Impact of angiotensin blockade on response to PD1/L1 inhibitors for patients with metastatic urothelial carcinoma (mUC).
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453 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis and cell proliferation. Preclinical data also indicate that angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients (pts) with metastatic urothelial carcinoma (mUC) receiving PD1/L1 inhibitors, we hypothesized that angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mUC pts receiving PD1/L1 inhibitors. Methods: Data from mUC pts who received PD1/L1 inhibitors as monotherapy were obtained: pts from the Dana-Farber Cancer Institute (DFCI) served as the discovery dataset, while data from Moffitt Cancer Center (MCC) served as the validation dataset. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting PD1/L1 inhibitor treatment. A logistic regression was used to investigate the impact of concurrent ACEI/ARB on any regression of tumor (ART, any decrease in size of tumor on scan) as the primary endpoint defined as any tumor regression after controlling for known prognostic factors (performance status, sites of metastasis, neutrophil/lymphocyte ratio, platelet count, hemoglobin). Overall survival (OS), the secondary endpoint, was analyzed using Cox proportional hazards regression. Results: Data was available for 178 pts from DFCI (discovery dataset) with mUC who received a PD1/L1 inhibitor of whom 153 (86%) had received prior platinum and 33 pts (18.5%) received concurrent AECI/ARBs. Multivariable analysis controlling for known prognostic factors revealed that patients who received ACEIs or ARBs had greater ART (HR 3.0 [95% CI 1.25-7.17], p = 0.014) and improved OS, (HR 0.49 [95% CI 0.28-0.88] p = 0.016). In the MCC validation dataset, 101 pts were available of whom 59 (58.4%) had received prior platinum and 22 pts (21.8%) received concurrent ACEI/ARBs. Univariate analysis showed that those patients who were treated with ACEI/ARB had an improved ART (OR 3.32 [95% CI 1.22-9.06] p = 0.019). On multivariable analysis, there was a borderline significant association of ACEI/ARB with ART (OR = 3.03, p = 0.075), but no association was observed with OS. Conclusions: In this hypothesis-generating study, concurrent angiotensin inhibitors including ACEI or ARBs were associated with tumor regression in mUC pts receiving PD-1/L1 inhibitors. The inconsistent association with OS may be partly due to modest sample size and comorbidities associated with the need for ACEI/ARBs. These results require validation in a prospective study.
