A Retrospective Study of Ipilimumab Plus Nivolumab in Anti-PD-L1/PD-1 Refractory Merkel Cell Carcinoma

August 17, 2022


Journal of Immunotherapy

Publication Date

August 17, 2022


Shalhout SZ, Emerick KS, Kaufman HL, Silk AW, Thakuria M, Miller DM

Merkelcell.org Summary

More than half of patients with advanced MCC will not respond persistently to one of the FDA-approved immune therapies (pembrolizumab or avelumab). Addressing this need is the most pressing issue in our field. This study by Dr. Shalhout and colleagues, carried out in Boston, found that none of 13 patients with such immune therapy-resistant MCC who were treated with the standard but aggressive combination of nivolumab and ipilimumab experienced significant benefit from this powerful immune drug combination. Prior reports had suggested that 20-30% of such patients may benefit from this combination. While we believe a subset of such patients can benefit from ‘ipi-nivo’, the Shalhout study emphasizes the urgent need to develop more effective and ideally less toxic treatments for patients who do not respond to our approved immune therapies.


Merkel cell carcinoma (MCC) is a very rare but highly aggressive cutaneous neuroendocrine carcinoma and is associated with chronic exposure to ultraviolet light and the Merkel cell polyoma virus. The incidence rate of MCC is increasing and MCC is associated with high rates of recurrence and mortality. Immune checkpoint inhibitors (ICIs) offer durable responses and significant clinical benefit with 2 agents-avelumab (anti-PD-L1) and pembrolizumab (anti-PD-1)-currently approved by the U.S. Food and Drug Administration for the treatment of advanced MCC. Despite the advances in systemic therapy options for MCC, ~50% of patients with advanced MCC treated with ICI progress on therapy. There is a paucity of studies assessing second-line systemic therapy following primary/acquired resistance to ICIs. Current management in this setting remains a clinical challenge especially in trial ineligible patients. We evaluated objective response to ipilimumab plus nivolumab in metastatic MCC refractory to anti-PD-(L)1 therapy. Thirty-one percent of patients experienced a grade III or grade IV immune-related adverse event (irAE) due to ipilimumab plus nivolumab. No patients (0/13) achieved a complete or partial response via RECISTv1.1/irRECIST. Twenty-three percent (3/13) of patients achieved stable disease as the best overall response but progressed shortly thereafter. The median progression-free survival was 1.3 months (90% CI 1.1-1.5) from the initiation of ipi-nivo. The median overall survival was 4.7 months (95% CI 3-17). This study suggests limited, if any, clinical benefit of ipi-nivo in patients with advanced anti-PD-L1/anti-PD-1 refractory MCC.

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