Introduction

We conducted a systematic literature review to identify evidence for use of vascular endothelial growth factor (VEGF)-targeted (anti-VEGF) treatment in patients with renal cell carcinoma (RCC) following prior checkpoint inhibitor (CPI)-based therapy.

Methods

This was a PRISMA-standard systematic literature review; registered with PROSPERO (CRD42021255568). Literature searches were conducted in MEDLINE®, Embase, and the Cochrane Library (January 28, 2021; updated September 13, 2022) to identify publications reporting efficacy/effectiveness and safety/tolerability evidence for anti-VEGF treatment in patients with RCC who had received prior CPI therapy.

Results

Of 2,639 publications screened, 48 were eligible and featured 2,759 patients treated in trials and 2,209 in real-world studies (RWS). Most patients with available data were treated with anti-VEGF tyrosine kinase inhibitor-based regimens (trials: 93 %; RWS: 100 %), most commonly cabozantinib, which accounted for 46 % of trial and 62 % of RWS patients in publications with available data. Collectively, there was consistent evidence of anti-VEGF treatment activity after prior CPI therapy. Activity was reported for all anti-VEGF regimens and regardless of prior CPI-based regimen. No new safety signals were detected for subsequent anti-VEGF therapy; no studies suggested increased immune-related adverse events associated with prior CPI therapy. The results were limited by data quality; study heterogeneity prohibited meta-analyses.

Conclusion

Based on the available data (most commonly for cabozantinib), anti-VEGF therapy appears to be a rational treatment choice in patients with RCC who have progressed despite prior CPI-based therapy. Results from ongoing trials of combination anti-VEGF plus CPI regimen post prior CPI therapy trials will contribute more definitive evidence.

Plain language summary

Anticancer treatments that work by reducing levels of a substance in the body called Vascular Endothelial Growth Factor are known as anti-VEGF drugs. Reducing VEGF levels helps to reduce blood supply to tumors, which can slow the speed at which the cancer grows. Some other types of anticancer drugs that help the immune system to fight cancer cells are called checkpoint inhibitors. Here, we looked at published studies that investigated how anti-VEGF drugs work, and what side effects they cause, in people who have already been treated with checkpoint inhibitors for a type of kidney cancer called renal cell carcinoma. We aimed to summarize the available evidence to help doctors decide how best to use anti-VEGF drugs in these patients. We found 48 studies that included almost 5,000 patients. The results of the studies showed that anti-VEGF drugs have anticancer effects in people with renal cell carcinoma who had already been treated with checkpoint inhibitors. All of the VEGF-targeting drugs had anticancer effects, irrespective of what checkpoint inhibitor treatment people had received before. There were different amounts of evidence available for the different anti-VEGF drugs. The anti-VEGF cabozantinib had the largest amount of evidence. Importantly, previous checkpoint inhibitor treatment did not seem to affect the number or type of side-effects associated with anti-VEGF drugs. Results from ongoing, well-designed studies will be helpful to confirm these results. Our findings may be useful for doctors considering using anti-VEGF drugs in patients with renal cell carcinoma who have received checkpoint inhibitor treatment.

中文翻译：

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免疫检查点抑制剂预处理的肾细胞癌患者的血管内皮生长因子靶向治疗：系统文献综述

介绍

我们进行了系统性文献综述，以确定在既往接受基于检查点抑制剂 (CPI) 治疗的肾细胞癌 (RCC) 患者中使用血管内皮生长因子 (VEGF) 靶向（抗 VEGF）治疗的证据。

方法

这是 PRISMA 标准的系统文献综述；已在 PROSPERO 注册 (CRD42021255568)。在 MEDLINE®、Embase 和 Cochrane 图书馆（2021 年 1 月 28 日；2022 年 9 月 13 日更新）中进行文献检索，以确定报告抗 VEGF 治疗对接受过肾细胞癌患者的疗效/有效性和安全性/耐受性证据的出版物既往 CPI 治疗。

结果

在筛选的 2,639 篇出版物中，有 48 篇符合资格，并收录了 2,759 名在试验中接受治疗的患者和 2,209 名在现实世界研究 (RWS) 中接受治疗的患者。大多数有可用数据的患者接受基于抗 VEGF 酪氨酸激酶抑制剂的治疗方案（试验：93%；RWS：100%），最常见的是卡博替尼，在现有出版物中占试验的 46% 和 RWS 患者的 62%数据。总的来说，在先前的 CPI 治疗后，有一致的证据表明抗 VEGF 治疗活性。报告了所有抗 VEGF 方案的活性，无论先前基于 CPI 的方案如何。后续抗 VEGF 治疗未检测到新的安全信号；没有研究表明与先前的 CPI 治疗相关的免疫相关不良事件增加。结果受到数据质量的限制；研究异质性禁止荟萃分析。

结论

根据现有数据（最常见的是卡博替尼），对于既往基于 CPI 的治疗但病情仍出现进展的 RCC 患者，抗 VEGF 治疗似乎是合理的治疗选择。在先前的 CPI 治疗试验之后，正在进行的抗 VEGF 联合 CPI 方案联合试验的结果将提供更明确的证据。

通俗易懂的语言总结

通过降低体内一种称为血管内皮生长因子的物质的水平来发挥作用的抗癌治疗被称为抗VEGF药物。降低 VEGF 水平有助于减少肿瘤的血液供应，从而减缓癌症的生长速度。其他一些帮助免疫系统对抗癌细胞的抗癌药物被称为检查点抑制剂。在这里，我们查阅了已发表的研究，这些研究调查了抗 VEGF 药物在已经接受过检查点抑制剂治疗肾细胞癌的患者中如何发挥作用，以及它们会引起哪些副作用。我们的目的是总结现有证据，帮助医生决定如何最好地在这些患者中使用抗 VEGF 药物。我们发现了 48 项研究，涉及近 5,000 名患者。研究结果表明，抗 VEGF 药物对已经接受检查点抑制剂治疗的肾细胞癌患者具有抗癌作用。所有 VEGF 靶向药物都具有抗癌作用，无论人们之前接受过何种检查点抑制剂治疗。不同的抗 VEGF 药物有不同数量的可用证据。抗 VEGF 卡博替尼的证据量最多。重要的是，之前的检查点抑制剂治疗似乎并不影响与抗 VEGF 药物相关的副作用的数量或类型。正在进行的、精心设计的研究结果将有助于证实这些结果。我们的研究结果可能对考虑对接受检查点抑制剂治疗的肾细胞癌患者使用抗 VEGF 药物的医生有用。