Advancing Merkel-Cell Carcinoma Treatment With Immunotherapy

Merkel-cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin cancer with rising incidence globally.

In a presentation at the Hematology/Oncology Pharmacy Association 2025 Annual Conference in Portland, OR, Andy Maldonado, PharmD, BCOP, Assistant Professor at the Medical University of South Carolina College of Pharmacy, and Oncology Pharmacy Specialist in the ambulatory care clinics at the Medical University of South Carolina Health Hollings Cancer Center in Charleston, discussed MCC and options for treating patients with this type of cancer.¹

Although rare, MCC incidence is increasing. In the United States, between 2006 and 2015, there were approximately 2000 new cases of MCC annually, with totals expected to exceed 3200 in 2025. An aging population, increased UV exposure, more frequent use of immunosuppressants, and improved diagnostic awareness are contributing to the increased diagnoses.

The 5-year survival rate for MCC ranges from 40% to 70%, while the recurrence rate is approximately 40%. Compared with basal-cell carcinoma (with >5 million cases yearly and <10% recurrence) and melanoma (≥100,000 cases yearly, <20% recurrence, and >90% 5-year survival), MCC stands out as both rarer and more lethal.

It is because of morbidity and mortality rates like these that Dr Maldonado noted that “it’s necessary to look in the future and see what’s on the horizon, because we don’t have a lot of options, unfortunately.”

Treatment Options

For early-stage disease, surgical resection is the primary treatment, often preceded by sentinel lymph node biopsy, and depending on nodal involvement, adjuvant radiation may be used, Dr Maldonado noted.

For locally advanced tumors, immunotherapy may help downstage disease before surgery, she said.

For patients with unresectable or advanced disease, immunotherapy is “changing the game,” Dr Maldonado added. Immune checkpoint inhibitors have dramatically improved outcomes for patients with MCC. Updated National Comprehensive Cancer Network guidelines recommend programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors as first-line treatment in advanced disease. Key agents include:

1. Nivolumab (PD-1 inhibitor)

• CheckMate 358: Phase 1/2 trial evaluating neoadjuvant nivolumab (240 mg on days 1 and 15, surgery on day 29)
  • More than 50% had >30% tumor shrinkage
  • Surgery was completed in ≥90% of patients
  • Grade 3/4 adverse events were <8%

2. Pembrolizumab (PD-1 inhibitor)

• KEYNOTE-017: Phase 2 study for treatment-naïve metastatic MCC
  • Overall response rate (ORR): Approximately 56% in initial cohort; 40% in full 116-patient cohort
  • Median progression-free survival, approximately 17 months
  • Three-year overall survival (OS), approximately 60%
  • Researchers noted no significant differences between virus-positive and virus-negative tumors

3. Avelumab (PD-L1 inhibitor)

• JAVELIN Merkel 200:
  • Cohort A: Previously treated patients: ORR, approximately 33%; median progression-free survival, approximately 3 months; 5-year OS, approximately 26%
  • Cohort B: Treatment-naïve patients: ORR, approximately 40%; 30%, durable responses >6 months
  • OS trended higher in PD-L1–positive and virus-positive patients

4. Retifanlimab-dlwr (PD-1 inhibitor)

• POD1UM-201: Phase 2 trial in treatment-naïve unresectable or metastatic MCC
  • Retifanlimab 500 mg intravenously every 4 weeks
  • ORR, approximately 46%; approximately 12% achieved complete response
  • Grade ≥3 adverse events: approximately 14%; grade 3 immune-related adverse events in <10%

Dr Maldonado noted that while half of patients have durable responses, the other half does not respond to anti–PD-1/PD-L1 therapy, so in these patients, ipilimumab plus nivolumab (CTLA-4 plus PD-1 blockade) may be considered, but with caution due to potentially increased toxicity.

In an email interview, Rebecca I. Hartman, MD, MPH, Chief of Dermatology, VA Boston Healthcare System, and one of the authors of a June 2025 report on MCC in the veteran population,² commented that she agrees that “immunotherapy has great potential in MCC.” While their study included data taken largely before immunotherapy was widely used, “PD-1/PD-L1 checkpoint inhibitors show objective response rates (ORR) of approximately 50% to 60% in first-line settings for MCC,” she said, adding that other published studies that she’s been involved with in veteran patients with melanoma noted “more pronounced increases in survival in stage IV patients in the VA in the era of immunotherapy compared with SEER. We hypothesize this could be due to demographic differences and/or access to therapy differences.”³

References

1. Maldonado A. Turning the tide: immunotherapy’s promise in the fight against Merkel cell carcinoma. Presented at: Hematology/Oncology Pharmacy Association (HOPA) 2025 Annual Conference. Portland, OR; April 9-12, 2025.
2. Kim DY, Huhmann L, Hippe DS, et al. Treatment and disease-specific survival differences among veterans with Merkel cell carcinoma. J Am Acad Dermatol. Published online June 7, 2025. www.jaad.org/article/S0190-9622(25)02242-X/abstract
3. Chang MS, La J, Trepanowski N, et al. Increased relative proportions of advanced melanoma among veterans: a comparative analysis with the Surveillance, Epidemiology, and End Results registry. J Am Acad Dermatol. 2022;87:72-79.

This article was generated in part with assistance from artificial intelligence.