FDA’s ODAC Votes to Defer Approval of Retifanlimab for Patients With Locally Advanced or Metastatic SCAC

The FDA’s Oncologic Drug Advisory Committee voted 13 to 4 for the deferral of the FDA approval of retifanlimab for the treatment of patients with locally advanced or metastatic squamous carcinoma of the anal canal who have progressed on or who are intolerant of platinum-based chemotherapy, pending more research.

The FDA’s Oncologic Drug Advisory Committee (ODAC) voted 13 to 4 for the deferral of the FDA approval of retifanlimab (formerly MGA012) for the treatment of patients with locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) who have progressed on or who are intolerant of platinum-based chemotherapy, pending more research.

"The main take home point from the discussion were that the panel felt that the response rate of 14% in the POD1UM-202 study was simply too low to justify a regulatory decision at this time. There was a clear desire to offer more treatment options for patients with a rare cancer, but we will need to await the results of the confirmatory study before making any final decisions. There were no concerns regarding the safety of retifanlimab, said Christopher Lieu, MD, associate director for Clinical Research, co-Director, Gastrointestinal Medical Oncology, University of Colorado Medicine told Targeted Oncology, in an interview.

Retifanlimab has been granted orphan drug and fast track designations from the FDA for the proposed approval indication. In January of this year, the FDA also granted priority review to the biologics license application (BLA) for retifanlimab and set a target action date of July 25, 2021. But, oncologists are questioning whether the benefit of the agent in SCAC is substantial enough to warrant an FDA approval. Further, the data comes from a trial with no control arm.

According to Sandra J. Casak, MD, of the FDA’s Office of Oncologic Diseases, the data supporting retifanlimab show an “inconsistent relationship between low objective response rates (ORRs) observed in other single-arm studies with immune checkpoint inhibitors and clinical benefit in confirmatory studies.”

During an ODAC meeting, held on June 24, the panel discussed whether the ORRs and response durations observed with retifanlimab are clinically meaningful and can predict clinical benefit in patients with recurrent, advanced, or metastatic SCAC.

The BLA for retifanlimab is supported by findings from the phase 2 POD1UM-202 clinical trial (NCT03597295), in which retifanlimab induced durable responses in patients with previously treated locally advanced or metastatic SCAC. PODIUM-202 is a single-arm, open-label phase 2 study exploring the primary end point of ORR by independent central review and the secondary end points of duration of response (DOR) disease control rate (DCR), overall survival (OS), and progression-free survival (PFS).

A total of 94 patients who met the criteria for enrollment have been enrolled. Patients were required to be at least 18 years of age with confirmed locally advanced or metastatic SCAC, have disease progression on or after platinum-based therapy, as well as an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1. Patients with were HIV-positive were eligible to enroll given they had a CD4-positive count ≥ 300 cells/μL, undetectable viral load, and receiving antiretroviral therapy.

At baseline, the median age of the study population was 64 years (range, 37–94), and 65% of patients were female. In terms of race, the population was 77% White, 22% other or had missing information, and 1% Black or African American. Ten percent of the patients were known to be positive for HIV. The majority of those enrolled had an ECOG performance status of 1 (59%), and the most common prior treatment was platinum-based therapy (97%).

Other disease characteristics assessed at baseline showed current M1 staging for 82% of patients, and 70% had more than 1 metastatic focus. Liver metastases were found in 42% of patients, locoregional disease in 61%, and hypercalcemia in 12%.

In the 94 patients evaluated, the ORR was 13.8% (95% CI, 7.6-22.5) with the best overall response being a complete response in 1.1% of the population. Also, partial responses were observed in 12.8%, and stable disease was observed in 35.1%. Progressive disease was observed in 45.1% of patients and 5.3% were not evaluable for response. These results led to a DCR of 48.9%.

It was also noted that the responses were observed regardless of gender, age, race, HIV status, liver metastasis, and PD-L1 status. In addition, 46% of patients had a decrease in tumor burden from baseline. The median OS seen with retifanlimab in the study was 10.1 months, which was considered to be a favorable result.

“Taken as a whole, these data strongly suggest that the clinical benefits of retifanlimab were experienced by a large proportion of the PODIUM-202 study population, and they are consistent with what has been achieved with PD-1 inhibition and other refractory HPV-driven cancers, including cervical and head neck cancer where PD-1 inhibitors are already approved,” said Mark Cornfeld, MD, MPH, vice president, Immuno-Oncology Drug Development, Incyte Corporation, during the company’s presentation.

In the SCAC population, exposure to the agent occurred at a median of 85 days (range, 1-592) after a median of 4 infusions (range, 1-18). Treatment lasted for 6 months or more in 25% of patients and 12 months or more in 2%.

Fifty-nine percent of patients with SCAC in the study experienced a treatment-related adverse event (TRAE). Grade 3 or higher TRAEs were seen in 12% of patients and serious AEs were seen in 54%. Overall, treatment discontinuation occurred in 7% of patients, and 11% of patients experience a fatal AE. Regarding immune-related AEs, both endocrine and non-endocrine events were observed. The most common from each group was hypothyroidism and skin reactions, respectively. The safety observed with retifanlimab in PODIUM-202 was also considered to be acceptable in the HIV-positive population and in those with PD-L1 expression.

“PODIUM-202 provides a basis for decision making in these patients and clinicians are now routinely seeing more HIV-positive patients who continued their retroviral therapy during the study, and, in general, they fared quite well. The safety profile was consistent with the general population experience, and of note, there were no opportunistic infections reported in this group. Additionally, we did rigorous assessments of CD4 counts and viral load, and no patient experienced the loss of HIV control during the study. The safety profile of retifanlimab is acceptable in advanced anal cancer, and the wide variety of tumor types that we studied in our clinical development program,” said Cornfeld.

Following the positive results of PODIUM-202, a confirmatory study was created (POD1UM-303 /InterAACT 2; NCT04472429), which will be reported in 2025. The study is designed to assesses carboplatin and paclitaxel with retifanlimab, compared with placebo, in patients with locally advanced or metastatic SCAC.

The question raised to the voting members of ODAC was if a regulatory decision on retifanlimab for the treatment of advanced or metastatic SCAC should be deferred until more data are available from the confirmatory clinical trial. The FDA harbors uncertainty of whether PODIUM-202 can be used to support the approval of retifanlimab. When an approval is granted with uncertainty, a post-marketing confirmation of clinical benefit is required, but the FDA noted during their presentation the confirmatory PODIUM-303 has slow recruitment so far.

Before their vote, treating oncologists and members of advocacy groups gave their opinion on the issue during the open public hearing.

"It is my personal experience as an oncologist and my experience with retifanlimab that I speak today. I have treated a dozen of patients with SCAC, and one of those patients was a patient in the setting of HIV infection who benefitted from the drug, said May T. Cho, MD, associate professor of UI Oncology, UCI Health. “Generally, when my patients progressed following frontline platinum doublet therapy, I have been able to give them an investigative immunotherapy combination, off-label. My experience is that we don’t expect to get immunotherapy in the second-line setting, and I am encouraged by both safety and efficacy data for retifanlimab by positively treating patients, including patients with positive HIV status, as well as scientific presentation of this drug.”

Considering the presentation from the Incyte Corporation, the FDA, and the comments made by public, the panel voted to defer the approval of the drug currently slotted for July 25. During the discussion about the vote, there was a consensus that response were sufficient to indicate a meaningful improvement in survival and quality-of-life for these patient later on.


June 24, 2021: Meeting of the Oncologic Drugs Advisory Committee Meeting. FDA website. June 24, 2021. Accessed June 24, 2021. https://bit.ly/3vVaIef