First-line ipilimumab plus nivolumab in advanced merkel cell carcinoma: a meta-analysis of prospective trials and real-world validation cohort

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BACKGROUND: Advanced Merkel cell carcinoma (MCC) has a high response rate to immune checkpoint blockade (ICB). While early phase studies have demonstrated activity of dual ICB with anti-PD-1 plus anti-CTLA-4 agents in both the first- and second-line settings, the role of combination therapy as a first-line approach remains controversial. METHODS: We conducted a systematic review and meta-analysis to summarize the current evidence of first-line ICB therapy in MCC and to compare the pooled objective response rate (ORR) between combination ICB and monotherapy. Pooled ORRs were estimated using fixed-effects meta-analyses, and these results were statistically compared between combination ICB and monotherapy. In addition to the meta-analysis and as real-world validation, we performed a retrospective chart review of MCC patients treated with first-line combination ICB at a single referral center. RESULTS: In the meta-analysis, the pooled ORR of ipilimumab plus nivolumab was significantly higher than that of either anti-PD(L)1 monotherapy when considering all anti-PD-1 and anti-PD-L1 agents (81.0% vs. 49.6%, p = 0.0001) as well as monotherapy when restricted to anti-PD-1 agents (81.0% vs. 57.0%, p = 0.0043). Concordant with pooled trial findings, we identified eight patients treated off protocol with first-line combination ICB at our institution, with seven (87.5%) achieving objective response. DISCUSSION: Based on meta-analysis of clinical trial data, first-line treatment of advanced Merkel cell carcinoma with ipilimumab plus nivolumab results in a higher objective response rate compared to monotherapy. The clinical decision to select combination therapy over monotherapy must weigh this response rate benefit with the unknown survival benefit and higher toxicity.

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