Ivetić Jelena, Dedeić Jovana, Milićević Srđan, Vidojević Katarina, Delić Marija
Faculty of Technical Sciences, University of Novi Sad, 21000 Novi Sad, Serbia.
J Clin Med. 2025 Jul 15;14(14):5017. doi: 10.3390/jcm14145017.
Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of metastatic melanoma. While combination regimens often demonstrate improved response and survival compared to monotherapy, they are also associated with a higher incidence of immune-related adverse events (irAEs). Understanding the balance between benefit and risk is essential for making informed treatment decisions, especially given the variability in reported outcomes across clinical trials. We conducted a systematic review and meta-analysis of 14 clinical trials (comprising 22 treatment arms and >5000 patients) comparing ICI monotherapy (nivolumab, ipilimumab, or pembrolizumab) and combination therapy (nivolumab + ipilimumab) in advanced melanoma. Treatment-related outcomes were synthesized using fixed-effects, random-effects, or generalized linear mixed models (GLMMs), depending on study variability. Survival data were extracted from published Kaplan-Meier curves and analyzed using longitudinal GLMMs to capture trends over time. Compared to monotherapy, combination immunotherapy achieved higher clinical benefit, with an overall response of 52.2% (vs. 31.6%), a five-year overall survival of 55.7% (vs. 34.3%), and a five-year progression-free survival of 39.0% (vs. 17.2%). However, this benefit came with a higher risk of toxicity: immune-related adverse events occurred in 93.2% of patients receiving combination therapy versus in 81.9% receiving monotherapy. Differences were consistent across all individual severe toxicities. Combination immunotherapy offers greater long-term clinical benefit than monotherapy in metastatic melanoma but at the cost of increased toxicity. By applying models adapted to study variability, we provide more reliable estimates of treatment efficacy and risk. GLMMs provide the most robust estimates and enable the modeling of survival dynamics over time. These findings support evidence-based decision-making and highlight the value of model-informed meta-analysis in oncology.
免疫检查点抑制剂（ICIs）重塑了转移性黑色素瘤的治疗格局。虽然与单药治疗相比，联合治疗方案通常显示出更好的反应和生存率，但它们也与更高的免疫相关不良事件（irAEs）发生率相关。了解获益与风险之间的平衡对于做出明智的治疗决策至关重要，尤其是考虑到各临床试验报告结果的差异。我们对14项临床试验（包括22个治疗组和超过5000名患者）进行了系统评价和荟萃分析，比较了晚期黑色素瘤中ICI单药治疗（纳武利尤单抗、伊匹木单抗或帕博利珠单抗）与联合治疗（纳武利尤单抗 + 伊匹木单抗）。根据研究的变异性，使用固定效应、随机效应或广义线性混合模型（GLMMs）综合治疗相关结果。生存数据从已发表的Kaplan-Meier曲线中提取，并使用纵向GLMMs进行分析以捕捉随时间的趋势。与单药治疗相比，联合免疫治疗获得了更高的临床获益，总体缓解率为52.2%（vs. 31.6%），五年总生存率为55.7%（vs. 34.3%），五年无进展生存率为39.0%（vs. 17.2%）。然而，这种获益伴随着更高的毒性风险：接受联合治疗的患者中有93.2%发生免疫相关不良事件，而接受单药治疗的患者中这一比例为81.9%。所有个体严重毒性的差异均一致。联合免疫治疗在转移性黑色素瘤中比单药治疗提供了更大的长期临床获益，但代价是毒性增加。通过应用适应研究变异性的模型，我们提供了更可靠的治疗疗效和风险估计。GLMMs提供了最稳健的估计，并能够对生存动态随时间进行建模。这些发现支持基于证据的决策，并突出了模型 informed 荟萃分析在肿瘤学中的价值。
