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

Patrick Y Wen, 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, Timothy F Cloughesy, Patrick Y Wen, 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, Timothy F Cloughesy

Abstract

Background: Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM).

Methods: Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. 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, and safety.

Results: Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome.

Conclusions: Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions.

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

Keywords: antiangiogenic; cabozantinib; naive; 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 tumor size change from baseline in target lesion per IRF using modified RANO criteria in patients who had measurable disease at baseline and ≥1 evaluable 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 6 patients in the 140 mg/day group and 17 in the 100 mg/day group. *Confirmed partial response.
Fig. 2
Fig. 2
Kaplan–Meier estimates of (A) progression-free survival and (B) overall survival by dose group.
Fig. 3
Fig. 3
Average daily glucocorticoid dose up to last treatment date among patients who reported any glucocorticoid use at baseline.

References

    1. Ostrom QT, Gittleman H, Fulop J et al. . CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 2015;17(Suppl 4):iv1–iv62.
    1. Stupp R, Mason WP, van den Bent MJ et al. ; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996.
    1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology—Central Nervous System Cancers v1 2016. Available at: . Accessed April 23, 2017.
    1. Reardon DA, Turner S, Peters KB et al. . A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw. 2011;9(4):414–427.
    1. AVASTIN (bevacizumab) solution for intravenous infusion [prescribing information]. South San Francisco, CA: Genentech; 2015. Available at: . Accessed September 15, 2016.
    1. Kreisl TN, Kim L, Moore K et al. . Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–745.
    1. Friedman HS, Prados MD, Wen PY et al. . Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733–4740.
    1. Taal W, Oosterkamp HM, Walenkamp AM et al. . Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943–953.
    1. Wick W, Brandes AA, Gorlia T et al. . EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma. J Clin Oncol. 2016;(suppl; abstr 2001):34.
    1. Abounader R, Laterra J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol. 2005;7(4): 436–451.
    1. Arrieta O, Garcia E, Guevara P et al. . Hepatocyte growth factor is associated with poor prognosis of malignant gliomas and is a predictor for recurrence of meningioma. Cancer. 2002;94(12):3210–3218.
    1. Kong DS, Song SY, Kim DH et al. . Prognostic significance of c-Met expression in glioblastomas. Cancer. 2009;115(1):140–148.
    1. Lu KV, Chang JP, Parachoniak CA et al. . VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell. 2012;22(1):21–35.
    1. Jahangiri A, De Lay M, Miller LM et al. . Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of anti-angiogenic therapy resistance. Clin Cancer Res. 2013;19(7):1773–1783.
    1. Hutterer M, Knyazev P, Abate A et al. . Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res. 2008;14(1):130–138.
    1. Keating AK, Kim GK, Jones AE et al. . Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity. Mol Cancer Ther. 2010;9(5):1298–1307.
    1. Onken J, Torka R, Korsing S et al. . Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo. Oncotarget. 2016;7(9):9876–9889.
    1. Vajkoczy P, Knyazev P, Kunkel A et al. . Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci U S A. 2006;103(15):5799–5804.
    1. Dunn GP, Rinne ML, Wykosky J et al. . Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26(8):756–784.
    1. Yakes FM, Chen J, Tan J et al. . Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–2308.
    1. You WK, Sennino B, Williamson CW et al. . VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 2011;71(14):4758–4768.
    1. Navis AC, Bourgonje A, Wesseling P et al. . Effects of dual targeting of tumor cells and stroma in human glioblastoma xenografts with a tyrosine kinase inhibitor against c-MET and VEGFR2. PLoS One. 2013;8(3):e58262.
    1. Elisei R, Schlumberger MJ, Müller SP et al. . Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639–3646.
    1. Kurzrock R, Sherman SI, Ball DW et al. . Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660–2666.
    1. Smith DC, Smith MR, Sweeney C et al. . Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31(4):412–419.
    1. Batchelor TT, Mulholland P, Neyns B et al. . Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31(26):3212–3218.
    1. Duerinck J, Du Four S, Van Binst A, Everaert H, D’Haens J, Neyns B. Axitinib for the treatment of recurrent glioblastoma—early results from a randomized phase II trial [poster]. Eur J Cancer. 2013;49(suppl 2):S791.
    1. Choueiri TK, Escudier B, Powles T et al. ; METEOR Investigators Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–1823.

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