Treatment Options After Avelumab Failure in Merkel Cell Carcinoma
After avelumab (Bavencio) failure in metastatic Merkel cell carcinoma, switch to alternative checkpoint immunotherapy with pembrolizumab or nivolumab as the next-line treatment, reserving cytotoxic chemotherapy only if immunotherapy is contraindicated or has definitively failed. 1
Algorithmic Approach to Post-Avelumab Treatment Selection
First Priority: Alternative Checkpoint Immunotherapy
Switch to anti-PD-1 agents (pembrolizumab or nivolumab) as the preferred next option after avelumab failure. 1 The NCCN guidelines explicitly recommend these agents for metastatic MCC, noting that while avelumab is the only FDA-approved checkpoint inhibitor for this indication, both pembrolizumab and nivolumab are included as recommended systemic therapy options. 1
Evidence Supporting Alternative Checkpoint Inhibitors:
Nivolumab demonstrated a 68% overall response rate in the CheckMate 358 trial, with responses observed in both treatment-naïve (71% ORR) and previously treated patients (63% ORR with 1-2 prior systemic therapies). 1
Pembrolizumab showed a 56% overall response rate in a phase II trial of patients with metastatic MCC, with response durations ranging from 2.2 to 9.7 months at early analysis. 1
Toxicity profiles are similar across all three checkpoint inhibitors (avelumab, pembrolizumab, nivolumab), with treatment-related adverse events occurring in 68-77% of patients and grade 3-4 events in only 5-21%. 1
Second Priority: Cytotoxic Chemotherapy (When Immunotherapy Fails)
Consider cytotoxic chemotherapy only after progression on checkpoint immunotherapy or when contraindications to immunotherapy exist. 1 The NCCN explicitly states that "use of cytotoxic therapies in this setting is discouraged unless the patient has contraindications to checkpoint immunotherapy or has experienced relapse or progression during or after previous treatment with checkpoint immunotherapy." 1
Specific Chemotherapy Regimens to Consider:
The following cytotoxic options have demonstrated activity in MCC, though responses are typically short-lived (median duration 2-9 months): 1
- Cisplatin with or without etoposide 1
- Carboplatin with or without etoposide 1
- CAV regimen (cyclophosphamide, doxorubicin or epirubicin, and vincristine) 1
- Topotecan 1
Important Chemotherapy Caveats:
Response rates decline with each line: First-line chemotherapy achieves 40-70% response rates, but second-line or subsequent chemotherapy drops to only 9-20%. 1
High toxicity burden: Toxic death rates range from 3-10%, with elderly patients at higher risk. 1
Poor durability: Median overall survival with second-line chemotherapy is only 4.4-5.7 months, compared to 12.9 months with avelumab in the same setting. 1
Third Priority: Clinical Trial Enrollment
Strongly consider enrollment in clinical trials testing targeted therapies (e.g., crizotinib) or novel checkpoint immunotherapies. 1 The NCCN emphasizes that "enrollment in clinical trials is encouraged whenever available and appropriate," particularly for trials testing therapies effective against other metastatic cancers like melanoma. 1
Critical Decision Points
When to Abandon Immunotherapy Entirely:
- Confirmed progression on two different checkpoint inhibitors (e.g., avelumab followed by pembrolizumab or nivolumab) 1
- Absolute contraindications to immunotherapy (active autoimmune disease requiring systemic immunosuppression, organ transplant recipients) 1
- Severe immune-related adverse events requiring permanent discontinuation 1
Common Pitfalls to Avoid:
Premature switch to chemotherapy: Don't abandon immunotherapy after avelumab failure alone—try an alternative anti-PD-1 agent first, as cross-resistance is not absolute. 1
Ignoring performance status: Chemotherapy carries 3-10% toxic death rates, particularly in elderly patients; ensure adequate performance status (ECOG 0-1) before initiating cytotoxic therapy. 1
Overlooking clinical trials: Given the poor outcomes with chemotherapy (median OS 4.4-5.7 months), clinical trial enrollment should be prioritized over standard chemotherapy. 1
Practical Implementation Strategy
Step 1: After confirmed progression on avelumab, initiate pembrolizumab or nivolumab if no contraindications exist. 1
Step 2: If progression occurs on second checkpoint inhibitor OR if immunotherapy is contraindicated, evaluate for clinical trial eligibility. 1
Step 3: If no trial available and patient has adequate performance status, consider platinum-based chemotherapy (cisplatin/carboplatin ± etoposide) or CAV regimen, with realistic expectations about limited durability. 1
Step 4: Monitor closely for treatment-related toxicities, particularly immune-related adverse events with checkpoint inhibitors and hematologic/renal toxicity with chemotherapy. 1