Citation
Miller DM, Sondak VK, Chandra S, Tchekmedyian V, Sullivan RJ, Merkin RD, Patel VA, Adamson AS, Brownell I, Drews RE, Khushalani NI, Bhatia S, Nghiem PT. Dual checkpoint blockade in Merkel cell carcinoma: Lessons from CheckMate 358 and the questions that remain. Journal of Cutaneous Oncology. Published June 14, 2025. doi:10.59449/joco.2025.06.14.
Why this article matters
PD-1 and PD-L1 monotherapy transformed the treatment of advanced Merkel cell carcinoma, but many patients never respond or eventually relapse. Dual checkpoint blockade with nivolumab plus ipilimumab offers a biologically compelling strategy to intensify immune activation, yet the prospective evidence remains inconsistent.
CheckMate 358 is the largest prospective study of nivolumab plus ipilimumab in immunotherapy-naïve advanced MCC. Its results provide critical context for a treatment already used in practice, while also challenging the assumption that adding CTLA-4 blockade necessarily improves frontline efficacy.
Dual checkpoint blockade is active in advanced MCC, but CheckMate 358 did not demonstrate a clear efficacy advantage over nivolumab monotherapy and showed greater toxicity. The regimen remains clinically relevant, but its value likely depends more on patient selection and treatment context than on a universal benefit from intensification.
CheckMate 358 at a glance
ICI-naïve patients
Twenty-five received nivolumab monotherapy and 43 received nivolumab plus ipilimumab.
Nivolumab versus combination
Overall response rates were similar across the two sequential, nonrandomized cohorts.
Higher toxicity with dual therapy
Severe treatment-related adverse events were more frequent with nivolumab plus ipilimumab.
What the study showed
- Both nivolumab and nivolumab plus ipilimumab produced durable responses.
- First-line response rates were higher than later-line response rates in both cohorts.
- The addition of ipilimumab did not produce a higher overall response rate.
- Progression-free and overall survival appeared numerically more favorable with nivolumab monotherapy.
- Toxicity and treatment discontinuation were more frequent with dual checkpoint blockade.
Why the comparison is difficult
The cohorts were not randomized
Nivolumab and combination therapy were enrolled sequentially, not concurrently, limiting any formal cross-arm comparison.
The treatment era changed
The combination cohort opened as PD-1 monotherapy was becoming standard care, potentially altering who entered the trial.
Baseline risk was imbalanced
Patients in the combination cohort had numerically more adverse prognostic features, including greater disease burden and more stage IV disease.
Rare-cancer samples remain fragile
Small cohorts produce wide uncertainty, making dramatic response rates difficult to distinguish from patient selection or random variation.
Reconciling conflicting prospective studies
A prior Moffitt–Ohio State study reported striking activity with nivolumab plus ipilimumab, including responses in all 13 immunotherapy-naïve patients treated without stereotactic radiation. CheckMate 358 reported a more moderate first-line response rate of 64% with the same broad strategy.
These studies should not be treated as direct competitors. They differed in design, sample size, enrollment period, patient mix, and availability of a monotherapy comparator. A Bayesian framework offers one way to integrate both datasets: early enthusiasm becomes a prior estimate, and the larger CheckMate 358 cohort updates that estimate toward a more calibrated range of likely efficacy.
Rather than choosing between an exceptionally optimistic small study and a more moderate larger cohort, evidence synthesis asks what both studies collectively imply. The result is not a single definitive response rate, but a probability distribution that preserves uncertainty while avoiding overreaction to either dataset.
Where dual checkpoint blockade may fit
- Patients with high tumor burden or rapidly progressive disease in whom clinicians seek greater upfront immune intensity.
- Patients with disease refractory to prior PD-1 or PD-L1 monotherapy, where standard alternatives remain limited.
- Selected fit patients who understand and accept the substantially greater toxicity burden.
- Situations in which a multidisciplinary team believes the potential incremental benefit justifies treatment risk.
- Clinical trials designed to clarify dose, sequence, biomarkers, and comparative effectiveness.
What clinicians reported
Dual checkpoint blockade had already entered real-world MCC practice before definitive comparative evidence emerged. Most surveyed clinicians had recommended nivolumab plus ipilimumab, particularly for high-burden or PD-1–refractory disease, but substantial variation remained in dosing, timing, and treatment intent.
- Toxicity was the most commonly cited barrier to broader use.
- Lack of high-level MCC-specific evidence remained a major concern.
- Insurance denial was less commonly reported than uncertainty about coverage outcomes.
- Most clinicians were aware that NCCN guidelines reference nivolumab plus ipilimumab as useful in certain circumstances.
- Guideline inclusion may support access but does not resolve optimal patient selection.
Nivolumab plus ipilimumab should not automatically replace PD-1 or PD-L1 monotherapy in the frontline setting. Its strongest role may be in carefully selected patients with aggressive disease or prior checkpoint resistance, where the possibility of additional activity is judged worth the added toxicity.
Authors
David M. Miller, Vernon K. Sondak, Sunandana Chandra, Vatche Tchekmedyian, Ryan J. Sullivan, Ross D. Merkin, Vishal A. Patel, Adewole S. Adamson, Isaac Brownell, Reed E. Drews, Nikhil I. Khushalani, Shailender Bhatia, and Paul T. Nghiem.