What are the treatment options for Stage IV Merkel cell carcinoma?

Treatment Options for Stage IV Merkel Cell Carcinoma

Immune checkpoint inhibitors should be offered as first-line systemic treatment for patients with stage IV Merkel cell carcinoma, with avelumab being the FDA-approved option of choice. 1

First-Line Treatment Options

Immunotherapy

• Preferred first-line agents:
  • Avelumab - FDA-approved for metastatic MCC in adults and pediatric patients 12 years and older 2
  • Pembrolizumab - Included in NCCN guidelines as a recommended option 1, 3
  • Nivolumab - Included in NCCN guidelines as a recommended option 1

Checkpoint immunotherapies provide response rates similar to chemotherapy but with potentially greater durability of response, which is why they are now preferred over cytotoxic therapies 1. Among these three options, only avelumab has received FDA approval specifically for metastatic MCC 1, 2.

Important considerations for immunotherapy:

• Safety profiles for checkpoint immunotherapies differ significantly from cytotoxic therapies
• Clinician and patient education about immune-related adverse events is critical
• Common immune-related side effects include thyroiditis and hypothyroidism 4
• Patients with HIV have traditionally been excluded from clinical trials but case reports suggest potential benefit 4

Second-Line Options (for patients who fail immunotherapy)

Chemotherapy options:

For patients with contraindications to checkpoint immunotherapy or who have experienced progression during or after immunotherapy, cytotoxic therapies may be considered 1:

• Platinum-based regimens:
  • Cisplatin ± etoposide
  • Carboplatin ± etoposide
• Other options:
  • Topotecan
  • CAV regimen (cyclophosphamide, doxorubicin [or epirubicin], and vincristine)

Important caveat: While MCC is chemosensitive with response rates of 40-60%, responses are typically short-lived (2-9 months) and unlikely to offer lasting clinical benefit 1. First-line chemotherapy may have response rates up to 70%, but this drops to 9-20% in subsequent lines of therapy 1.

Emerging Treatment Approaches

Combination Immunotherapy

Recent research shows promising results with combined nivolumab plus ipilimumab:

• 100% objective response rate in immune checkpoint inhibitor-naïve patients
• 31% response rate in patients previously treated with checkpoint inhibitors
• 41% complete response rate in treatment-naïve patients 5

Combined Radio-Immunotherapy

• Case reports suggest that combining radiation therapy with immunotherapy may lead to complete clinical regression in some patients with stage IV disease 6
• Consider this approach for patients with oligometastatic disease or symptomatic lesions

Multidisciplinary Approach

The NCCN recommends multidisciplinary tumor board consultation for all patients with distant metastatic disease to consider management options 1:

1. Comprehensive imaging should be performed for all patients with metastatic disease
2. Clinical trial enrollment is preferred when available
3. Treatment modalities to consider:
   • Systemic therapy (immunotherapy preferred)
   • Radiation therapy (consider for symptomatic lesions)
   • Surgery (only in highly selective circumstances for oligometastasis or symptomatic lesions)
4. Best supportive care should be provided to all patients

Treatment Algorithm

1. First-line therapy: Immune checkpoint inhibitor (preferably avelumab as the FDA-approved option)
2. If contraindicated or progression occurs: Consider chemotherapy options
3. For oligometastatic or symptomatic disease: Consider radiation therapy or surgical resection
4. For patients who fail standard options: Consider clinical trials or combination approaches

Pitfalls to Avoid

1. Delaying immunotherapy in favor of chemotherapy as first-line treatment
2. Failing to monitor for immune-related adverse events during checkpoint inhibitor therapy
3. Not considering combination approaches for patients who fail monotherapy
4. Overlooking the potential benefit of local therapies (radiation, surgery) for symptomatic or oligometastatic disease
5. Toxic death rates of 3-10% have been reported with chemotherapy, with elderly patients at higher risk 1

Remember that management must be tailored based on the extent of disease, patient performance status, and comorbidities. The goal of treatment is to maximize quality of life while extending survival.