Retifanlimab Adds FDA-Approved Option to Merkel Cell Carcinoma Treatment Landscape

With the 2023 FDA approval of retifanlimab-dlwr (Zynyz), which was supported by data from the phase 2 POD1UM-201 trial (NCT03599713), patients with Merkel cell carcinoma (MCC) gained a safe and effective treatment option with response durability and quality of life advantages compared with traditional chemotherapy-based approaches, according to Shailender Bhatia, MD.

“It’s nice to have multiple options available for our patients; there was a time in MCC [when] the only agent that we had access to outside of clinical trials was cytotoxic chemotherapy,” Bhatia said in an interview with OncLive®. “[Historically], chemotherapy has a very high response rate in patients with metastatic MCC, to the tune of [approximately] 60% in some retrospective series. [Unfortunately], those responses were not very durable. The median progression-free survival [PFS] in patients with chemotherapy was only [approximately] 3 to 4 months at best.”

Bhatia is a professor in the Clinical Research Division at Fred Hutch Cancer Center and a professor in the Division of Hematology and Oncology at the University of Washington, both in Seattle.

Retifanlimab is an IgG4 monoclonal antibody that targets PD-1.1 The agent received accelerated approval from the FDA in March 2023 for the treatment of adult patients with metastatic or recurrent locally advanced MCC.2 Updated data from POD1UM-201 presented during the 2023 European Society for Medical Oncology Congress demonstrated that the agent had clinically meaningful activity in chemotherapy-naive patients with advanced or metastatic MCC with a manageable safety profile.1

At the March 10, 2023, data cutoff, patients who received retifanlimab (n = 101) achieved an objective response rate (ORR) of 53.5% (95% CI, 43.3%-63.5%), including a complete response rate of 16.8%. At a median follow-up of 17.6 months (range, 1.1-38.7), the median duration of response (DOR) was 25.3 months (95% CI, 14.2-not estimable [NE]). The 6-, 12-, and 24-month DOR rates were 82% (95% CI, 68%-90%), 71% (95% CI, 57%-82%), and 56% (95% CI, 39%-69%), respectively. The disease control rate (DCR) was 59.4%.

“These responses were very durable,” Bhatia noted. “Many of these patients have continued to maintain their responses in my clinic. The response rates with retifanlimab and other [similar] agents are in the same range as chemotherapy, but the differentiating factor is that these responses are very durable.”

The median overall survival (OS) was not reached (95% CI, NE-NE) and the median PFS was 12.7 months (95% CI, 7.3-24.9). Data from a subgroup analysis revealed that retifanlimab was active across subgroups with the highest ORRs being reported in patients who were not White (n = 23; 69.6% [95% CI, 47.1%-86.8%]), those who were Hispanic or Latino (n = 26; 61.5% [95% CI, 40.6%-79.8%]), and those with advanced stage disease (n = 10; 60.0% [95% CI, 26.2%-87.8%]).

Patients who were positive for the MCC polyomavirus with a PD-L1 tumor proportion score (TPS) of less than 1% (n = 57) achieved an ORR of 43.9% (95% CI, 30.7%-57.6%); patients with a PD-L1 TPS of at least 1% (n = 15) experienced an ORR of 86.7% (95% CI, 59.5%-98.3%). These respective rates among patients who were MCC polyomavirus negative were 43.8% (95% CI, 19.8%-70.1%; n = 7/16) and 75.0% (95% CI, 19.4%-99.4%; n = 3/4).

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 91.1% of patients. Any-grade treatment-related TEAEs (66.3%), grade 3 or higher TEAEs (31.7%), grade 3 or higher treatment-related TEAEs (16.8%), any-grade serious TEAEs (25.7%), and any-grade serious treatment-related TEAEs (11.9%) also occurred. TEAEs leading to treatment discontinuation or death occurred at rates of 20.8% and 4.0%, respectively.

Any-grade and grade 3 or higher immune-related TEAEs were reported in 34.7% and 10.9% of patients, respectively. Any-grade immune-related adverse effects (irAEs) included skin reaction (9.9%), hypothyroidism (7.9%), and hyperthyroidism (5.9%). Grade 3 or higher irAEs consisted of skin reaction (2.0%), pneumonitis (2.0%), and adrenal insufficiency (1.0%).

“The safety profile of retifanlimab is similar to other drugs in this class, [such as] pembrolizumab [Keytruda], avelumab [Bavencio], and nivolumab [Opdivo],” Bhatia said. “MCC is generally considered to be a disease of more elderly [patients], and now we have great data [showing] that these immune checkpoint inhibitors, specifically PD-1/PD-L1 blocking monotherapy agents have very good safety and tolerability, even in an elderly population.”

POD1UM-201 Study Design

POD1UM-201 was an open-label, single-arm, multicenter trial that enrolled adult patients with MCC with distant metastatic disease or recurrent, advanced locoregional disease who were not amenable to surgery or radiation.1,3 Eligible patients also needed to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and available tumor tissue for central pathology review.

The study initially included arms for chemotherapy-refractory and -naive patients; enrollment was limited to chemotherapy-naive patients per an April 9, 2020, protocol amendment.1 All patients received 500 mg of intravenous retifanlimab over 60 minutes every 4 weeks on day 1 of each 28-day cycle. Treatment continued for up to 2 years or until disease progression, intolerable toxicity, patient withdrawal, loss to follow-up, death, or premature discontinuation for any other reason.

“Since the majority of the patients have responses [to retifanlimab] we had the happy problem of people continuing on treatment for a long time,” Bhatia explained. “As they continue treatment, the logistics start becoming a problem when patients have to come in every 2 or 3 weeks [with other agents]. After a while, it starts adding to the burden of care, not only on the provider side, but also the patient side. Our interest in exploring retifanlimab as an alternative agent was mostly driven by the reduced frequency of every 4 weeks.”

The primary end point was ORR per RECIST 1.1 criteria per independent central radiographic review.3 Secondary end points included DOR, DCR, PFS, OS, and safety. As of June 28, 2024, POD1UM-201 is completed.

“Retifanlimab appears to be similarly effective [compared with] other agents and, over time, the reduced frequency benefits start to add up,” Bhatia said. “If you look at many phase 1 trials of novel immunotherapies that are being tested, MCC is an outlier in terms of how it responds to those [agents]. [Although] it’s a severe cancer, there are certainly great opportunities to keep testing immunotherapies in this [disease].”

Inclusion criteria

• Diagnosis of MCC with distant metastatic disease or recurrent, advanced locoregional disease not amenable to surgery or radiation
• ECOG performance status of 0 or 1
• Measurable disease per RECIST 1.1
• Availability of tumor tissue (fresh or archival) for central pathology review
• Willingness to avoid pregnancy or fathering children based on protocol-defined criteria

N = 107

Arm 1 Chemotherapy Naive

IV retifanlimab 500 mg once every 4 weeks

Arm 2 Chemotherapy Refractory

IV retifanlimab 500 mg once every 4 weeks

End points

Primary

• ORR per RECIST 1.1 by ICR

Secondary

• DOR
• DCR
• PFS
• OS
• TEAEs
• First-dose Cmax of retifanlimab
• First-dose Cmin of retifanlimab
• First-dose AUC0-t of retifanlimab

AUC0-t, area under the plasma concentration-time curve from time zero to time t; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration over the dose interval; DCR, disease control rate; DOR, duration of response; ICR, independent central radiographic review; MCC, Merkel cell carcinoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TEAE, treatment-emergent adverse effect.

References

1. Grignani G, Rutkowski P, Lebbe C, et al. Updated results from POD1UM-201: a phase II study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC). Ann Oncol. 2023;34(suppl 2):S686. doi:10.1016/j.annonc.2023.09.2280
2. FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma. FDA. March 22, 2023. Accessed March 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-retifanlimab-dlwr-metastatic-or-recurrent-locally-advanced-merkel
3. A study of INCMGA00012 in metastatic Merkel cell carcinoma (POD1UM-201). ClinicalTrials.gov. Updated October 15, 2024. Accessed March 10, 2025. https://clinicaltrials.gov/study/NCT03599713