weber, MD, PhD
Most patients who appear to progress after they begin receiving anticancer immunotherapy will never exhibit a response to therapy. They will continue to progress, just as quickly as they would with no treatment and just as predicted by the Response Evaluation Criteria in Standard Tumors (RECIST) that have long guided clinical trial evaluations and treatment decisions. The trajectory is different, however, for a small minority of patients.
These patients seem to progress significantly after they begin treatment and sometimes keep on progressing for more than a month before they finally respond to the medication. The percentage of patients who follow this pattern varies among medications, tumor types, and other factors, but the average is probably somewhere between 4% and 5%, according to Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center, codirector of the Melanoma Program, and head of Experimental Therapeutics at New York University Langone Medical Center.
Delayed response, in other words, is hardly common, but it is common enough for many leading investigators to suspect that new immunotherapy trials would be better judged—and patient treatment would be better guided—by a newer rubric called the immune-related Response Criteria (irRC), which accounts for the phenomenon, rather than by RECIST standards that do not.
The FDA has partially accommodated this viewpoint. It allows the use of irRC for deciding how long to keep trial patients on a particular treatment, but it requires extra safety precautions that would not be needed if investigators used RECIST to time treatment decisions. The FDA also allows the use of irRC as a secondary endpoint in many immunotherapy trials.
The agency still gives greater weight, however, to results measured by RECIST version 1.1, and it plans to keep on favoring RECIST unless future research can prove irRC to be a superior proxy for extended survival.
In theory, the issue should matter little to clinical oncologists. Formal response evaluation criteria exist to guide research trials, not everyday practice. Indeed, standard patients rarely undergo enough testing for the timely application of either irRC or RECIST to treatment decisions. That said, there is plenty of anecdotal evidence that what doctors believe about trial standards can influence how they treat patients. Oncologists who intuitively support the use of irRC seem more likely to keep their own patients on immunotherapy after some apparent progression than oncologists who side with RECIST (or who do not even know of the challenge to RECIST).
“Definitive evidence in favor of the predictive power of either RECIST or irRC would certainly make life easier for investigators, who must currently work with both standards, but I’m not sure it would have any impact whatsoever on either new drug approvals or new label indications. The FDA is already allowing us to use irRC enough that most late responders do show up somewhere in the literature as responders,” said Weber, who thinks irRC is almost a more accurate survival proxy but also that its superiority is limited by the relatively small number of patients who seem to progress before responding.
“I’m more concerned about individual practitioners stopping treatment too early,” Weber added. “The assumption that any lesion growth or new lesion signals the failure of one treatment and the need for another has been around for decades. It is a fundamental assumption of RECIST, and that assumption appeared fully justified until immunotherapy came along. I suspect that most practitioners still abide by it for the most part and that it will take some time for the ideas that underlie irRC to be broadly accepted.”
The Start of the IRRC
RECIST and irRC differ in many particulars, but the most important conceptual differences probably lie in their methods for measuring and their timetables for conceding disease progression. Any new lesions or significant growth in 5 or fewer carefully tracked “target lesions” constitutes progression under RECIST. The irRC, on the other hand, is more concerned with total tumor burden. It calls on investigators to track up to 15 lesions, and if the shrinkage of some lesions equals or exceeds growth elsewhere—even if that growth involves totally new lesions—irRC reports stable disease (SD) or responsive disease.
Even when aggregate tumor burden does grow, irRC does not conclude that a patient has progressed unless the initial findings are confirmed by a second assessment performed at least 4 weeks later. RECIST requires no confirmation to diagnose progression. A single test showing a single new lesion is enough.