尽管Nivolumab与Ipilimumab的联合治疗在晚期黑色素瘤中比Nivolumab单药疗法无疑有益，但目前还没有综合分析将该联合疗法与晚期非黑色素瘤癌其他类型的Nivolumab单药疗法进行比较。本研究的目的是检验Ipilimumab与标准剂量Nivolumab的加入是否安全地改善非黑色素瘤晚期癌症患者的临床结果。系统地检索了PubMed、EBSCO Information Services、Embase和Cochrane Library等电子数据库中发表的有关晚期非黑色素瘤癌（截至2022年10月31日）的标准剂量Nivolumab与Ipilimumab联合治疗与Nivolumab单药治疗的研究。符合选择标准的共有8项研究（患者总数1727人；Nivolumab与Ipilimumab组854人；Nivolumab单药治疗组873人）。被纳入研究的患者主要患有鳞状细胞肺癌、非小细胞肺癌，且有1%或更高程度的程序性细胞死亡配体1水平、小细胞肺癌、胸膜间皮瘤、膀胱尿路上皮癌、食管胃癌、肉瘤或胶质母细胞瘤。为比较总生存期（OS）和无进展生存期（PFS）的疗效，首先根据从每个研究的总结统计数据中提取的Kaplan-Meier曲线的摘要统计，对每个纳入研究的OS和PFS进行了危害比（HR）及SE的估计。然后，使用逆方差加权法计算了汇总的HR（95% CI）。对于二分数据（与治疗相关的3-4级不良事件和中断治疗），使用了比值比（OR），并使用Mantel-Haenszel方法估计了汇总的OR（95% CI）。与Nivolumab单药治疗相比，Nivolumab与Ipilimumab联合治疗与OS改善无关（HR汇总为0.95；95% CI为0.85-1.06；P = .36），其中8项研究中有4项中位数OS较低。与Nivolumab单药治疗相比，Nivolumab与Ipilimumab联合治疗在PFS改善方面具有轻微但无临床意义的优势（HR汇总为0.88；95% CI为0.79-0.98；P = .02）。与该联合疗法相关的3-4级不良事件（OR汇总为1.84；95% CI为1.47-2.31；P < .001）及中断治疗（OR汇总为1.96；95% CI为1.44-2.65；P < .001）明显增加。这一发现在肝毒性、胃肠道毒性、肺炎、内分泌功能障碍、皮炎和疲劳等各个3-4级不良事件的亚组分析中得到重复。在这8项非黑色素瘤的综合分析中，Nivolumab与Ipilimumab联合治疗与Nivolumab之间在OS和PFS方面的差异虽然具有统计学意义，但临床上并无实际意义。与该联合疗法相关的较高级别毒性和中断治疗明显更高。数据表明，对于非黑色素瘤晚期癌症，研究应该结合抗PD-1单抗疗法开展抗PD-1联合抗CTLA-4疗法，以明确抗CTLA-4的添加对其疗效产生的净效应，并避免不必要的CTLA-4抑制与相关的毒性副作用（无论是临床上还是经济上）。

Although the combination of nivolumab plus ipilimumab has unquestionable benefit over nivolumab monotherapy in advanced melanoma, currently no summative analyses have compared the combination with nivolumab monotherapy for advanced cancers other than melanoma.To examine whether the addition of ipilimumab to standard-dose nivolumab safely improves clinical outcomes in patients with advanced cancers other than melanoma.Electronic databases (PubMed, EBSCO Information Services, Embase, and Cochrane Library) were systematically searched for studies of standard-dose nivolumab plus ipilimumab vs nivolumab alone in the treatment of advanced cancers other than melanoma published from database inception to October 31, 2022.Eight studies (total patients, 1727; nivolumab plus ipilimumab group, 854; nivolumab monotherapy group, 873) met the selection criteria. Patients had squamous cell lung cancer, non-small cell lung cancer with programmed death ligand 1 level of 1% or higher, small cell lung cancer, pleural mesothelioma, urothelial carcinoma, esophagogastric carcinoma, sarcoma, or glioblastoma multiforme.For comparison of overall survival (OS) and progression-free survival (PFS) outcomes, estimation of log(hazard ratios [HRs]) and SEs was initially performed for OS and PFS of each included study based on summary statistics extracted from individual Kaplan-Meier curves. Inverse-variance weighting was then used to compute pooled HRs (95% CIs). For comparison of dichotomous data (treatment-related grade 3 to 4 adverse events and discontinuations), odds ratios (ORs) were used, and the Mantel-Haenszel method was used to estimate pooled ORs (95% CIs).Treatment with nivolumab plus ipilimumab was not associated with improvement in OS over treatment with nivolumab alone (pooled HR, 0.95; 95% CI, 0.85-1.06; P = .36), with 4 of the 8 studies having numerically lower median OS with the combination. Nivolumab plus ipilimumab combination therapy was associated with marginal, but not clinically meaningful, improvement in PFS over nivolumab alone (pooled HR, 0.88; 95% CI, 0.79-0.98; P = .02). The combination was associated with substantially higher treatment-related grade 3 to 4 adverse events (pooled OR, 1.84; 95% CI, 1.47-2.31; P < .001) and treatment-related discontinuations (pooled OR, 1.96; 95% CI, 1.44-2.65; P < .001). This finding was recapitulated in meta-analyses of individual grade 3 to 4 adverse events of hepatotoxicity, gastrointestinal toxicity, pneumonitis, endocrine dysfunction, dermatitis, fatigue.In this meta-analysis of 8 advanced cancers other than melanoma, the differences detected in OS and PFS between nivolumab plus ipilimumab and nivolumab were not clinically meaningful (even though statistical significance was detected in PFS). Treatment-related higher-grade toxicity and discontinuations were substantially higher with the combination therapy. The data indicate that investigations of anti-programmed death 1 (PD1) plus anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies in any nonmelanoma advanced cancer should be conducted along with anti-PD1 monotherapy to ensure that the net effect of the addition of anti-CTLA-4 to anti-PD1 can be clearly established for that cancer and setting and that unnecessary CTLA-4 inhibition with related toxic effects (both clinical and financial) can be avoided.