ASIs Demonstrate OS Benefit in mRCC, Appear Synergistic with Anti-VEGF Therapies

Rana McKay, MD

A vast, pooled retrospective analysis has demonstrated that the use of angiotensin system inhibitors (ASIs) may significantly improve survival outcomes in patients with metastatic renal cell carcinoma (mRCC).

“This is the largest analysis to our knowledge, evaluating the role of ASIs on outcomes, not just in metastatic RCCs, but for all cancers,” said lead author Rana R. McKay, MD, a clinical oncology fellow at Dana-Farber Cancer Institute, Boston, Massachusetts, during a pre-meeting press cast of the 2014 Genitourinary Cancers Symposium. “In this analysis, we demonstrate that concomitant use of angiotensin system inhibitors may improve survival outcomes in patients with metastatic renal cell carcinoma treated in the era of targeted therapy.”

According to McKay, there has been increasing evidence to suggest that angiotensin II plays a role in various pathologic situations, such as cell proliferation, inflammation, angiogenesis, tissue repair, and carcinogenesis.

“ACE inhibitors and ARBs are known to basically augment the renin-angiotensin system pathway and decrease the action or decrease the production of angiotensin II, which has been implicated in some of these pathologic processes, and so this was the thinking behind initially doing this analysis,” she said. “There have been other retrospective studies that have looked at the role of angiotensin system inhibitors in not just kidney cancer but in other cancers as well.”

The analysis by McKay and colleagues used data from Pfizer-sponsored phase II and III trials of patients with mRCC (N=4736) between the years 2003 and 2013. Patients had been treated with VEGF-targeted agents (such as sunitinib, sorafenib, axitinib, bevacizumab), mTOR-targeted agents (temsirolimus), and interferon. Most patients were <65 years of age (69%), male (71%), with clear-cell histology (89%), and prior nephrectomy (70%).

According to International mRCC Database Consortium risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. 1383 (29%) patients received treatment with an ASI. Baseline hypertension was present in 84% of ASI users and in 33% of ASI nonusers.

The analysis evaluated overall survival (OS) in ASI users versus nonusers. OS was analyzed using the Kaplan-Meier method. The Cox regression model was used in the multivariable analysis, which was adjusted for age, sex, race, risk group, presence of baseline hypertension, and presence of treatment-related hypertension.

“We demonstrated that OS was significantly longer in ASI users compared to nonusers for the overall cohort,” McKay said.

OS was 27 months compared to 17 months (ASI users vs nonusers, respectively. Hazard ratio [HR] =1.2).

McKay also mentioned that in users of antihypertensive therapy on VEGF agents, ASI users had significantly prolonged survival compared to nonusers (31 months vs 22 months, respectively [HR=1.38]). According to an ASCO press release, the cancer was more likely to shrink in patients taking ASIs.

In a subset analysis stratified by types of therapy for mRCC, including VEGF-targeted therapy, mTOR-targeted therapy, and IFN-α therapy, the researchers showed that OS was improved in ASI users compared to nonusers; however, this was only statistically significant for patients receiving VEGF-targeted therapy, with an OS of 31 months versus 20 months, respectively; HR=1.36.

“This was not statistically significant for the mTOR classification or the cytokine classification, suggesting a synergistic interaction between VEGF-targeted therapy and ASIs,” McKay said. “However, it is too early to determine if ASIs should be used for patients with metastatic renal cell carcinoma who do not also have hypertension or another medical condition to warrant ASI treatment.”

Lab-based prospective studies are required to explore this relationship further, according to McKay. “In patients with metastatic RCCs who warrant an antihypertensive agent, ASIs may be the agent of choice for patients with no contraindications for their use,” she said.

McKay RR, Rodriguez GE, Lin X, et al. Impact of angiotensin system inhibitors (ASI) on outcomes in patients with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database. Presented at pre-meeting press cast of the 2014 Genitourinary Cancers Symposium; January 28, 2014. Abstract #437.

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