Introduction

Merkel cell carcinoma (MCC) is a rare, highly metastatic cutaneous neuroendocrine cancer that originates from specialized Merkel cells responsible for touch sensation in the skin. MCC often manifests as a firm, rapidly expanding nodule on sun-exposed skin areas1. MCC has a high mortality rate, with reported overall survival rates ranging from 14% for distant disease to 51% for local disease (https://www.jaad.org/article/S0190-9622(17)32755-X/fulltext). Advanced-age, immunocompromised, and fair-skinned individuals are the high-risk group2. This article aims to provide updated guidelines on the properties, dosing, and mechanism of action of U.S. Food and Drug Administration (FDA)-approved retifanlimab while discussing its use for the management of MCC.

Pathophysiology

MCC, a rapidly growing, erythematous skin cancer, is developed either through Merkel cell polyomavirus (MCV) or by ultraviolet (UV) radiation from prolonged sun exposure. MCV has been found to be a major causative agent of MCC.

MCV-positive MCC tumors arise from the integration of the viral genome into the host cell DNA, leading to the expression of viral oncoproteins3.

In contrast, MCV-negative MCC tumors are associated with chronic UV exposure, which causes DNA damage in the skin cells. This damage can eventually result in somatic mutations in tumor suppressors, including TP53 and RB1, that lead to the development of MCC4.

Current treatment Avelumab

Avelumab, the first FDA-approved drug for MCC in March 2017, is a human IgG1 monoclonal antibody. It possesses the ability to inhibit the PD-1/PD-L1 pathway, restoring the immune response against tumor cells. As the drug targets the body’s healthy cells, frequent adverse effects include immune-mediated and potentially fatal infusion-related reactions (https://go.drugbank.com/drugs/DB11945).

Pembrolizumab

Pembrolizumab, which received FDA approval in December 2018 for recurrent MCC, is also a monoclonal antibody targeting the PD-1 cell surface receptor (https://www.cancer.gov/news-events/cancer-currents-blog/2019/pembrolizumab-merkel-cell-carcinoma-fda-approval). Despite its potential suppressive effect on tumor size, some patients undergoing therapy developed infectious complications and cardiac failures5.

Another alternative to immunotherapy includes a first-line combination of nivolumab and ipilimumab for MCC but with significant toxic effects6. Chemotherapy was formerly thought to be the first line of treatment against MCC, but given the substantial risk of toxicities, it is now the final recourse. The therapy regimen often administered to patients includes a combination of platinum and etoposide7.

Retifanlimab as an adjunct therapy

Retifanlimab (Zynyz) was given accelerated FDA approval in March 2023 for the treatment of adults with metastatic or recurrent locally advanced MCC. The following decision was based on data obtained from the POD1UM-201 clinical trial (https://www.onclive.com/view/fda-approves-retifanlimab-for-metastatic-or-recurrent-locally-advanced-merkel-cell-carcinoma). This humanized IgG4κ antibody against programmed cell death receptor (PD)-1 functions as an immune checkpoint inhibitor. The binding of PD-L1 and PD-L2 with PD-1 on T cells is believed to suppress the immune system. Thus, the drug mainly acts by blocking PD-L from interacting with T-cell activation. Retifanlimab effectively shrinks tumor size in geriatric patients (65 years of age and older); however, further research is required for pediatric patients. The pharmacokinetic profile of retifanlimab was not substantially influenced by age, sex, body weight, race, renal function, and mild hepatic impairment. At a steady state, the drug’s half-life is 19 days, and its clearance is 0.24 l/day (https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761334s000lbl.pdf).

Clinical trials

The effectiveness of retifanlimab was assessed in research POD1UM-201 (NCT03599713), an open-label, multiregional, single-arm trial involving 65 patients with metastatic or recurrent locally advanced MCC who had not previously received systemic therapy for their progressive disease. For up to 24 weeks, or until disease progression or intolerable toxicity, study participants received a 500-mg dose of retifanlimab every 4 weeks. The objective response rate was 52% across all patients. Twelve patients (18%) experienced a full recovery, whereas 22 patients (34%) experienced a partial recovery. Response times ranged from 1.1 to 24.9 months; 76% of respondents reported responses lasting at least 6 months, and 62% reported responses lasting at least a year (https://clinicaltrials.gov/ct2/show/record/NCT03599713).

Recommended dosage and side effects

The recommended dosage of retifanlimab is 500 mg given as an intravenous infusion over 30 min every 4 weeks until the condition progresses, intolerable toxicity occurs, or up to 24 months have passed. The intravenous solution retifanlimab injection is sterile, free of preservatives, clear to slightly opalescent, colorless to pale yellow. A 20-ml solution containing 500 mg of retifanlimab is contained in each single-dose vial. Each milliliter (ml) contains 25 mg of retifanlimab, 0.18 mg of glacial acetic acid, 0.1 mg of polysorbate 80, 0.57 mg of sodium acetate, 90 mg of sucrose, and Water for Injection, USP (United States Pharmacopeia). The pH is 5.1 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761334s000lbl.pdf).

In the POD1UM-201 trial, 105 patients with metastatic or recurrent locally advanced MCC underwent safety evaluations of retifanlimab. The exposure length ranged from day 1 to 23 months, with a median of 5.6 months. Patients who received retifanlimab had a median age of 71 years (range: 38–90); 74% were over 65; 68% were men; 79% were white; 20% did not report their race; and 1% were Asian (https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761334s000lbl.pdf). Patients experienced serious adverse effects in 22% of cases. Fatigue, arrhythmia, and pneumonitis were the most common significant adverse effects, occurring in less than 2% of patients. 11% of patients had their use of retifanlimab permanently discontinued because of an adverse reaction. 25% of individuals had dosage interruptions because of a negative response. Increased transaminases, increased lipase, and increased amylase were the laboratory abnormalities that caused dosage interruption in less than 2% of patients. The side effects which affected the patients frequently (10%) were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-retifanlimab-dlwr-metastatic-or-recurrent-locally-advanced-merkel).

Conclusion

Retifanlimab offers a first-line response in patients with metastatic and recurrent locally advanced MCC by improving the body’s immune response. Retifanlimab immunotherapy resulted in a noteworthy objective response rate of 52% in the PODIUM-201 study. The drug showed promising results, especially in geriatric patients, making it an adjunct therapy for MCC. However, multiple large-scale trials are still needed to determine its efficacy over the already-present first-line treatment for MCC.

Ethical approval

Ethical approval was not required for this corresponding article.

Consent

Consent was not required for this corresponding article

Sources of funding

No funding relationship to disclose.

Author contribution

A.S.: conceptualization and project administration; A.K. and R.R.: writing – original draft of the manuscript; U.E.A.B.: writing – reviewing and editing the manuscript; A.M.: writing – reviewing and editing the manuscript.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest with regard to the content of this report.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Ayesha Shaukat.

Data availability statement

All data are publicly available through PubMed and online articles.

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