Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline 23 Ave., DANA 1230, Boston, MA 02215, United States.
Moores Cancer Center, University of California San Diego, La Jolla, CA, United States.
Clin Genitourin Cancer. 2022 Aug;20(4):301-306. doi: 10.1016/j.clgc.2022.04.012. Epub 2022 Apr 29.
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.
肾素-血管紧张素系统抑制剂（RASi）已被证明通过影响肿瘤微环境来增强免疫谱并改善药物输送，从而改善多种恶性肿瘤的研究结果。将 RASi 重新用于联合免疫检查点抑制剂（ICI）治疗转移性肾细胞癌（mRCC），可能会提高生存率，同时提高耐受性和成本效益。我们评估了 RASi 对接受 ICI 治疗的 mRCC 患者结局的影响。
这是一项多中心、回顾性队列研究，纳入了接受 ICI 联合或不联合 RASi 治疗的 mRCC 患者。达纳-法伯癌症研究所（DFCI）的患者被用作发现队列，加利福尼亚大学圣地亚哥分校（UCSD）的患者被用于验证。需要接受 ICI（PD1/L1 和/或 CTLA-4 抑制剂）治疗。RASi 的使用定义为在 ICI 起始时和 ICI 起始后至少 30 天内接受 RASi。对于发现和验证队列，主要观察终点是总生存期（OS），次要终点是治疗失败时间（TTF）和客观缓解率（ORR）。
共纳入 229 名接受 ICI 治疗的患者：DFCI 组 100 例，UCSD 组 129 例。DFCI 队列中有 30 例（30%）患者同时接受 RASi 治疗，UCSD 队列中有 59 例（45%）患者同时接受 RASi 治疗。两组患者 ICI 起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）显著相关。在验证队列中，RASi 与 TTF 相关（调整后的 HR 0.60 [0.39-0.92]，P = 0.02），但与 OS 无统计学相关性（调整后的 HR 0.60 [0.34-1.06]，P = 0.07）。对来自两个队列的 83 名同时接受 RASi 和 ICI 治疗的患者和 83 名未接受 RASi 治疗的患者进行倾向评分匹配后发现，RASi 显著改善了 OS（HR 0.59 [0.37-0.95]，P = 0.03）和 TTF（HR 0.60 [0.43-0.85]，P = 0.0034）。
RASi 与接受 ICI 治疗的 mRCC 患者的 OS 和 TTF 改善相关。这为在 mRCC 患者中联合使用 ICI 和 RASi 的前瞻性随机研究提供了依据。
