Larotrectinib Shown Effective and Tolerable in NTRK Fusion+ CNS Tumors

Promising responses and disease control rates were observed with larotrectinib (Vitrakvi) administered as treatment of patients with TRK fusion-positive central nervous system (CNS) tumors, underscoring the importance of NTRK gene fusion testing in all patients with CNS tumors.

“Now larotrectinib is an active and well-tolerated targeted therapy for patients with NTRK fusion-positive primary CNS tumors,” said Sébastien Perreault, MD, MSc , FRCPC, while presenting findings gathered from 2 clinical trials at the 2021 ASCO Annual Meeting.¹

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

The majority of patients (79%; n = 26) were under the age of 18. 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, while 15% had NTRK1 fusion, and 12% had NTRK3 fusion.

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

“We demonstrated a rapid response and durable disease control,” Perreault said.

Overall, there was a 30% ORR (95% CI, 16%-49%). Nine percent (n = 3) experienced a complete response, while 21% (n = 7) had a partial response. 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 that lasted 24 weeks or longer; 15% (n = 5) had stable disease that lasted less than 24 weeks, and 9% (n = 3) had progressive disease. There was a 73% (95% CI, 54%-87%) disease control rate of 24 weeks or longer.

In the 28 patients with measurable disease, 23 of them (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%). Median overall survival (OS) at that follow-up period was not reached, and the 12-month OS rate was 85% (95% CI, 71%-99%).

Larotrectinib was well-tolerated, with the majority of adverse events (AEs) being grade 1 and 2. Thirty-nine percent (n = 13) of patients experienced grade 3 or 4 AEs, and 9% had a grade 3 or 4 AE related to Larotrectinib, including grade 3 decreased neutrophil count, increased gamma-glutamytransferase, hyperglycemia, hypermatremia, and hypoatremia. There were no grade 5 AEs.

No patients had to permanently discontinue treatment due to AEs, but 2 patients (6%) required dose reductions and 11 patients (33%) skipped or delayed doses due to AEs.

The most common neurological AE was grade 1 to 2 headache (18%). One patient (3%) had a grade 3 headache, and out of the 6 patients who experienced neurological AEs from larotrectinib, all were grade 1 and 2.

“These results support testing for NTRK fusion for our patients with CNS tumors, especially if there’s no known driver, and especially in infants with glioma,” Perreault concluded.

_References

_{1. Perreault S, Martinus van Tullburg C, Georger B, et. Al. Efficacy and safety of Larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK)-positive primary central nervous system tumors. Presented at: 2021 ASCO Annual Meeting, 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 to test 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}