Impact of renin-angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors.
Impact of renin-angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors.
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DOI：
10.1016/j.clgc.2022.04.012
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发表时间：
2022-08
影响因子：
3.2
通讯作者：
中科院分区：
文献类型：
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在这项多中心回顾性研究中，我们研究了同时使用肾素-血管紧张素系统抑制剂 (RASi) 对 229 名接受免疫检查点抑制剂 (ICI) 治疗的转移性肾细胞癌 (mRCC) 患者的预后的影响。研究结果表明，RASi 可以重新用于增强 mRCC 患者 ICI 的预后，考虑到其成本效益，这可能会产生巨大的全球影响。肾素-血管紧张素系统抑制剂 (RASi) 已被证明可以通过影响肿瘤微环境来增强免疫库和改善药物输送，从而改善多种恶性肿瘤的研究结果。重新利用 RASi 与免疫检查点抑制剂 (ICI) 联合治疗转移性肾细胞癌 (mRCC) 可能会提高生存率、耐受性和成本效益。我们评估了 RASi 对接受 ICI 的 mRCC 患者预后的影响。这项多中心、回顾性队列研究包括接受 ICI 联合或不联合 RASi 治疗的 mRCC 患者。来自丹纳法伯癌症研究所 (DFCI) 的患者被用作发现队列，来自加州大学圣地亚哥分校 (UCSD) 的患者被用于验证。需要收到 ICI（PD1/L1 和/或 CTLA-4 抑制剂）。 RASi 使用被定义为在基线时和 ICI 启动后至少 30 天收到 RASi。对于发现队列和验证队列，评估的主要结局是总生存期（OS），次要终点是治疗失败时间（TTF）和客观缓解率（ORR）。总体而言，纳入了 229 名接受 ICI 的患者：100 名来自 DFCI 的患者和 129 名来自 UCSD 的患者。 DFCI 队列中的 30 名患者（30%）和 UCSD 队列中的 59 名患者（45%）同时接受了 RASi。两个队列中 ICI 开始时的中位年龄均为 62.5 岁。 DFCI 队列的中位随访时间为 3.8 [IQR 3-5.3] 年，UCSD 队列的中位随访时间为 2.3 [IQR 1.4-3.6] 年。在 DFCI 队列中，RASi 与更长的 OS（调整后的 HR 0.35 [95% CI，0.17-0.70]，P = 0.003）和 TTF（调整后的 HR 0.57 [0.36-0.92]，P = 0.02）显着相关。在验证队列中，RASi 与 TTF 相关（调整后 HR，0.60 [0.39-0.92]，P = .02），与 OS 没有统计相关性（调整后 HR 0.60 [0.34-1.06]，P = .07）。倾向分析将两个队列中 83 名接受 ICI 治疗期间接受 RASi 的患者与 83 名未接受 ICI 治疗的患者进行匹配，结果显示 RASi 显着改善 OS（HR 0.59 [0.37-0.95]，P = .03）和 TTF（HR 0.60 [0.43-0.85]，P = .0034）。 RASi 与接受 ICI 的 mRCC 患者的 OS 和 TTF 改善相关。这为在 mRCC 患者中结合 ICI 和 RASi 的前瞻性随机研究提供了理论基础。
In this multicenter retrospective study, we studied the impact of the concurrent use of renin-angiotensin system inhibitors (RASi) on the outcomes of 229 metastatic renal cell carcinoma (mRCC) patients treated with immune-checkpoint inhibitors (ICI). The findings suggest that RASi could be repurposed to enhance outcomes with ICI in patients with mRCC, which may have a large global impact given their cost-efficacy. Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI. This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR). Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034). RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients.
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影响因子：
17.1
作者：
Pinter M;Jain RK
通讯作者：
Jain RK
影响因子：
3.2
作者：
Jain RK;Skelton Iv WP;Pond GR;Naqvi M;Kim Y;Curran C;Freeman D;Nuzzo PV;Alaiwi SA;Nassar AH;Jain RK;Sonpavde G
通讯作者：
Sonpavde G
DOI：
10.1158/1078-0432.ccr-17-0256
发表时间：
2017-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liu H;Naxerova K;Pinter M;Incio J;Lee H;Shigeta K;Ho WW;Crain JA;Jacobson A;Michelakos T;Dias-Santos D;Zanconato A;Hong TS;Clark JW;Murphy JE;Ryan DP;Deshpande V;Lillemoe KD;Fernandez-Del Castillo C;Downes M;Evans RM;Michaelson J;Ferrone CR;Boucher Y;Jain RK
通讯作者：
Jain RK
DOI：
10.1073/pnas.1819889116
发表时间：
2019-05-28
影响因子：
11.1
作者：
Chauhan, Vikash P.;Chen, Ivy X.;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
DOI：
10.1007/s00432-009-0587-3
发表时间：
2009-10-01
影响因子：
3.6
作者：
Wilop, Stefan;von Hobe, Sabine;Jost, Edgar
通讯作者：
Jost, Edgar