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

AbstractBACKGROUND:
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.
AuthorsBrian I Rini, Darrel P Cohen, Dongrui R Lu, Isan Chen, Subramanian Hariharan, Martin E Gore, Robert A Figlin, Michael S Baum, Robert J Motzer
JournalJournal of the National Cancer Institute (J Natl Cancer Inst) Vol. 103 Issue 9 Pg. 763-73 (May 4 2011) ISSN: 1460-2105 [Electronic] United States
PMID21527770 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Indoles
  • Pyrroles
  • sunitinib
Topics
  • Angiogenesis Inhibitors (adverse effects)
  • Antineoplastic Agents (administration & dosage, adverse effects)
  • Blood Pressure (drug effects)
  • Carcinoma, Renal Cell (drug therapy, secondary)
  • Confounding Factors (Epidemiology)
  • Disease-Free Survival
  • Humans
  • Hypertension (chemically induced)
  • Indoles (administration & dosage, adverse effects)
  • Kaplan-Meier Estimate
  • Kidney Neoplasms (drug therapy, pathology)
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Pyrroles (administration & dosage, adverse effects)
  • Retrospective Studies
  • Risk Factors
  • Treatment Outcome

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