Benjamin M Ellingson1,2, Dana T Aftab3, Gisela M Schwab3, Colin Hessel3, Robert J Harris1,4, Davis C Woodworth1,4, Kevin Leu1,4, Ararat Chakhoyan1,4, Catalina Raymond1,4, Jan Drappatz5, John de Groot6, Michael D Prados7, David A Reardon8, David Schiff9, Marc Chamberlain10, Tom Mikkelsen11, Annick Desjardins12, Jaymes Holland3, Jerry Ping3, Ron Weitzman3, Patrick Y Wen8, Timothy F Cloughesy2,13. 1. UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 2. UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 3. Exelixis, South San Francisco, California. 4. Departments of Radiological Sciences and Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 5. Department of Neurology and Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 6. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 7. Department of Neurosurgery, University of California San Francisco (UCSF), San Francisco, California. 8. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 9. Neuro-Oncology Center, University of Virginia Health System, Charlottesville, Virginia. 10. Department of Neurology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington. 11. Henry Ford Health System, Detroit, Michigan. 12. Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina. 13. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
Abstract
Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.
Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.
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