Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

Abstract

Background: Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors.

Methods: Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR).

Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified.

Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.

Keywords: NTRK gene fusions; TRK fusion; larotrectinib; primary CNS tumors.

Fig. 1

(A) Maximum change in target lesion size for 28 patients with baseline measurable disease^a and (B) duration of treatment and response for all patients (n = 33). ^aTumor responses in patients recorded at data cutoff, based on RANO sum of products of diameters, unless noted otherwise. RECIST v1.1 was used for target lesions that were not measurable with RANO at baseline or for tumor types for which RANO measurement is difficult. Five patients were excluded as they did not have measurable disease at baseline by either criterion. ^‡Based on RECIST v1.1 sum of longest diameter. ^§Discontinued treatment due to progression. “Other” includes glioneuronal, neuroepithelial, diffuse leptomeningeal, neuroblastoma, and recurrent small round blue cell brain tumors. CR: complete response; HGG: high-grade glioma; LGG: low-grade glioma; PD: progressive disease; PR: partial response; RANO: Response Assessment in Neuro-Oncology; RECIST: Response Evaluation Criteria in Solid Tumors; SD: stable disease.

Fig. 2

Case study: pediatric primary spinal high-grade glioma harboring an ETV6-NTRK3 gene fusion (A) at baseline prior to commencing treatment with larotrectinib, and (B) after cycle 22 with no evidence of disease. A pediatric patient was diagnosed with primary spinal high-grade glioma at 4 months of age. The patient was treated with chemotherapy which consisted of 72 weeks of vincristine, cyclophosphamide, cisplatin and etoposide. The best overall response to this regimen was stable disease. At 3 years old, the patient experienced progression of disease. An ETV6-NTRK3 gene fusion was identified and the patient commenced on larotrectinib (Figure 2A). A complete response was achieved after two cycles of treatment and there was no evidence of disease after 22 cycles (Figure 2B). No significant adverse events were reported. Duration of treatment at the time of data cutoff was 15.7 months, with treatment ongoing. NTRK: neurotrophic tyrosine receptor kinase.