Larotrectinib Is Efficacious and Tolerable in NTRK-Fusion Positive CNS Tumors

Larotrectinib (Vitrakvi) elicited promising responses and disease control rates in patients with TRK fusion-positive central nervous system (CNS) tumors, highlighting the importance of testing NTRK gene fusion in all patients with CNS tumors.

“Larotrectinib is now an active and well-tolerated targeted therapy for patients with NTRK fusion-positive primary CNS tumors,” said Sébastien Perreault, MD, MSc, FRCPC, during the presentation of findings collected from 2 clinical studies at the ASCO 2021 annual meeting

Perreault, director of the pediatric neurology program at CHU Sainte-Justine Hospital in Montreal, discussed the phase 1 basket study, NAVIGATE (NCT02576431), which involved 9 patients 12 years of age or older with advanced solid tumors and TRK fusion-positive cancers, as well as the phase 1/2 SCOUT study (NCT02637687)3, which involved 24 pediatric and young adult patients under 21 years of age who had locally advanced or metastatic solid tumors or CNS tumors.

The majority of patients (79%; n = 26) were under 18 years of age. Eighty-two percent had glioma (high grade, 58%; low grade, 24%). Other diseases observed were glioneuronal tumor (6%), neuroepithelial tumor (6%), CNS neuroblastoma (3%) and small round blue cell brain tumor (3%). Nearly two-thirds of patients (73%) had NTRK2 fusions, 15% had NTRK1 fusion, and 12% had NTRK3 fusion.

The subset analysis of NAVIGATE and SCOUT analyzed objective response rate (ORR) and investigator-assessed response assessment in neuro-oncology (RANO).

“We have demonstrated rapid response and sustainable disease control,” Perreault said.

Overall, there was an ORR of 30% (95% CI, 16%-49%). Nine percent (n = 3) experienced a complete response, while 21% (n = 7) had a partial response. The ORR in patients with high-grade glioma was 26% (95% CI, 9%-51%) and 38% (95% CI, 9%-76%) in patients with low-grade glioma. The median time to best response was 1.87 months (range 0.99-3.75).

Forty-five percent of patients (n = 15) had stable disease lasting 24 weeks or longer; 15% (n = 5) had stable disease lasting less than 24 weeks, and 9% (n = 3) had progressive disease. There was a disease control rate of 73% (95% CI, 54%-87%) of 24 weeks or longer.

Of the 28 patients with measurable disease, 23 (82%) experienced tumor shrinkage.

At a median follow-up of 16.5 months, the median progression-free survival (PFS) for patients with primary CNS tumors was 18.3 months, with a 12-month PFS rate of 56% (95% CI, 38% 74%). The median overall survival (OS) at that follow-up period was not achieved and the OS rate at 12 months was 85% (95% CI, 71%-99%).

Larotrectinib was well tolerated with most adverse reactions (AEs) being Grade 1 and 2. Thirty-nine percent (n=13) of patients received Grade 3 or 4 AEs and 9% had Grade 3 or 4 AE related to larotrectinib, including Grade 3 neutrophil count decreased, gamma-glutamytransferase increased, hyperglycaemia, hypermatremia, and hypoatraemia. There were no grade 5 AEs.

None of the patients required permanent discontinuation due to adverse events, but 2 patients (6%) required dose reductions and 11 patients (33%) skipped or delayed dosing due to adverse events.

The most common neurologic AE was Grade 1 to 2 headache (18%). One patient (3%) had Grade 3 headache and of the 6 patients who had neurologic adverse reactions to larotrectinib, all were Grade 1 and 2.

“These results support testing for NTRK fusion for our patients with CNS tumors, especially in the absence of a known driver, and especially in infants with glioma,” concluded Perreault.

References

1. Perreault S, Martinus van Tullburg C, Georger B, et. Already. Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) positive primary tumours of the central nervous system. Presented at: ASCO Annual Meeting 2021, June 1-8, 2021. Virtual.

2. A study to test the effect of the drug Larotrectinib in adults and children with NTRK Fusion Positive Solid Tumors (NAVIGATE). ClinicalTrials.gov. Updated May 28, 2021. Accessed June 7, 2021. https://clinicaltrials.gov/ct2/show/NCT02576431

3. A study of the safety and efficacy of the drug Larotrectinib for the treatment of tumors with fusion in children (SCOUT). Clinicaltrials.gov. Updated May 12, 2021. Accessed June 7, 2021. https://clinicaltrials.gov/ct2/show/NCT02637687

Comments are closed.