Angiotensin receptor blockers, commonly used to treat hypertension, may improve outcomes in patients treated with anti–PD-1/L1 agents, according to an observational study of almost 600 patients reported at the virtual 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.¹ The conference is jointly provided by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).

Julius Strauss, MD

Overall and complete response rates as well as median overall survival were significantly higher for patients taking angiotensin receptor blockers than for patients not receiving these drugs. Numerical improvements were observed with angiotensin-converting enzyme (ACE) inhibitors, but they were not statistically significant, according to lead researcher Julius Strauss, MD, of the Center for Cancer Research at the National Cancer Institute, Bethesda, Maryland.

If the findings are validated by further research, it might be reasonable for immunotherapy recipients who are taking ACE inhibitors to switch to an angiotensin receptor blocker, if deemed safe by their physician, said Dr. Strauss.

Large Observational Study

Dr. Strauss led a study that evaluated 597 patients with a variety of cancer types treated in clinical trials at the U.S. National Institutes of Health. All patients had received an anti–PD-1/L1 antibody delivered with or without other immunotherapies, such as anticytotoxic T-lymphocyte–associated protein 4 (CTLA-4) checkpoint inhibitors or targeted agents.

Some were also receiving, at baseline, angiotensin receptor blockers or ACE inhibitors. The researchers compared outcomes according to receipt of concomitant angiotensin receptor blockers (n = 71), ACE inhibitors (n = 83), or none of either agent (n = 444).

Study Rationale

Not only can angiotensin II modulate blood pressure, it can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta); both have been linked to cancer growth and tumor resistance to immune system attack. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both growth factors.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II and indirectly block both the AT1 and AT2 receptors. In contrast, angiotensin receptor blockers inhibit the AT1 receptor alone and not the AT2 counter-regulatory receptor, Dr. Strauss explained.

Considering these mechanisms of action, the researchers asked whether ACE inhibitors and/or angiotensin receptor blockers could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors. And they found an association with angiotensin receptor blockers.

“The benefit seen with angiotensin receptor blockers but not ACE inhibitors may be due to selective AT1 blockade by angiotensin receptor blockers vs dual AT1/AT2 blockade by ACE inhibitors,” Dr. Strauss said. “We need further study to determine whether AT1 blockade can improve outcomes when combined with anti–PD-1/L1-based therapy.”

Improved Outcomes With Angiotensin Receptor Blockers

In pooled trial data, response rates were 17.0% for patients not receiving an angiotensin receptor blocker or ACE inhibitor compared with 33.8% for patients receiving angiotensin receptor blockers (P = .001) and 19.5% for those treated with ACE inhibitors (P = .60), as shown in Table 1. Complete response rates were, respectively, 3.1% vs 11.3% (P = .002) and 3.7% (P = .81).

In the multiple regression analysis controlling for age, gender, body mass index, tumor type, and additional therapies given, the addition of angiotensin receptor blockers remained significant for response rate (P = .039) and complete response rate (P = .002), whereas there continued to be no significant additional benefit with ACE inhibitors, Dr. Strauss reported.

Angiotensin receptor blockers also conveyed a statistically significant overall survival benefit, improving median survival from 18.8 months without an ACE inhibitor or angiotensin receptor blocker to 35.2 months (P = .0078); the 26.2-month median survival with ACE inhibitors did not significantly differ (P = .13). Again, in the regression analysis, the overall survival benefit remained significant (P = .006) for angiotensin receptor blockers but not for ACE inhibitors (P = .078), he added.

Outcomes by Tumor Type

In this early study, the improvement with angiotensin receptor blockers appeared to most notable in bladder cancer, where response rates were 77.8% vs 30.2% for those not receiving ACE inhibitors or angiotensin receptor blockers (P = .019) and complete response rates were 55.6% vs 9.3%, respectively (P = .005). In patients with this type of cancer, median overall survival was not reached with angiotensin receptor blockers but was 14.2 months without them (P = .005), Dr. Strauss reported.

“On the multivariable analysis angiotensin receptor blockers were associated with improved response rates, complete response rates, and overall survival in patients with bladder cancer. A similar numerical pattern was noted in ovarian and prostate cancers, although without statistical significance,” he said. Dr. Strauss emphasized the benefit according to tumor type is solely “hypothesis-generating” and a prospective study is needed to confirm relative efficacy. 

DISCLOSURE: Dr. Strauss reported no conflicts of interest.

REFERENCE

1. Strauss J, Rajan A, Apolo A, et al: Impact of angiotensin II pathway inhibition on tumor response to anti PD(L)1 based therapy. 2020 EORTC-NCI-AACR Symposium. Abstract 7. Presented October 25, 2020.