ImportanceDespite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known.ObjectiveTo compare the safety and efficacy of dual checkpoint inhibitors with anti–programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM.Design, Setting, and ParticipantsIn this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti–cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM.InterventionsPatients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab.Main Outcomes and MeasuresThe main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered.ResultsAmong 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy.Conclusion and RelevanceIn this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.

中文翻译：

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新辅助双检查点抑制剂与抗 PD1 疗法治疗高风险可切除黑色素瘤

重要性尽管新辅助治疗具有明显的潜在益处，但高危可切除黑色素瘤（HRRM）患者的最佳新辅助治疗方案尚不清楚。 目的比较双检查点抑制剂与抗程序性细胞死亡蛋白-1（抗程序性细胞死亡蛋白-1）的安全性和有效性。 HRRM 患者的新辅助治疗中的 PD1）治疗。设计、设置和参与者在这项临床试验的汇总分析中，选择了研究免疫检查点抑制剂治疗的研究，这些研究于 2018 年 1 月至 2023 年 3 月期间发表，并且是 1 期， 2 或 3 项临床试验。分析中包含的参与者数据来自评估抗 PD1 单一疗法以及抗细胞毒性 T 淋巴细胞相关蛋白 4 与抗 PD1 组合在新辅助治疗中（特别是 HRRM 患者）的疗效和安全性的试验。接受过抗 PD1 单一疗法；双重检查点抑制（DCPI），常规剂量为 3 mg/kg ipilimumab 和 1 mg/kg nivolumab；或 DCPI 采用 1 mg/kg ipilimumab 和 3 mg/kg nivolumab 的替代剂量方案。 主要结果和测量主要结果是放射学完全缓解 (rCR)、放射学总体客观缓解 (rOOR) 和放射学进展性疾病。此外，还考虑了病理完全缓解 (pCR)、接受手术切除的患者比例以及 3 级或 4 级免疫相关不良事件 (irAE) 的发生率。 结果 在 6 项临床试验中入组的 573 名患者中，DCPI 新辅助治疗与与抗 PD1 单一疗法相比，实现 pCR 的几率更高（优势比 [OR]，3.16；磷< .001）。与抗 PD1 单一疗法相比，DCPI 与 3 级或 4 级 irAE 的发生率较高相关（OR，3.75；磷< .001）。将替代剂量易普利姆玛和纳武单抗 (IPI-NIVO) 方案与常规剂量 IPI-NIVO 进行比较时，未发现 rCR、rOOR、放射学进展性疾病或 pCR 方面存在统计学显着差异。然而，常规剂量 IPI-NIVO 方案与 3 级或 4 级 irAE 增加相关（OR，4.76；磷< .001）。常规剂量 IPI-NIVO 与实现改善 rOOR 的可能性更大相关（OR，1.95；磷= .046) 和 pCR (OR, 2.99;磷< .001) 与抗 PD1 单一疗法相比。 IPI-NIVO 的替代剂量也与实现 rCR 的较高几率相关（OR，2.55；磷= .03) 和 pCR (OR, 3.87;磷< .001) 与抗 PD1 单一疗法相比。常规剂量的 3 级或 4 级 irAE 风险较高（OR，9.59；磷< .001) 和替代剂量 IPI-NIVO 方案 (OR, 2.02;磷= .02) 与抗 PD1 单药治疗相比。结论和相关性在这项对 6 项临床试验的汇总分析中，尽管 DCPI 与实现病理和放射学缓解的可能性增加相关，但抗 PD1 治疗的 3 级或 4 级 irAE 的相关风险显着降低。 - HRRM 新辅助治疗中的 PD1 单一疗法。此外，与替代剂量 IPI-NIVO 相比，常规剂量的 IPI-NIVO 与 3 级或 4 级 irAE 风险增加相关，但放射学或病理学疗效没有显着差异。