Impact of renin-angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors

Published:April 28, 2022DOI:



      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.



      ACEi (angiotensin-converting enzyme inhibitors), aHTN (anti-hypertensive), ARB (angiotensin receptor blockers), CI (confidence interval), CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), DFCI (Dana Farber Cancer institute), ECM (extracellular matrix), ECOG PS (Eastern Cooperative Oncology Group Performance Status), HR (hazard ratio), HTN (hypertension), ICI (immune checkpoint inhibitors), IMDC (international Metastatic RCC Database Consortium), IQR (interquartile range), MCC (Moores Cancer Center), mRCC (metastatic renal cell carcinoma), OR (odds ratio), ORR (overall response rate), OS (overall survival), PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), RAS (renin-angiotensin system), RASi (renin-angiotensin system inhibitors), TTF (time-to-treatment failure), UCSD (University of California San Diego)
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        • Hofmann F.
        • Hwang E.C.
        • Lam T.B.
        • et al.
        Targeted therapy for metastatic renal cell carcinoma.
        Cochrane Database Syst Rev. 2020; 10Cd012796
        • George A.J.
        • Thomas W.G.
        • Hannan R.D.
        The renin-angiotensin system and cancer: old dog, new tricks.
        Nat Rev Cancer. 2010; 10: 745-759
        • Chauhan V.P.
        • Martin J.D.
        • Liu H.
        • et al.
        Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.
        Nat Commun. 2013; 4: 2516
        • Pinter M.
        • Jain R.K.
        Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy.
        Sci Transl Med. 2017; 9
        • Chauhan V.P.
        • Chen I.X.
        • Tong R.
        • et al.
        Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy.
        Proc Natl Acad Sci U S A. 2019; 116: 10674-10680
        • Liu H.
        • Naxerova K.
        • Pinter M.
        • et al.
        Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma.
        Clin Cancer Res. 2017; 23: 5959-5969
        • Okwan-Duodu D.
        • Landry J.
        • Shen X.Z.
        • Diaz R.
        Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis.
        Am J Physiol Regul Integr Comp Physiol. 2013; 305: R205-R215
        • Wilop S.
        • von Hobe S.
        • Crysandt M.
        • Osieka R.
        • Jost E.
        • Esser A.
        Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy.
        J Cancer Res Clin Oncol. 2009; 135: 1429-1435
        • Zhao Y.
        • Cao J.
        • Melamed A.
        • et al.
        Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma.
        Proc Natl Acad Sci U S A. 2019; 116: 2210-2219
        • Nakai Y.
        • Isayama H.
        • Ijichi H.
        • et al.
        Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine.
        Br J Cancer. 2010; 103: 1644-1648
        • Tozuka T.
        • Yanagitani N.
        • Yoshida H.
        • et al.
        Impact of renin-angiotensin system inhibitors on the efficacy of anti-PD-1/PD-L1 antibodies in NSCLC patients.
        Anticancer Res. 2021; 41: 2093-2100
        • Jain R.K.
        • Skelton Iv W.P.
        • Pond G.R.
        • et al.
        Angiotensin blockade modulates the activity of PD1/L1 inhibitors in metastatic urothelial carcinoma.
        Clin Genitourin Cancer. 2021; 19: 540-546
        • Coulson R.
        • Liew S.H.
        • Connelly A.A.
        • et al.
        The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma.
        Oncotarget. 2017; 8: 18640-18656
        • Pinter M.
        • Kwanten W.J.
        • Jain R.K.
        Renin-angiotensin system inhibitors to mitigate cancer treatment-related adverse events.
        Clin Cancer Res. 2018; 24: 3803-3812
        • McKay R.R.
        • Rodriguez G.E.
        • Lin X.
        • et al.
        Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma.
        Clin Cancer Res. 2015; 21: 2471-2479
        • Murphy J.E.
        • Wo J.Y.
        • Ryan D.P.
        • et al.
        Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial.
        JAMA Oncol. 2019; 5: 1020-1027