Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib

Abstract

Background: Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib. We evaluated the association of sunitinib-induced HTN with antitumor efficacy and HTN-associated adverse events in patients with metastatic renal cell carcinoma.

Methods: This retrospective analysis included pooled efficacy (n = 544) and safety (n = 4917) data from four studies of patients with metastatic renal cell carcinoma who were treated with sunitinib 50 mg/d administered on a 4-week-on 2-week-off schedule (schedule 4/2). Blood pressure (BP) was measured in the clinic on days 1 and 28 of each 6-week cycle. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods; hazard ratios (HRs) for survival were also estimated by a Cox proportional hazards models using HTN as a time-dependent covariate. Efficacy outcomes were compared between patients with and without HTN (maximum systolic BP [SBP] ≥140 mm Hg or diastolic BP [DBP] ≥90 mm Hg). Adverse events were also compared between patients with and without HTN (mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg). All P values were two-sided.

Results: Patients with metastatic renal cell carcinoma and sunitinib-induced HTN defined by maximum SBP had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all). Similar results were obtained when comparing patients with vs without sunitinib-induced HTN defined by maximum DBP. In a Cox proportional hazards model using HTN as a time-dependent covariate, PFS (HR of disease progression or death = .603, 95% CI = .451 to .805; P < .001) and OS (HR of death = .332, 95% CI = .252 to .436; P < .001) were improved in patients with treatment-induced HTN defined by maximum SBP; OS (HR of death = .585, 95% CI = .463 to .740; P < .001) was improved in patients with treatment-induced HTN defined by maximum DBP, but PFS was not. Few any-cause cardiovascular, cerebrovascular, ocular, and renal adverse events were observed. Rates of adverse events were similar between patients with and without HTN defined by mean SBP; however, hypertensive patients had somewhat more renal adverse events (5% vs 3%; P = .013).

Conclusions: In patients with metastatic renal cell carcinoma, sunitinib-associated HTN is associated with improved clinical outcomes without clinically significant increases in HTN-associated adverse events, supporting its viability as an efficacy biomarker.

Figure 1

Kaplan–Meier estimates of overall survival (OS) by hypertension (HTN) status (post-cycle 1, day 1). In (A) HTN is defined by a maximum systolic blood pressure of at least 140 mm Hg. In (B), HTN is defined by a maximum diastolic blood pressure of at least 90 mm Hg. N = number at risk; S = survival percentage, with 95% confidence interval (CI) in parentheses.

Figure 2

Kaplan–Meier estimates of overall survival (OS) by hypertension (HTN) status experienced by the end of cycle 2 (12 weeks). In (A), HTN is defined by a maximum systolic blood pressure of at least 140 mm Hg. In (B), HTN is defined by a diastolic blood pressure of at least 90 mm Hg. N = number at risk; S = survival percent, with 95% confidence interval (CI) in parentheses.

Figure 3

Kaplan–Meier estimates of overall survival (OS) by hypertension (HTN) control and status. HTN was defined by a maximum systolic blood pressure of at least 140 mm Hg (post-cycle 1, day 1). N = number at risk; NR = not reached; S = survival percent, with 95% confidence interval (CI) in parentheses.