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FDA advisors told the agency to wait on more data before approving an investigational immunotherapy for squamous carcinoma of the anal canal (SCAC), largely due to questions over the drug's activity.

By a 13-4 margin, the (ODAC) agreed that data from a randomized trial was needed for approval, as the overall response rate (ORR) in a single-arm trial did not sufficiently support the accelerated approval of retifanlimab in locally advanced or metastatic SCAC patients who progressed on or were refractory to standard chemotherapy.

"With a response rate of 14%, and only half of that population showing a significant durable response, it is certainly problematic, and doesn't predict clinical benefit," said Christopher Lieu, MD, of the University of Colorado in Aurora. "I think everyone feels the pressure and stress of trying to improve treatment options for what is essentially an orphan disease, but unfortunately the response is simply too low to support the indication at this time."

In addition to the low ORR, Pamela Kunz, MD, of Yale University School of Medicine in New Haven, Connecticut, said she had concerns about the lack of diversity in the phase II trial's population, as well as the low number of HIV-positive patients enrolled.

The phase II POD1UM-202 study fell short of the trial's primary endpoint -- an ORR of 25% -- a showing that gave committee members pause regarding the drug's efficacy.

"The study was a negative study -- it did not meet its primary endpoint," said Colin Weekes, MD, PhD, of Harvard Medical School and Massachusetts General Hospital in Boston. "Unfortunately, the low response rate does not really translate into clinical benefit. I do appreciate the urgency to offer our patients options, but I think we should be offering patients the right options."

Currently, the preferred first-line regimen for locally advanced or metastatic SCAC is carboplatin plus paclitaxel. There are no approved second-line treatments in the metastatic setting. Thus, according to the drug's sponsor, Incyte, there is a clear unmet need for patients who progress on chemotherapy.

included 94 patients. In addition to the ORR of 14% (95% CI 8%-22%), the median estimated duration of response was 9.5 months, while median progression-free survival and overall survival were 2.3 and 10.1 months, respectively.

In presentations on Thursday, FDA staff explained the agency's reservations concerning the potential accelerated approval of the drug.

May Tun Saung, MD, a clinical reviewer at the Office of Oncologic Diseases, said the agency was uncertain that the observed ORR was "reasonably likely" to predict a clinical benefit, and cited a number of other limitations to the study and its findings:

• A small number of target lesions in the responding patients, with few patients having sustained responses lasting longer than 6 months
• The trial included few patients with HIV, and few ethnic or racial minorities
• While mostly well-tolerated, some patients experienced significant toxicity
• The safety data was limited by the fact that it was a single-arm trial

ODAC Chair Philip C. Hoffman, MD, of the University of Chicago, was one of the four dissenting votes. "What is true with checkpoint inhibitors in general is that the measurable response rates are often low," he said. "But some patients get a durable response."

Hoffman said he found statements from speakers during the public comment period -- all of which talked about the dire need for therapies for this disease -- to be compelling. "I think waiting 4 or 5 more years for the randomized trial is too long not to have something available to try for these patients," he said.

That confirmatory trial -- POD1UM-303 -- is an ongoing randomized, double-blind, placebo-controlled clinical trial investigating chemotherapy plus either retifanlimab or placebo. The primary endpoint is progression-free survival, and the trial is powered to demonstrate a 33% reduction in the PFS hazard ratio, with overall survival as a key secondary endpoint. The trial is scheduled to be completed in 2024, and reported in 2025.

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