Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumour types, including central nervous system (CNS) tumours. At ASCO 2021, results were presented of a study evaluating the TRK inhibitor larotrectinib in patients harbouring tropomyosin receptor kinase (TRK) fusion-positive CNS tumours. In this trial, larotrectinib induced rapid and durable responses, a high disease control rate, and a favourable safety profile.
Larotrectinib is a first-in-class, highly selective and CNS-active TRK inhibitor approved for the treatment of adult and paediatric patients with TRK fusion cancer. Larotrectinib previously demonstrated an objective response rate (ORR) of 78% across 175 adult and paediatric patients with various non-CNS cancers.1 At ASCO 2021, data with larotrectinib in patients with TRK fusion-positive primary CNS tumours were presented.2 Patients with primary CNS tumours harbouring an NTRK gene fusion enrolled in two clinical trials (NAVIGATE and SCOUT) were identified (n=33). Nine of these patients were enrolled in the NAVIGATE study while the other 24 patients were part of the paediatric phase I/II SCOUT trial. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. The primary endpoint of this analysis consisted of objective response rate (ORR) and was investigator assessed per Response Assessment in Neuro-Oncology (RANO). For patients whose target lesions were inadequate for RANO assessment (n=5), RECIST v1.1 was used.2
Efficacy and safety of larotrectinib
As of July 2020, 33 patients with TRK fusion-positive CNS tumours were identified: 19 high-grade gliomas (HGG), 8 low-grade gliomas (LGG), 2 glioneuronal tumours, 2 neuroepithelial tumours, 1 CNS neuroblastoma, and 1 small round blue cell tumour. Three quarters of patients had gene fusions involving NTRK2 (n=24; 73%) while the remaining patients had fusions in NTRK1 (n=5; 15%), and NTRK3 (n=4; 12%). Twenty-six of the enrolled patients were paediatric (<18 years), resulting in a median age of 8.9 years (range 1.3–79.0). In general, patients were heavily pre-treated with 45% of patients having received two or more prior lines of systemic therapy.2
The ORR in all patients was 30% with three complete responses (all in paediatric patients), seven partial responses (2 pending confirmation), twenty patients with disease stabilization (including 15 patients with stable disease for at least 24 weeks) and three progressive disease. The 24-week disease control rate in all patients was high at 73%. For patients with HGG, the ORR was 26%, while this was 38% for patients with LGG. Tumour shrinkage was seen in 23 out of 28 (82%) patients with measurable disease. Treatment duration ranged from 1.2 to 31.3 months. Four patients continued treatment beyond progression, two of these patients received treatment for more than one month. At the data cut-off, eighteen patients were still receiving treatment. The median time to best response was 1.87 months (range 0.99-3.75). At a median follow-up of 16.5 months, the median progression-free survival (PFS) was 18.3 months with a 12-month PFS rate of 56%. Median overall survival (OS) was not reached (95% CI 16.9–not estimable) at a median follow-up of 16.5 months, with a 12-month OS rate of 85%.
Treatment-emergent adverse events (TEAEs) were mainly of grade 1 and 2, with grade 3/4 TEAEs in only 39% of patients (no grade 5 events). Only three patients (9%) reported grade 3 or 4 AEs related to larotrectinib. Two patients required dose reductions and eleven patients had doses skipped, missed or delayed due to a TEAE, but this never led to a treatment discontinuation. The most common neurological TEAE was headache, reported in six patients (18%) at grade 1-2 and one patient (3%) at grade 3. Six patients had neurological AEs related to larotrectinib, all were of grade 1 or 2.2
Larotrectinib is active and well tolerated in patients with TRK fusion-positive primary CNS tumours, a population with a high unmet need for tolerable targeted therapeutic options. Objective responses and durable stable disease were seen in patients with primary CNS tumours treated with larotrectinib, with no treatment-related safety concerns. These results support testing for NTRK gene fusions in patients of all ages with CNS tumours.
1. McDermott R, et al. Survival benefits of larotrectinib in an integrated dataset of patients with TRK fusion cancer. Presented at ESMO 2020; Abstract 1955P.
2. Perreault S, et al. Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system tumors. Presented at ASCO 2021; Abstract 2002.