The U.S. Food and Drug Administration (FDA) has approved retifanlimab-dlwr (Zynyz™, Incyte)*, a humanized monoclonal antibody targeting programmed death receptor-1 (PD-1), for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC).
The Biologics License Application (BLA) for retifanlimab for this indication has been approved under accelerated approval by the FDA based on tumor response rate and duration of response (DOR). Continued approval of retifanlimab for this indication may be contingent on verification and description of clinical benefit in confirmatory trials.
Merkel cell carcinoma is a rare and aggressive type of skin cancer that frequently appears as a single, painless, reddish-purple skin nodule on the head, neck and arms in skin exposed to sunlight . The disease tends to grow quickly and has a high rate of metastatic disease, leading to a poor prognosis.  The estimated five-year overall survival (OS) rate is 14% in patients with Merkel cell carcinoma who present with distant metastatic disease. 
Merkel cell carcinoma impacts less than 1 per 100,000 people in the U.S., but incidence rates are rapidly rising, especially in adults over the age of 65 
Retifanlimab was previously developed by MacroGenics and licensed to Incyte pursuant to an exclusive global collaboration and license agreement in October 2017.
The agent is a a humanized, hinge-stabilised, IgG4κ monoclonal antibody that recognizes human PD-1 and contains a human IgG4 Fc domain to limit effector function while retaining neonatal Fc receptor binding to extend circulating half-life. Tye drug is designed to target PD-1-expressing cells, including T-cells, and restore their effector function by blocking checkpoint inhibitory interactions between PD-1 and its 2 ligands, PD-L1 and PD-L2
In the United States, the intravenous PD-1 inhibitor is indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” said Shailender Bhatia, MD, University of Washington and Fred Hutchinson Cancer Center.
“The approval of retifanlimab offers healthcare providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease, and I look forward to having retifanlimab in our treatment portfolio for these difficult-to-treat patients.”
The FDA approval was based on data from the POD1UM (PD1 Clinical Program in Multiple Malignancies) clinical trial program, which includes the POD1UM-201 and several other Phase 1, 2 and 3 studies for patients diagnosed with solid tumors, including the registration-directed POD1UM trials evaluating retifanlimab as a monotherapy for patients with microsatellite instability-high endometrial cancer and squamous cell carcinoma of the anal canal (SCAC); and in combination with platinum-based chemotherapy for patients with non-small cell lung cancer and SCAC.
The POD1UM-201 trial, an open-label, multi-regional, single-arm study that evaluated retifanlimab in adults with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy for their advanced disease. Among chemotherapy-naïve patients (n=65).
Patients received retifanlimab 500 mg intravenously every four weeks until disease progression, unacceptable toxicity, for up to 24 months. Tumor response assessments were performed every eight weeks for the first year of therapy and 12 weeks thereafter.
The primary endpoint of the study was objective response rate (ORR) as determined by independent central radiographic review using RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS); safety and pharmacokinetics.
Retifanlimab monotherapy resulted in an objective response rate (ORR) of 52% (95% confidence interval [CI]: 40-65) as determined by independent central review (ICR) using RECIST v1.1. Complete response was seen in 12 patients (18%), and 22 patients (34%) showed partial response. Among the responding patients, the duration of response (DOR) ranged from 1.1 to 24.9+ months, and 76% (26/34) experienced a DOR of six months or longer, and 62% (21/34) experienced a DOR of 12 months or longer by landmark analysis.
Serious adverse reactions occurred in 22% of patients receiving retifanlimab. The most frequent serious adverse reactions (≥ 2% of patients) were fatigue, arrhythmia and pneumonitis. Permanent discontinuation of retifanlimab due to an adverse reaction occurred in 11% of patients. The most common (≥10%) adverse reactions that occurred in patients receiving retifanlimab were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia and nausea.
“Retifanlimab offers patients and healthcare professionals an additional first-line anti-PD-1 option for patients with metastatic or recurrent locally advanced MCC, which can be a challenging and aggressive disease to treat,” said Hervé Hoppenot, Chief Executive Officer, Incyte.
“Incyte is grateful to the investigators and patients around the world who participated in the POD1UM-201 trial. We continue to study the potential of retifanlimab in additional tumor types and in combination with other Incyte pipeline compounds.”
Following the approval of retifanlimab, MacroGenics will receive a US $ 15 million milestone payment from Incyte.
“The FDA approval of retifanlimab represents the third approval of a product originating from MacroGenics’ pipeline of proprietary or partnered product candidates,” noted Scott Koenig, M.D., Ph.D., President and Chief Executive Officer of MacroGenics.
“We are delighted that with the approval of retifanlimab, there is now an additional option for treating patients with Merkel cell carcinoma, a rare and aggressive type of skin cancer. We also look forward to Incyte’s continued progress in advancing their development of retifanlimab across additional indications and geographies.”
Under the terms of the license agreement, beyond the US $ 15 million approval milestone, MacroGenics is also eligible to receive up to a total of US $ 320 million in potential remaining development and regulatory milestones and up to US $ 330 million in potential commercial milestones from Incyte. In addition, MacroGenics is eligible to receive tiered royalties of 15% to 24% on any global net sales of the product. Finally, MacroGenics has an agreement with Incyte under which it manufactures a portion of Incyte’s global commercial supply of retifanlimab.
Note: * Retifanlimab is marketed by Incyte in the U.S. In 2017, Incyte entered into an exclusive collaboration and license agreement with MacroGenics for global rights to retifanlimab.
A Study of INCMGA00012 in Metastatic Merkel Cell Carcinoma (POD1UM-201) –NCT03599713
Highlights of Prescribing information
Retifanlimab-dlwr (Zynyz™, Incyte) [Prescribing Information]
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 Paulson KG, Bhatia S., et al. Advances in Immunotherapy for Metastatic Merkel Cell Carcinoma: A Clinician’s Guide. JNCCN. 2018;16(6):782-790.
 Harms KL, et al. Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System. Ann Surg Oncol. 2016;23:3564-3571.
 Jacobs D, et al. Assessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States. JAMA Dermatol. 2021;157:59–65.
 Paulson KG, et al. Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018;78:457–463.e2
Featured image: Immunofluorescent staining of Merkel cell carcinoma tumor tissue illustrating expression of CD200 (green) on the surface of tumor cells. CD200 plays a role in immunosuppression. The endothelial marker CD31 (red) highlights blood vessels. Merkel cell carcinoma is a rare and aggressive skin cancer. Photo courtesy: © 2014 Isaac Brownell, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH Bethesda, Maryland, USA. Used with permission.