Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy

Timothy F Cloughesy, Jan Drappatz, John de Groot, Michael D Prados, David A Reardon, David Schiff, Marc Chamberlain, Tom Mikkelsen, Annick Desjardins, Jerry Ping, Jaymes Holland, Ron Weitzman, Patrick Y Wen, Timothy F Cloughesy, Jan Drappatz, John de Groot, Michael D Prados, David A Reardon, David Schiff, Marc Chamberlain, Tom Mikkelsen, Annick Desjardins, Jerry Ping, Jaymes Holland, Ron Weitzman, Patrick Y Wen

Abstract

Background: Cabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM).

Methods: Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety.

Results: Among 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions.

Conclusions: Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM.

Clinical trials registration number: NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).

Keywords: antiangiogenic; cabozantinib; pretreated; progressive glioblastoma; recurrent.

© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Figures

Fig. 1
Fig. 1
Best changes from baseline in IRF measurements of tumor lesions using modified RANO criteria in patients who had measurable disease at baseline and ≥1 postbaseline radiographic scan. Lines indicate the threshold for response and progression per RANO criteria, ≥50% decrease and ≥25% increase, respectively. Partial responses were confirmed in 1 patient in the 140 mg/day group and 2 patients in the 100 mg/day group. *Confirmed partial response. †No prior bevacizumab therapy.
Fig. 2
Fig. 2
Kaplan–Meier estimates of (A) progression-free survival and (B) overall survival by dose group on the basis of central assessment of radiographic images. Circles = censored records.
Fig. 3
Fig. 3
Average daily glucocorticoid dose up to last treatment date among patients who reported any glucocorticoid use at baseline.

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