Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma

Benjamin M Ellingson, Dana T Aftab, Gisela M Schwab, Colin Hessel, Robert J Harris, Davis C Woodworth, Kevin Leu, Ararat Chakhoyan, Catalina Raymond, Jan Drappatz, John de Groot, Michael D Prados, David A Reardon, David Schiff, Marc Chamberlain, Tom Mikkelsen, Annick Desjardins, Jaymes Holland, Jerry Ping, Ron Weitzman, Patrick Y Wen, Timothy F Cloughesy, Benjamin M Ellingson, Dana T Aftab, Gisela M Schwab, Colin Hessel, Robert J Harris, Davis C Woodworth, Kevin Leu, Ararat Chakhoyan, Catalina Raymond, Jan Drappatz, John de Groot, Michael D Prados, David A Reardon, David Schiff, Marc Chamberlain, Tom Mikkelsen, Annick Desjardins, Jaymes Holland, Jerry Ping, Ron Weitzman, Patrick Y Wen, Timothy F Cloughesy

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.

Figures

Fig. 1
Fig. 1
Precontrast T1-weighted images, postcontrast T1-weighted images, and contrast-enhanced T1-weighted digital subtraction maps in 2 representative recurrent GBM patients with a sustained volumetric response following treatment with 100 mg of cabozantinib. (A) Pretreatment and (B) posttreatment MRI scans showing precontrast T1-weighted images (left column), postcontrast T1-weighted images (middle column), and T1 subtraction maps (right column) in a 62-year-old patient with an OS of 16.8 months following treatment. (C) Pretreatment and (D) posttreatment MRI scans showing precontrast T1-weighted images, postcontrast T1-weighted images, and T1 subtraction maps in a 57-year-old patient who was still alive (censored) 20.5 months following treatment. Note that in both cases, as in many patients exhibiting a durable response, we observed significant T1 shortening on precontrast T1-weighted images following therapy, which resulted in a significant decrease in true contrast-enhancing tumor burden following digital subtraction.
Fig. 2
Fig. 2
Log-linear or linear associations between baseline or change in contrast-enhancing tumor burden and OS following treatment with cabozantinib in recurrent GBM. (A) Log-linear (OS = a•log10(Volume)+b) association between baseline tumor volume and OS. (B) Linear (OS = a•(Change in Volume) + b) association between initial change in tumor volume and OS. Solid lines represent best fit line after log-linear or linear regression and dashed lines represent 95% CIs for the respective model fits.
Fig. 3
Fig. 3
Kaplan–Meier plots showing the association between confirmed volumetric response (VR) and OS in recurrent GBM patients treated with cabozantinib. (A) Kaplan–Meier plots demonstrating a significant survival advantage in patients with a confirmed VR treated with cabozantinib pooled across both 100 mg and 140 mg dose levels (log-rank, P < 0.0001, HR = 0.3050). (B) Kaplan–Meier survival plots showing a significant survival advantage in patients with confirmed VR treated with 100 mg and 140 mg. Note that patients with confirmed response treated with 140 mg had a significantly longer OS compared with volumetric responders treated with 100 mg (log-rank, P = 0.0211).

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