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Abstract：
BACKGROUND: There is a significant gap in the literature concerning the effective management of second-line therapy for patients with metastatic renal cell carcinoma (RCC) who have received immune checkpoint inhibitors (ICIs). Most of the published articles were small multicenter series or phase 2 studies. To our knowledge, a systematic review that comprehensively outlines the range of treatment options available for patients with metastatic RCC who do not respond to first-line ICIs has not yet been conducted. Our aim was to synthesize evidence on second-line therapies for patients with metastatic RCC after initial treatment with ICIs and to offer recommendations on the best treatment regimens based on the current literature.
METHODS: We conducted a search in PubMed, Embase, and the Cochrane Library on 29 February 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We selected articles that met the predetermined inclusion criteria (written in English, retrospective observational studies, prospective series, and randomized trials reporting second-line therapy for metastatic RCC after failure of ICI-based therapy). Relevant articles were identified in the reference lists. The main endpoint was the overall response rate (ORR), with the median progression-free survival (PFS) and overall survival (OS) as secondary endpoints.
RESULTS: We included 27 studies reporting the outcomes of 1970 patients. Salvage therapies were classified as targeted therapy (VEGFR TKIs) in 18 studies and ICIs in 8 studies. In studies where TKIs were the second line of choice, the pooled ORR was 34% (95% CI: 30.2-38%). In studies where ICIs, alone or in combination with TKIs, were used as second-line therapies, the ORR was 25.7% (95% CI: 15.7-39.2%). In studies where TKIs and ICIs were the second-line choices, the pooled median PFS values were 11.4 months (95% CI: 9.5-13.6 months) and 9.8 months (95% CI: 7.5-12.7 months), respectively.
CONCLUSIONS: This systematic review shows that VEGFR TKIs and ICIs are effective second-line therapies following an initial treatment with anti-PD(L)1 alone or in combination. The treatment choice should be personalized, taking into account the patient\'s response to first-line ICIs, the site of the disease, the type of first-line combination (with or without VEGFR TKIs), and the patient\'s overall condition.
METHODS: We conducted a search in PubMed, Embase, and the Cochrane Library on 29 February 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We selected articles that met the predetermined inclusion criteria (written in English, retrospective observational studies, prospective series, and randomized trials reporting second-line therapy for metastatic RCC after failure of ICI-based therapy). Relevant articles were identified in the reference lists. The main endpoint was the overall response rate (ORR), with the median progression-free survival (PFS) and overall survival (OS) as secondary endpoints.
RESULTS: We included 27 studies reporting the outcomes of 1970 patients. Salvage therapies were classified as targeted therapy (VEGFR TKIs) in 18 studies and ICIs in 8 studies. In studies where TKIs were the second line of choice, the pooled ORR was 34% (95% CI: 30.2-38%). In studies where ICIs, alone or in combination with TKIs, were used as second-line therapies, the ORR was 25.7% (95% CI: 15.7-39.2%). In studies where TKIs and ICIs were the second-line choices, the pooled median PFS values were 11.4 months (95% CI: 9.5-13.6 months) and 9.8 months (95% CI: 7.5-12.7 months), respectively.
CONCLUSIONS: This systematic review shows that VEGFR TKIs and ICIs are effective second-line therapies following an initial treatment with anti-PD(L)1 alone or in combination. The treatment choice should be personalized, taking into account the patient\'s response to first-line ICIs, the site of the disease, the type of first-line combination (with or without VEGFR TKIs), and the patient\'s overall condition.
摘要：
背景：关于接受免疫检查点抑制剂（ICIs）的转移性肾细胞癌（RCC）患者二线治疗的有效管理的文献存在显著差距。大多数发表的文章是小型多中心系列或第二阶段研究。据我们所知,尚未进行系统评价,全面概述对一线ICIs无反应的转移性RCC患者的治疗选择范围.我们的目的是综合ICI初始治疗后转移性RCC患者二线治疗的证据，并根据现有文献提供最佳治疗方案的建议。
方法：我们在PubMed中进行了搜索，Embase,以及2024年2月29日的Cochrane图书馆，遵循系统审查和荟萃分析(PRISMA)指南的首选报告项目。我们选择了符合预定纳入标准的文章(用英语写，回顾性观察研究，前瞻性系列,以及报告基于ICI的治疗失败后转移性肾癌二线治疗的随机试验)。参考清单中确定了相关文章。主要终点是总有效率（ORR），以中位无进展生存期（PFS）和总生存期（OS）为次要终点。
结果：我们纳入了27项研究，报告了1970例患者的结局。救助疗法在18项研究中被分类为靶向疗法（VEGFRTKIs），在8项研究中被分类为ICIs。在TKIs是第二选择线的研究中，合并ORR为34%(95%CI:30.2-38%).在ICIs的研究中，单独或与TKIs结合使用，被用作二线疗法，ORR为25.7%(95%CI:15.7-39.2%)。在TKIs和ICIs是二线选择的研究中，合并的中位PFS值分别为11.4个月(95%CI:9.5-13.6个月)和9.8个月(95%CI:7.5-12.7个月),分别。
结论：本系统评价显示，VEGFRTKIs和ICIs是单独或联合使用抗PD(L)1初始治疗后的有效二线治疗方法。治疗选择应该是个性化的，考虑到患者对一线ICI的反应，疾病的部位，一线组合的类型（有或没有VEGFRTKIs），和病人的整体状况。
方法：我们在PubMed中进行了搜索，Embase,以及2024年2月29日的Cochrane图书馆，遵循系统审查和荟萃分析(PRISMA)指南的首选报告项目。我们选择了符合预定纳入标准的文章(用英语写，回顾性观察研究，前瞻性系列,以及报告基于ICI的治疗失败后转移性肾癌二线治疗的随机试验)。参考清单中确定了相关文章。主要终点是总有效率（ORR），以中位无进展生存期（PFS）和总生存期（OS）为次要终点。
结果：我们纳入了27项研究，报告了1970例患者的结局。救助疗法在18项研究中被分类为靶向疗法（VEGFRTKIs），在8项研究中被分类为ICIs。在TKIs是第二选择线的研究中，合并ORR为34%(95%CI:30.2-38%).在ICIs的研究中，单独或与TKIs结合使用，被用作二线疗法，ORR为25.7%(95%CI:15.7-39.2%)。在TKIs和ICIs是二线选择的研究中，合并的中位PFS值分别为11.4个月(95%CI:9.5-13.6个月)和9.8个月(95%CI:7.5-12.7个月),分别。
结论：本系统评价显示，VEGFRTKIs和ICIs是单独或联合使用抗PD(L)1初始治疗后的有效二线治疗方法。治疗选择应该是个性化的，考虑到患者对一线ICI的反应，疾病的部位，一线组合的类型（有或没有VEGFRTKIs），和病人的整体状况。
