Larotrectinib Is Promising for Pediatric TRK Fusion-Positive CNS Tumors

Larotrectinib led to rapid/durable responses and high disease control rates in children with TRK fusion-position central nervous system cancers.

Larotrectinib (Vitrakvi) elicited rapid and durable responses and high disease control rates (DCR) in children with TRK fusion-positive central nervous system (CNS) tumors, according to data from an independent review committee (IRC)–assessed analysis.¹

Findings, which were presented at the 2024 Society for Neuro-Oncology Annual Meeting, showed the overall response rate (ORR) for patients in the pediatric group (n = 38) was 37% (95% CI, 22%-54%), and the 24-week DCR was 74% (95% CI, 57%-87%). These rates in the adult patient (n = 17) group were 6% (95% CI, 0%-29%) and 12% (95% CI, 1%-36%), respectively.

Furthermore, best overall responses in the pediatric and adult populations, respectively, included complete response (CR; 8%; 0%), partial response (PR; 29%; 6%), stable disease (SD; 45%; 41%), and progressive disease (PD; 13%; 41%); however, some patients were not evaluable (NE; 5%; 12%).

“Larotrectinib had a manageable safety profile in all patients with TRK fusion[–positive] primary CNS tumors,” lead study author Sébastien Perreault, MD, MSc, FRCPC, stated in a presentation of the data. “Five patients entered ‘wait-and-see’ and did not have documented progression. Longer follow-up is needed to determine which patients could be candidates for elective discontinuation of treatment.”

Perreault is a clinical assistant professor in the Department of Neurosciences in the Faculty of Medicine at the Université de Montréal in Quebec. He is also a clinical researcher at CHU Sainte-Justine in Montreal, where he also serves as the director of the pediatric neurology program.

Study Rationale and Design

NTRK gene fusions are oncogenic drivers across a wide variety of adult and pediatric tumor types that can occur in up to 1% of adult primary brain tumors and are observed in approximately 6.2% of high-grade gliomas and 1.6% of low-grade gliomas in pediatric patients. The first-in-class and highly selective CNS-active TRK inhibitor larotrectinib is FDA approved for tumor-agnostic use in both adult and pediatric patients with NTRK fusion–positive cancers based on evidence demonstrating robust ORRs and durations of response (DOR).²

In this analysis, investigators evaluated the clinical outcomes of larotrectinib-treated patients with TRK fusion–positive primary CNS tumors across 2 clinical trials.¹ The phase 1/2 SCOUT trial (NCT02637687) evaluated 36 patients younger than 21 years of age with advanced solid tumors, and the phase 2 NAVIGATE basket study (NCT02576431) included 19 patients ages 12 years and older with advanced, TRK fusion–positive solid tumors. In total, 55 patients with TRK fusion–positive primary CNS tumors were included in this analysis.

In the SCOUT trial, a “wait-and-see” approach was permitted. Patients who demonstrated no signs of on-treatment disease progression were allowed to stop larotrectinib therapy and were actively monitored for progression in accordance with the trial protocol. If progression occurred, responses to retreatment with larotrectinib were evaluated by investigators.

This IRC-assessed analysis had a data cutoff of July 20, 2023, and pediatric patients received larotrectinib at a dose of 100 mg/m2 (maximum of 100 mg) twice daily.

ORR as assessed by IRC according to Response Assessment in Neuro-Oncology criteria served as the primary end point of the investigation. Secondary end points included DOR, progression-free survival (PFS), overall survival (OS), and safety.

Baseline Characteristics

The median age of the patients was 11 years (range, 0-79). Pediatric patients younger than 18 years of age made up 69% of the study population, and adult patients ages 18 years and older made up 31% of the population. Most patients were female (51%). Additionally, most patients had an ECOG performance status of 0 (56%), whereas 29% and 9% of patients had an ECOG performance status of 1 or 2, respectively.

Regarding genetic profiles, NTRK1, NTRK2, and NTRK3 gene fusions were observed in 22%, 67%, and 11% of patients, respectively. Tumor histologies included high-grade gliomas (HGG; 58%), low-grade gliomas (LGG; 27%), and other types of tumors (15%). The diagnoses for LGG and HGG in children were based on local site evaluations without systematic molecular testing, including methylation profiling.

In total, 76% of patients had received systemic therapy, 75% of patients had undergone surgery, and 51% of patients had received radiotherapy as prior treatments; the median number of prior systemic therapies was 1 (range, 0-8). Additionally, 24% of patients had received no prior systemic therapy, 45% of patients had received 1 prior therapy, 20% of patients had received 2 prior therapies, and 11% of patients had received 3 or more prior therapies.

Additional Efficacy Data

Among pediatric patients with HGG (n = 18), the ORR was 33% (95% CI, 13%-59%), including best overall responses of CR (11%), PR (22%), SD (50%), PD (11%), and NE (6%). The 24-week DCR was 72% (95% CI, 47%-90%).

Among pediatric patients with LGG (n = 12), the ORR was 42% (95% CI, 15%-72%), including best overall responses of PR (42%), SD (50%), and PD (8%). The 24-week DCR was 92% (95% CI, 62%-100%).

Among pediatric patients with other tumor types (n = 8), the ORR was 38% (95% CI, 9%-76%), including best overall responses of CR (13%), PR (25%), SD (25%), PD (25%), and NE (13%). The 24-week DCR was 50% (95% CI, 16%-84%).

Regarding PFS, in the pediatric population, at a median follow-up of 40 months, the median PFS was 20 months (95% CI, 11-51), and the 3-year PFS rate was 43% (95% CI, 24%-61%). In the adult population, at a median follow-up of 5 months, the median PFS was 3 months (95% CI, 2-12), and the 3-year PFS rate was 0.

Regarding OS, in the pediatric population, at a median follow-up of 46 months, the median OS was not reached (95% CI, 33-NE), and the 3-year OS rate was 64% (95% CI, 46%-81%). In the adult population, at a median follow-up of 19 months, the median OS was 19 months (95% CI, 4-22), and the 3-year OS rate was 15% (95% CI, 0%-41%).

The median DOR in pediatric patients was 17 months (95% CI, 6-NE), and the 3-year DOR rate was 37% (95% CI, 0%-75%). The median DOR for adult patients was 11 months (95% CI, NE-NE; median follow-up, NE), and the 3-year DOR rate was 0%.

“Wait-and-See” and Safety Findings

In the SCOUT study, 4 patients with LGG and 1 patient with HGG entered the “wait-and-see” period. The median duration of this period was 20 months (range, 4-29). One patient with LGG exited the “wait- and-see” analysis due to noncompliance with required tumor assessment visits. Importantly, none of the 5 patients in this analysis had documented progression, and all were alive at the data cutoff date.

The best responses before or at the time of stopping larotrectinib among the “wait-and-see” population were pathologic CR (n = 1; median time on treatment prior to the first “wait-and-see” period, 11 months [range, 11-11]), PR (n = 1; median time on treatment prior to the first “wait-and-see” period, 27 months [range, 27-27]), and SD (n = 3; median time on treatment prior to the first “wait-and-see” period, 28 months [range, 23-31]).

Regarding safety, treatment-related adverse effects (TRAEs) occurred in 58.2% of patients and were mainly grade 1/2, though grade 3/4 TRAEs occurred in 9.1% of patients, including increased gamma-glutamyltransferase levels, hyperglycemia, hypernatremia, hyponatremia, decreased neutrophil counts, and increased transaminase levels. Investigators noted that no patients discontinued treatment due to a TRAE. However, treatment discontinuations not related to treatment occurred in 14.5% of patients.

The most common any-grade TRAEs included increased alanine aminotransferase levels (23.6%), increased aspartate aminotransferase levels (16.4%), anemia (9.1%), vomiting (5.5%), headache (3.6%), diarrhea (1.8%), and cough (1.8%). Serious TRAEs occurred in 5.5% of patients, and dose modifications due to TRAEs were required in 14.5% of patients.

“These results support the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing patients with CNS tumors,” Perreault concluded in the presentation.

References

1. Perreault S, Spano JP, Nilsson A, et al. Long-term efficacy and safety of larotrectinib in patients with TRK fusion primary central nervous system (CNS) tumors: an updated analysis. Presented at: 2024 SNO Annual Meeting; November 21-24, 2024; Houston, TX.Abstract CTNI-07.

2. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA, November 26, 2018. Accessed November 24, 2024. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions