Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial

Abstract

Background: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1.

Methods: Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009.

Findings: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one).

Interpretation: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results.

Funding: Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

Figure 1

The design of pilot phase II trial of imatinib mesylate in neurofibromatosis patients with plexiform neurofibromas.

Figure 2

Treatment with imatinib mesylate changes natural history of plexiform neurofibromas in NF1 patients. 2A, left. Plexiform neurofibroma growth in natural history studies over time in untreated NF1 patients indicates that virtually no tumours shrink over time; instead, they continue to slowly increase in volume (data plotted from reference ; Table (E)T-3). 2A, right. In striking contrast, a significant fraction of plexiform neurofibromas shrink in response to oral imatinib mesylate. Other plexiform neurofibromas continue to grow in imatinib-treated patients, demonstrating the clinical heterogeneity of these locally invasive tumours. Green lines with asterisks represent tumours that decrease volume over time as evidenced by MRI measurements; grey lines represent growing tumours including those not decreasing by ≥ 20% in volume. 2B. Relative percent of tumours in historical controls (left, ref 17) and imatinib treated patients (right) expressed by percent change in tumour volume.