Abstract
BACKGROUND
This phase II study was designed to determine the efficacy of nilotinib in a biomarker-selected population of recurrent glioblastoma (GBM), enriched for platelet-derived growth factor receptor-alpha (PDGFR-alpha) activation. Nilotinib is a multi-kinase inhibitor approved as treatment for Philadelphia-chromosome/Bcr-Abl chronic myelogenous leukemia. In addition to targeting Bcr-Abl tyrosine kinase, it also inhibits PDGFR-alpha signaling.
METHODS
Patients with recurrent GBM, with either PDGFR-alpha amplification or PDGFR-alpha overexpression by immunohistochemistry (IHC) were enrolled in a single-arm, single institution phase II study. Nilotinib was administered at 400 mg twice a day. The primary end point was progression-free survival at 6 months (PFS6). Secondary end points were safety, overall survival (OS) and Objective Response Rate (ORR).
RESULTS
34 patients were treated (22 IDH-wild type GBM, 2 IDH-mutant GBM, 10 GBM NOS). 26 were male and 8 were female. Median age was 55.5 (range 22–78 years). Four patients had PDGFR-alpha amplification, and 30 had overexpression by IHC. Median lines of prior therapy were 1 (range 1–7). 6/34 patients (18%) experienced related adverse events grade ≥ 3. There were no grade 5 events. The PFS6 was 9% (3/34), and PFS12 was 6% (2/34). Median PFS was 1.3 months and the median OS was 6.6 months. Best response was stable disease (SD) for 8 patients and complete response (CR) for one patient. ORR was 1/34 patients (3%). The patient with a CR was IDH-wild type, unmethylated, had PDGFR-alpha overexpression by IHC, and had a durable response > 5 years.
CONCLUSION
Nilotinib had limited activity in recurrent GBM enriched for PDGFR-alpha, although there were a small number of durable responders. Further molecular characterization is warranted to determine additional biomarkers of response that could be used to select patients that may benefit from nilotinib.