下一代检查点组合：在高级、佐剂和新佐剂环境中优化基于PD-（L）1的治疗

摘要(中文译文)

程序性细胞死亡蛋白1（PD-1）和程序性死亡配体1（PD-L1）抑制剂是多种实体瘤治疗的基础组成部分，然而原发性和获得性耐药限制了相当比例患者的持久获益。本综述并未试图对每个疾病领域进行广泛调查，而是有意聚焦于三种肿瘤类型——肾细胞癌（RCC）、尿路上皮（膀胱）癌和非小细胞肺癌（NSCLC），在这些肿瘤中，基于PD-(L)1的联合治疗已产生最为成熟、最具实践相关性的证据，且该领域发展最为迅速。针对每种肿瘤，我们审视了联合治疗如何在晚期、辅助和新辅助/围手术期环境中被开发和定位，并将选定的交叉策略（双免疫检查点阻断、抗体药物偶联物、缺氧诱导因子[HIF]-2α抑制及其他联合伙伴）置于该疾病特异性背景中加以讨论。在RCC中，免疫检查点抑制剂（ICI）联合血管内皮生长因子受体（VEGFR）酪氨酸激酶抑制剂（TKI）的双药方案已成为确立的一线标准，辅助帕博利珠单抗是首个在肾切除术后改善无病生存期和总生存期的药物，而HIF-2α抑制剂贝组替凡已成为ICI/TKI治疗后的选择，同时正在疾病更早期阶段进行测试。在膀胱癌中，抗体药物偶联物恩诺单抗联合帕博利珠单抗已取代铂类化疗成为晚期疾病的一线治疗，围手术期度伐利尤单抗加入新辅助化疗可改善肌层浸润性疾病的無事件生存期和总生存期。在NSCLC中，新辅助和围手术期化疗免疫治疗方案现已显示出总生存获益，补充了已确立的晚期疾病和辅助治疗策略。我们还总结了失败的联合方案——最显著的是在致癌基因驱动的NSCLC中PD-(L)1阻断与EGFR或ALK TKI同步联合，以及III期抗TIGIT抗体——因为这些阴性结果与成功案例同样具有启发性。在RCC、膀胱癌和NSCLC中，下一代PD-(L)1联合方案正在重塑所有疾病阶段的治疗。获益幅度、相关生物标志物和毒性权衡因肿瘤类型和治疗环境而存在显著差异。成功的开发取决于合理的生物学依据、生物标志物指导的患者选择和审慎的毒性管理，且证据基础仍不均衡——从成熟的III期数据到早期信号——我们在全文中对此予以明确说明。

Abstract

Programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors are foundational components of therapy across many solid tumors, yet primary and acquired resistance limit durable benefit for a substantial proportion of patients. Rather than attempting a broad survey of every disease area, this review deliberately focuses on three tumor types in which PD-(L)1-based combinations have generated the most mature, practice-relevant evidence and in which the field is evolving most rapidly: renal cell carcinoma (RCC), urothelial (bladder) cancer, and non-small cell lung cancer (NSCLC). For each, we examine how combinations are being developed and positioned across the advanced, adjuvant, and neoadjuvant/perioperative settings, and we place selected cross-cutting strategies (dual checkpoint blockade, antibody-drug conjugates, hypoxia-inducible factor [HIF]-2α inhibition, and other partners) in that disease-specific context. In RCC, immune checkpoint inhibitor (ICI) plus vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) doublets are established first-line standards, adjuvant pembrolizumab is the first agent to improve both disease-free and overall survival after nephrectomy, and the HIF-2α inhibitor belzutifan has become a post-ICI/TKI option while being tested earlier in disease. In bladder cancer, the antibody-drug conjugate enfortumab vedotin combined with pembrolizumab has displaced platinum chemotherapy as first-line therapy for advanced disease, and perioperative durvalumab added to neoadjuvant chemotherapy improves event-free and overall survival in muscle-invasive disease. In NSCLC, neoadjuvant and perioperative chemoimmunotherapy regimens now demonstrate overall survival benefit, complementing established advanced-disease and adjuvant strategies. We also summarize combinations that have failed-most notably concurrent PD-(L)1 blockade with EGFR or ALK TKIs in oncogene-driven NSCLC, and anti-TIGIT antibodies in phase III-because these negative results are as instructive as the successes. Within RCC, bladder cancer, and NSCLC, next-generation PD-(L)1 combinations are reshaping treatment across all disease stages. The magnitude of benefit, the relevant biomarkers, and the toxicity trade-offs differ substantially by tumor type and by setting. Successful development depends on a sound biologic rationale, biomarker-informed patient selection, and careful toxicity management, and the evidence base remains uneven-ranging from mature phase III data to early signals-which we make explicit throughout.

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