FDA slams Incyte's PD-1 over single-arm study, low response and trial deaths
The ever-growing PD-1 landscape could see a new entrant as an Incyte program is slated for an FDA decision next month. But first, the biotech will have to get through an adcomm Thursday, and briefing documents from the agency appear to cast doubt over how effective the candidate really is.
Atop the issues is whether or not the compound retifanlimab has enough data for an accelerated approval, after Incyte treated second-line patients with squamous carcinoma of the anal canal in a single-arm trial. Incyte’s study showed an overall response rate of just 14% among 94 patients, and the FDA says they’re unsure whether this would correspond to a clinical benefit in a larger, placebo-controlled trial.
The figure fell well short of the 25% rate Incyte told regulators they were seeking with the study, according to documents detailing the biotech’s September 2020 meeting. At that time, the FDA said the BLA package would be stronger with data from a bigger trial and noted an adcomm would be likely with just the one trial, but Incyte submitted their pitch two months later.
Regulators also raised concerns over the trial’s demographics, highlighting there was only one Black patient and four Hispanic or Latino patients. And given that HIV increases the risk of developing this specific cancer by about 15- to 35-fold, the FDA said it’s unclear how the program could affect these patients since only nine HIV-positive individuals took part in the study.
Much like other latecomer PD-1 players, Incyte is targeting an indication where the bigger names have yet to win approval. Efficacy data in the second-line setting for this cancer are limited and patients generally end up taking more chemotherapy if they progress after their first round of treatments.
Nonetheless, the FDA attempted to draw some cross-trial comparisons between Incyte and other small, experimental studies. Looking at trials testing Opdivo, Keytruda, and two different chemo regimens, regulators found ORRs between 17% and 33%, figures numerically higher than Incyte’s reported figure.
Among these trials, only Opdivo’s enrolled more than two dozen patients, with Bristol Myers Squibb having recruited 37 participants.
Generally speaking, the FDA said, checkpoint inhibitors using accelerated approval pathways with ORR as their primary endpoint have not gone on to confirm clinical benefit in bigger studies. Out of the 76 checkpoint inhibitor approvals granted by the agency, 35 were given an accelerated OK, the FDA said. Of those 35, nine of the 10 to fail confirmatory trials had previously used a single-arm study looking at ORR.
Those other drugs had been greenlit mainly due to their duration of response figures, but the FDA is uncertain over Incyte’s data here as well. While most other programs had prolonged responses lasting years, Incyte reported a median of only 9.5 months among the 13 responders.
There also appeared to be a dispute between how the FDA and Incyte interpreted the study’s safety data. In its report, Incyte says there was only one death connected to a side effect from the treatment, but regulators say there were 10 fatal treatment-related adverse events. The FDA said, however, that the safety profile was consistent with PD-1 therapies in other settings.
Whether Incyte’s next study is conducted to confirm an accelerated approval or if it’s part of a new package following a CRL, the company plans to read out data by the end of 2024.
Should retifanlimab win approval, analysts have said it likely won’t be a blockbuster. Truist’s Srikripa Devarakonda modeled peak worldwide sales in this particular disease at $43 million — although new indications such as lung cancer and Merkel cell carcinoma may push it to around $500 million. SVB Leerink, meanwhile, is projecting about $100 million in peak sales in 2030.