Abstract LB-302: Potential role of larotrectinib (LOXO-101), a selective pan-TRK inhibitor, in NTRK fusion-positive recurrent glioblastoma
Authors: Schram Alison M. , Taylor Barry S. , Hechtman Jaclyn F. , Benayed Ryma , Wang Lu , Hanusch Bethany , Young Robert , Grommes Christian , Ku Nora , Hyman David M. , Kaley Thomas , Drilon Alexander 
Published: July 2017

Efforts to develop genomically targeted therapy for glioblastoma (GBM) have been unsuccessful to date. Fusions involving the tropomyosin receptor kinases (TrkA/B/C) encoded by NTRK1/2/3 represent a potential therapeutic target in diffuse gliomas. Novel TRK inhibitors have shown remarkable efficacy in patients with TRK fusions in a myriad of solid tumor types; however, there is little clinical data on TRK inhibitor efficacy in diffuse gliomas. Here, we report the case of a 35 year-old woman with recurrent GBM whose NTRK3 fusion tumor was treated to response with larotrectinib. The patient was initially diagnosed with an IDH1 R132H-mutant, 1p/19q intact anaplastic astrocytoma of the right temporal lobe. Three years later, she developed a local recurrence treated with temozolomide with disease progression. Resection identified transformation to GBM for which she received temozolomide and an IDO inhibitor with rapid tumor growth. Urgent piecemeal debulking was performed and confirmed recurrent GBM in both the central and hippocampal components. She was started on CCNU and bevacizumab. Prospective clinical sequencing of the central tumor and matched normal DNA confirmed clonal IDH1 R132H and a mutational signature of temozolomide-induced hypermutation. Multi-region custom RNA sequencing of her disease utilizing the Archer Anchored multiplex technology revealed an in-frame EML4-NTRK3 fusion in the dominant clone of the central tumor that was absent from the hippocampal specimen, indicating intratumoral heterogeneity of a potential therapeutically sensitizing alteration. After further clinical deterioration due to progressive disease involving multiple other brain regions, the patient received larotrectinib via expanded access under an emergency single patient use protocol. A partial response was achieved after only three weeks, the degree of which was radiologically discrepant between disease sites, consistent with the subclonality of the fusion oncoprotein. While there was significant periventricular tumor shrinkage (67x52mm to 8x4mm), there was no shrinkage in the right frontal and occipital lobes. A repeat MRI 1 month later showed disease progression with increasing tumor in the latter sites, but ongoing response of periventricular tumor. This led to clinical deterioration and ultimate discontinuation of lacrotrectinib. In summary, the observed mixed response persisting even at the time of drug discontinuation suggests that while heterogeneous, the EML4-NTRK3-mutant subclone was sensitive and responded to larotrectinib therapy, highlighting larotrectinib’s potential role in TRK fusion CNS disease. TRK fusions may therefore be therapeutic targets in GBM. Patients with TRK fusion CNS tumors are eligible for the ongoing NAVIGATE Phase 2 larotrectinib trial to further understand this biological effect.

Citation Format: Alison M. Schram, Barry S. Taylor, Jaclyn F. Hechtman, Ryma Benayed, Lu Wang, Bethany Hanusch, Robert Young, Christian Grommes, Nora Ku, David M. Hyman, Thomas Kaley, Alexander Drilon. Potential role of larotrectinib (LOXO-101), a selective pan-TRK inhibitor, in NTRK fusion-positive recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-302. doi:10.1158/1538-7445.AM2017-LB-302