Real-world outcomes of patients receiving salvage therapies for immune checkpoint inhibitor-resistant Merkel cell carcinoma: a rationale for future clinical trials
September 29, 2025
Journal
Journal for Immunotherapy of Cancer
Publication Date
September 29, 2025
Authors
Merkelcell.org Summary
Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer that spreads far beyond where it originally started in 3 in 10 patients, called advanced/metastatic MCC. The main treatment for advanced MCC is immunotherapy, a drug that boosts the immune system to better fight cancer. However, immunotherapy only works long-term for about 40% these of patients. It is unclear which treatments are best if immunotherapy stops working, also known as salvage therapies.
This study followed 106 MCC patients whose cancer grew/spread while receiving immunotherapy. They received other treatments, such as different immunotherapies, radiation, chemotherapy, or varying combinations of these. Patients were grouped into two types; patients with “primary resistance,” meaning their cancer never responded/shrank while on immunotherapy, and patients with “acquired resistance,” meaning their cancer responded positively at first, but later stopped responding.
Patients with acquired resistance lived longer than those with primary resistance. Adding radiation to immunotherapy when appropriate (radiation is not always possible because it depends on where and/or how much cancer there is) was the only salvage treatment regimen clearly linked to better survival after disease progression on immunotherapy. A group of 14 patients lived more than 3 years after their cancer returned, often with personalized treatment plans that combined different therapies.
Overall, this study shows that patients whose cancer comes back after immunotherapy face tough challenges and establishes baseline survival metrics that can be used in making future clinical trials. Some patients may benefit from combining treatments like immunotherapy and radiation, but new treatment strategies are still very much needed to help patients facing resistance to immunotherapy.
Abstract
Background: Merkel cell carcinoma is an aggressive skin cancer that progresses to advanced/metastatic disease in~40% of patients. First-line immune checkpoint inhibitors (ICI) that block the programmed cell death protein-1/programmed death-ligand 1 axis provide 3-year progression-free responses in only~40% of patients. The relative efficacy of salvage therapies in this setting is unclear.
Methods: In a prospectively enrolled single-center cohort, 106 patients had disease progression during or shortly after ICI and received at least one local or systemic salvage therapy. Baseline disease characteristics, treatments, and outcomes data were collected. Patients were stratified by primary resistance (no response to initial ICI) or acquired resistance (loss of ICI response after initial benefit). Primary outcomes were progression-free survival (PFS) and disease-specific survival (DSS). Associations between salvage therapies and outcomes were evaluated using Cox models with time-varying covariates for treatments and adjustments for disease burden and ICI resistance type.
Results: In this cohort, 44 patients (42%) met criteria for primary resistance and 31 (29%) had acquired resistance. Median PFS from salvage initiation was more than double for patients with acquired versus primary resistance (9.5 vs 4.7 months; p=0.006). Median DSS was not reached for acquired resistance and 14.3 months for primary resistance (p=0.006). A minority of patients (n=14) survived ≥3 years after salvage initiation, typically following customized, multimodal salvage strategies. Among salvage regimens (ICI alone, ICI+radiation therapy (RT), chemotherapy, chemotherapy+ICI), only ICI+RT had a statistically significant association with improved DSS relative to ICI alone (after adjustment, including disease burden and ICI resistance type: adjusted HR 0.35, 95% CI 0.14 to 0.91).
Conclusions: Patients with acquired resistance receiving salvage therapy have improved survival compared with those with primary resistance. While the addition of radiation to ICI was clearly associated with improved DSS, there continues to be a major need for new approaches to address ICI-resistant disease. Nevertheless, a durable benefit in select patients is possible via sequential, individualized, multidisciplinary treatments. We anticipate these data will be relevant for the design of clinical trials for this challenging ICI-resistant setting.
Keywords: Immune Checkpoint Inhibitor; Immunotherapy; Neuroendocrine and Adrenal Tumor; Radiotherapy/radioimmunotherapy; Relapse.
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