Phase II study of axitinib in patients with NF2-related schwannomatosis and progressive vestibular schwannomas

Abstract

Background: Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS).

Methods: Eligible patients were age > 5 years with a clinical diagnosis of NF2-related schwannomatosis (NF2-SWN) and at least one volumetrically measurable, progressive VS. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Primary endpoint was objective volumetric response rate to axitinib, hearing response was a secondary endpoint, along with validated quality of life assessments (NFTI-QOL).

Results: Twelve patients were enrolled and 8 completed 12 cycles, including 2 pediatric patients. Ten patients were evaluated for the primary endpoint, defined as ≥ 20% decrease in VS volume, with 2 volumetric responses observed; both were reached after 3 cycles and sustained during treatment. The best volumetric response was -53.9% after 9 cycles. Three hearing responses were observed, one of which was sustained during treatment. All patients experienced drug-related toxicities, the most common were diarrhea, hematuria, and skin toxicity, not exceeding grade 2, as well as hypertension, not exceeding grade 3. NFTI-QOL scores remained stable or improved during treatment.

Conclusions: Axitinib therapy targeting VEGFR, PDGFR and c-KIT is feasible in this population and associated with volumetric and hearing responses in a subset of patients. However, convenience of oral administration should be balanced with respect to efficacy and safety of axitinib in comparison with other molecular-targeted therapies, including intravenous bevacizumab.

Keywords: NF2-related schwannomatosis; axitinib; phase 2 trial; vestibular schwannoma.

Figure 1.

Waterfall plot of the percentage of change in tumor volume, from baseline, for each evaluable target tumor (n = 12). Each column represents a volumetrically measurable individual VS. For each tumor, the best response while on study is shown. For tumors that did not show any volume reduction, the largest percentage of volumetric growth during therapy is indicated.

Figure 2.

Kaplan–Meier estimates of cumulative PFS probability. This figure illustrates the overall (black line) PFS probability as measured from first dose of study drug to date of progression for all evaluable VS. Dashed lines indicate 95% confidence intervals.