Researchers have found that a class of commonly used heart drugs may also improve patients’ responses to PD-L1 inhibitors, according to preliminary findings presented by Strauss et al at the 32th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (Abstract 7).

Angiotensin receptor blockers are often prescribed for high blood pressure, heart failure, kidney failure, and following a heart attack. They work by reducing the action of angiotensin II, which plays a role in narrowing blood vessels and increasing blood pressure. Angiotensin receptor blockers block AT1 receptors that angiotensin II works on, and which are found in the heart, blood vessels, and kidneys.

Julius Strauss, MD, Co-Director of the Clinical Trials Group, Laboratory of Tumor Immunology and Biology at the National Cancer Institute’s Center for Cancer Research, presented this latest research. He said, “There are data suggesting that when angiotensin II, a protein in the body, binds to one of its receptors, AT1R, it has the potential to increase the levels of other proteins, VEGF and TGF beta, both of which have been linked to cancer growth and resistance to the immune system.”

The researchers thought that this overlap between the angiotensin II and the TGF beta pathways might mean that it plays a crucial role in the onset of cancer, its growth, and also how cancer cells evade the immune system.

“We decided to look at all the medications our patients were taking to see if any common medication or class of drugs might increase the likelihood of responding to anti–PD-L1 treatment. After an initial review, angiotensin receptor blockers seemed to be the most promising,” said Dr. Strauss.

Methods

Researchers analyzed data from 597 patients being treated with anti–PD-L1 drugs in 20 clinical trials at the National Institutes of Health Clinical Center. The patients had more than three dozen different cancers, including prostate, lung, colon, ovarian, bladder, and cervical cancers. Many were already taking angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for heart problems unrelated to their cancer.

Dr. Strauss compared 71 patients who were taking angiotensin receptor blockers together with PD-L1 inhibitors with those who were not. He also compared 82 patients receiving angiotensin-converting enzyme inhibitors with those who were not.

Results

“Patients who were taking angiotensin receptor blockers seemed to respond better and more often to anti–PD-L1 therapy for their cancer than patients who were not. We found that angiotensin receptor blockers were associated with a statistically significant increase in the objective response rate as well as the complete response rate, compared to patients not taking angiotensin receptor blockers,” he said.

Among patients taking angiotensin receptor blockers, the objective response rate was 34% compared to 17% in patients not taking angiotensin receptor blockers, while the complete response rate was 11% in patients taking angiotensin receptor blockers compared to 3% in those who were not. However, there was no statistically significant improvement in objective response or complete response rates among patients taking angiotensin-converting enzyme inhibitors compared to those who were not taking them.

Dr. Strauss said, “The possible reason for the different effects seen with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors might be that although angiotensin II increases levels of VEGF and TGF beta when it binds to the AT1R receptor, it can actually decrease levels of VEGF and TGF beta when it binds to another receptor, AT2R. Therefore, angiotensin receptor blockers, which selectively block just AT1R, potentially work better at lowering VEGF and TGF beta levels than angiotensin-converting enzyme inhibitors, which block both AT1R and AT2R.

He continued: “In addition to angiotensin receptor blockers potentially increasing the likelihood of responding to anti–PD-L1 therapy, we also saw evidence that angiotensin receptor blockers may help patients live longer. This beneficial effect of angiotensin receptor blockers was seen in some cancer types more than others, and was most notable in [patients with] bladder cancer. However, these findings are very preliminary and other trials are needed to evaluate if angiotensin receptor blockers may be beneficial to patients with cancer and to determine what, if any, cancer types may benefit the most, particularly in combination with anti–PD-L1 therapy.”