David Goldstein1, Jonathan E Rosenberg2, Robert A Figlin3, Raymond R Townsend4, Lauren McCann5, Christopher Carpenter6, Lini Pandite7. 1. University of New South Wales and Prince of Wales Hospital, High St., Randwick, Sydney 2031, Australia. Electronic address: d.goldstein@unsw.edu.au. 2. Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Electronic address: rosenbj1@mskcc.org. 3. Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: robert.figlin@cshs.org. 4. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5. GlaxoSmithKline, Collegeville, PA, USA. Electronic address: futed@alum.mit.edu. 6. GlaxoSmithKline, Collegeville, PA, USA. 7. GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC, USA. Electronic address: lini.pandite@adaptimmune.com.
Abstract
AIM: Pazopanib, an oral antiangiogenic agent, is associated with improved outcomes in patients with metastatic renal cell carcinoma. In this retrospective analysis, we explore hypertension, an on-target adverse event, as a predictive marker. METHODS: Data from the pazopanib arm of the phase III COMPARZ trial (NCT00720941) comprised the test set. Pooled data from phase II (NCT00244764) and III (NCT00334282) pazopanib trials comprised the validation set. Data from the sunitinib arm of COMPARZ were analysed separately. Measures of efficacy were response rate, progression-free survival (PFS), and overall survival (OS). Mean arterial blood pressure (MAP) was the primary metric, and systolic hypertension (S-HTN) and diastolic hypertension (D-HTN) were secondary metrics; 4- and 12-week landmark analyses were performed. RESULTS: Analyses revealed no significant associations at the landmarks between response and MAP. We observed a trend towards improved PFS with S-HTN at week 4 (hazard ratio [HR] = 0.79, P = 0.060) and week 12 (HR = 0.75, P = 0.073) among pazopanib-treated patients in COMPARZ. This trend was not confirmed at week 12 in the validation set or in sunitinib-treated patients. In the test set, there was a trend towards increased OS in patients with S-HTN by week 4 (HR = 0.76, P = 0.062) and with D-HTN by week 4 (HR = 0.71, P = 0.016) but not by week 12. No significant differences in OS were observed in sunitinib-treated patients for S-HTN or D-HTN. CONCLUSION: Neither hypertension nor any blood pressure elevation above baseline was associated with efficacy outcomes of pazopanib or sunitinib. Accordingly, management of tyrosine kinase inhibitor-induced hypertension is unlikely to compromise outcome.
AIM: Pazopanib, an oral antiangiogenic agent, is associated with improved outcomes in patients with metastatic renal cell carcinoma. In this retrospective analysis, we explore hypertension, an on-target adverse event, as a predictive marker. METHODS: Data from the pazopanib arm of the phase III COMPARZ trial (NCT00720941) comprised the test set. Pooled data from phase II (NCT00244764) and III (NCT00334282) pazopanib trials comprised the validation set. Data from the sunitinib arm of COMPARZ were analysed separately. Measures of efficacy were response rate, progression-free survival (PFS), and overall survival (OS). Mean arterial blood pressure (MAP) was the primary metric, and systolic hypertension (S-HTN) and diastolic hypertension (D-HTN) were secondary metrics; 4- and 12-week landmark analyses were performed. RESULTS: Analyses revealed no significant associations at the landmarks between response and MAP. We observed a trend towards improved PFS with S-HTN at week 4 (hazard ratio [HR] = 0.79, P = 0.060) and week 12 (HR = 0.75, P = 0.073) among pazopanib-treated patients in COMPARZ. This trend was not confirmed at week 12 in the validation set or in sunitinib-treated patients. In the test set, there was a trend towards increased OS in patients with S-HTN by week 4 (HR = 0.76, P = 0.062) and with D-HTN by week 4 (HR = 0.71, P = 0.016) but not by week 12. No significant differences in OS were observed in sunitinib-treated patients for S-HTN or D-HTN. CONCLUSION: Neither hypertension nor any blood pressure elevation above baseline was associated with efficacy outcomes of pazopanib or sunitinib. Accordingly, management of tyrosine kinase inhibitor-induced hypertension is unlikely to compromise outcome.
Authors: Remy B Verheijen; Jos H Beijnen; Jan H M Schellens; Alwin D R Huitema; Neeltje Steeghs Journal: Clin Pharmacokinet Date: 2017-09 Impact factor: 6.447
Authors: Otto Hemminki; Nathan Perlis; Johan Bjorklund; Antonio Finelli; Alexandre R Zlotta; Akseli Hemminki Journal: Eur Urol Open Sci Date: 2020-11-28