Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas

Abstract

This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as ≥15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%-47%), with median time to response of 4.5 months (range, 3-12). In responders, reduction in VS volumes ranged from -15.7% to -23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%-58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9%-82.1%) and 70.6% (95% CI, 43.1%-86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab.

Recommendations for imaging tumor response in neurofibromatosis clinical trials

“…Therefore, more sensitive methods, such as volume segmentation, were developed for the analysis of PN and schwannomas. [10][11][12][13][14][15] These methods documented the feasibility of reproducibly measuring tumor volumes in natural history studies and treatment trials for PN and VS. 13,14,[16][17][18][19] Using the MEDx-based lesion detection method developed for PN, interobserver differences were less than 10% and intraobserver variation was #5%. 10 For VS measured using the Vitrea2 workstation, the coefficient of variation ranged from 0.6% to 6.8%.…”

“…29 Volumetric analysis of MRIs has been recommended to determine changes in tumor size 30 and has been incorporated into clinical trials targeting NF2-related VS. 17,18,31 Guidelines for response evaluation of benign NF tumors in clinical trials. Image acquisition and analysis.…”

Chemotherapie von Hirntumoren bei Erwachsenen

“…[33,34]. Bei malignen peripheren Nervenscheidentumoren (MPNST) kann bei Versagen der lokalen Therapieoptionen ein Behandlungsversuch mit Protokollen wie bei Weichteilsarkomen unternommen werden [35].…”

Current Concepts in Management of Vestibular Schwannomas in Neurofibromatosis Type 2

“…However, Erlotinib, a pure EGFR tyrosine kinase inhibitor [22], and Lapatinib, an ErbB2/EGFR inhibitor [23], have both failed to show significant beneficial tumour responses. A phase II study of the second-generation mTORC1 inhibitor, Everolimus was prematurely terminated due to a lack of volumetric response in the target VS [24].…”