Evaluating the efficacy and safety of nivolumab and ipilimumab combination therapy compared to nivolumab monotherapy in advanced cancers (excluding melanoma): a systemic review and meta-analysis

Abstract Background Nivolumab (Nivo) and ipilimumab (Ipi) have revolutionized cancer treatment by targeting different pathways. Their combination shows promising results in various cancers, including melanoma, but not all studies have demonstrated significant benefits. A meta-analysis was performed to assess the effectiveness and safety of Nivo-Ipi compared to Nivo alone in advanced cancer types (excluding melanoma). Methods Following PRISMA guidelines, we conducted a meta-analysis up to September 30, 2023, searching databases for randomized controlled trials (RCTs). We focused on advanced solid malignancies (excluding melanoma) with specific Nivo and Ipi dosing. Primary outcomes were overall survival (OS), progression-free survival (PFS), grades 3–4 adverse events (AEs), and treatment-related discontinuations. Secondary outcomes included specific adverse events. Statistical analysis in Review Manager included hazard ratio (HR) and risk ratio (RR), assessing heterogeneity (Higgins I 2 ). Results Nine RCTs, involving 2152 patients covering various malignancies, were analyzed. The Nivo plus Ipi group exhibited a median OS of 12.3 months and a median PFS of 3.73 months, compared to monotherapy with 11.67 months and 3.98 months, respectively. OS showed no significant difference between Nivo and Ipi combination and Nivo alone ( HR = 0.97, 95% CI : 0.88 to 1.08, p = 0.61). PFS had a slight improvement with combination therapy ( HR = 0.91, 95% CI : 0.82 to 1.00, p = 0.04). Treatment-related cumulative grades 3–4 adverse events were higher with Nivo and Ipi ( RR = 1.52, 95% CI : 1.30 to 1.78, p < 0.00001), as were treatment-related discontinuations ( RR = 1.99, 95% CI : 1.46 to 2.70, p < 0.0001). Hepatotoxicity ( RR = 2.42, 95% CI : 1.39 to 4.24, p = 0.002), GI toxicity ( RR = 2.84, 95% CI : 1.44 to 5.59, p = 0.002), pneumonitis ( RR = 2.29, 95% CI : 1.24 to 2.23, p = 0.008), dermatitis ( RR = 2.96, 95% CI : 1.08 to 8.14, p = 0.04), and endocrine dysfunction ( RR = 6.22, 95% CI : 2.31 to 16.71, p = 0.0003) were more frequent with Nivo and Ipi. Conclusions Combining nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone in advanced cancers (except melanoma). However, it did show slightly better PFS at the cost of increased toxicity, particularly grades 3–4 adverse events. Specific AEs occurred more frequently in the combination group. Further trials are needed to fully assess this combination in treating advanced cancers.