In a 13 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee chose to hold off on a decision regarding accelerated approval for retifanlimab for the treatment of patients with locally advanced or metastatic squamous carcinoma of the anal canal who have progressed on or are intolerant of platinum-based chemotherapy.
In a 13 to 4 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) chose to hold off on a decision regarding accelerated approval for retifanlimab (INCMGA 0012) for the treatment of patients with locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) who have progressed on or are intolerant of platinum-based chemotherapy.1
Incyte, the developer of retifanlimab, submitted a biologics license application to the FDA seeking approval for the investigational, humanized, proprietary anti–PD-1 monoclonal antibody in January 2021, citing data from the single-arm POD1UM-202 trial (NCT03597295).
Committee members said it would be “premature” to issue a ruling based on the available data, preferring to wait for results from a randomized clinical trial before making a decision.
“I believe strongly in trying to find better treatments for rare diseases,” said Pamela L. Kunz, MD, a professor of medicine at Yale University School of Medicine, and an ODAC committee member. “However, I also share the concern about the low total number of respondents and the low response rate. I also have some concerns about lack of applicability to a broader population given the lack of diversity of this particular patient group.”
In January 2021, the FDA granted a priority review designation to retifanlimab, based on data from POD1UM-202 (N = 94), which were initially released at the 2020 ESMO Virtual Congress.2,3
Results showed that retifanlimab induced an objective response rate (ORR) of 13.8% (95% CI, 7.6%-22.5%) per independent central review using RECIST v1.1 criteria, with 1 complete response and 12 partial responses. The median duration of response (DOR) was 9.5 months.
“The tumor control was quite durable, in some cases exceeding 1 year, as is typical with immunotherapy,” said Mark Cornfeld, MD, MPH, Incyte’s vice president of immuno-oncology, during the ODAC hearing. “Notably, all of the responding patients were still alive at the time of the primary analysis, which suggests that a survival benefit may emerge in randomized studies.”
Investigators enrolled 94 adults with confirmed locally advanced or metastatic SCAC into the open-label, single-arm, multicenter, phase 2 trial. Eligible patients experienced progressive disease on or following platinum-based chemotherapy.
All patients were assigned to 500 mg retifanlimab once every 4 weeks as part of a 28-day treatment cycle for up to 2 years. The primary end point of the trial was ORR by independent central review and RECIST v1.1 criteria.
The median age of study participants was 64 years, 61% were female, and 77% were White. Fifty-nine percent of patients had an ECOG performance status of 1, 10% had known HIV positivity, and 42% had liver metastases. Seventy-three percent of patients received prior chemoradiation, 17% had prior radiation therapy, and 97% had previously received platinum-based treatment.
Regulators struggled to see how the results could be expanded to a larger population. Not only was the ORR relatively low, but the trial included a single Black patient, no Asian patients, and only 4 Hispanic or Latino patients. Furthermore, only 9 HIV-positive patients were included in the trial even though the virus is a known risk factor for anal cancer—compared with the general population, the incidence rate for anal cancer is 30 times greater in HIV-infected patients.4
Responses were observed irrespective of gender, race, PD-L1 status, or presence of liver metastasis. The ORR was 22.2% (95% CI, 2.8%-60.0%) among HIV-positive patients compared with 12.9% (6.6%-22.0%) for those who were HIV-negative.
Study co-author Marwin Fakih, MD, a professor in the Department of Medical Oncology & Therapeutics Research and Medical Director, Judy & Bernard Briskin Center for Clinical Research at City of Hope, pushed for approval of retifanlimab, citing the clear unmet medical need in SCAC. Currently, there are no approved treatments for patients who have progressed on platinum-based chemotherapy and incidence of SCAC has increased at approximately 3% per year over the past decade. Moreover, clinical trial data will not be available for several years.
“The POD1IUM-202 data supports accelerated approval of retifanlimab. Retifanlimab demonstrates meaningful activity…with outcomes that align with expectations for other PD-1 inhibitors in HPV-driven malignancies,” Fakih said. “Importantly, patients urgently need this treatment to be approved by the FDA since access to off-label therapy is limited.
“[A] retifanlimab accelerated approval affords us an opportunity to make a PD-1 inhibitor accessible to patients in need, who cannot afford to wait until 2025.”
Committee members were sensitive to the lack of options for patients with SCAC. Committee chair Phillip C. Hoffman, MD, professor of medicine in the Section of Hematology/Oncology at The University of Chicago, voted to move forward with the approval, saying that these patients can’t afford to wait 4 or 5 years for clinical trial results.
“We know the response rate is very low, certainly inferior to what was expected,” said Massimo Cristofanilli, MD, associate director of translational research and precision medicine at the Robert H. Lurie Comprehensive Cancer Center. “We just need a randomized study to really prove that this drug, a PD-L1 inhibitor, together with chemotherapy definitely will impact long-term outcome for these patients. We all understand that these patients need better treatment.”
Incyte has already enrolled 32 patients into the confirmatory POD1UM-303/InterAACT 2 clinical trial (NCT04472429), results of which are expected in late 2025.