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, who is an Assistant Professor at the Medical University of South Carolina College of Pharmacy and an 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.

In June 2025, a brief report that was published on MCC in the veteran population looked at 312 VA Cancer Registry (VACR) patients with MCC and compared them with 3351 patients in the Surveillance, Epidemiology, and End Results (SEER) program, and noted older age and rural residence as more commonly seen in patients in VACR when compared with patients identified through SEER.²

The 5-year survival rate for MCC ranges from 40% to 70%, with the study of MCC in veterans, which included data from 2009 through 2017, before wider use of immunotherapy, demonstrating a 49.4% survival rate in SEER patients, compared with only 35% in veterans.² 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, as 5-year mortality in patients was 34.7% in the patients in the VACR compared with those in the SEER group at 21.7%.

It is because of morbidity and mortality rates like these that Maldonado 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, Maldonado noted.

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

For patients with unresectable or advanced disease, immunotherapy is “changing the game,” Maldonado added. Immune checkpoint inhibitors have dramatically improved outcomes for MCC patients. 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, 3 months; 5-year OS, approximately 26%
• Cohort B: Treatment-naïve patients: ORR, approximately 46%; 30%, durable responses >6 months
• OS trended higher in PD-L1–positive and virus-positive patients

4. Retifanlimab (PD-1 inhibitor)

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

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 + PD-1 blockade) may be considered, but with caution due to potentially increased toxicity.

In an email interview with this publication, Rebecca I. Hartman, MD, MPH, who is chief of dermatology, VA Boston Healthcare System and one of the authors on the VACR study, 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. JAAD. In press. June 7, 2025. www.jaad.org/article/S0190-9622(25)02242-X/abstract
3. Chang MS, La J, Trepanowski N, et al. Increased relative proportion of advanced melanoma among veterans: a comparative analysis with the Surveillance, Epidemiology, and End Results registry. 2022;87:27-29.

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