Larotrectinib Induces Rapid, Durable Responses in Pediatric Patients with TRK Fusion+ CNS Tumors

Treatment withlarotrectinib produced rapid and durable responses and high disease control rates (DCR) in pediatric patients with TRK fusion-positive primary central nervous system (CNS) tumors, according to an analysis of data submitted for 2024 independent review committee (IRC) review.

The overall response rate (ORR) of patients in the pediatric group (n=38) was 37% (95% confidence interval [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. Additionally, best overall response included complete response (CR; 8%; 0%), partial response (PR; 29%; 6%), stable disease (SD; 45%; 41%), and progressive disease (PD; 13%; 41%) in the pediatric and adult populations, respectively; however, some patients were not evaluable (NE; 5%; 12%).

In a data report showing that larotrectinib had a manageable safety profile in all patients with TRK fusion [positive] primary central nervous system tumors, five patients entered a 'wait and see period' with no documented progression. Longer follow-up is needed to determine which patients may be candidates for elective discontinuation.

1. Research principles and design

NTRK gene fusions are oncogenic drivers of multiple adult and pediatric tumor types and 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 U.S. Food and Drug Administration approved larotinib, the first intraclass and highly selective CNS-active TRK inhibitor, for tumor-agnostic use in adult and pediatric patients with NTRK fusion-positive cancers, based on evidence of robust ORR and duration of response (DOR).

In this analysis, researchers evaluated the clinical outcomes of larotrectinib in 2 clinical trials in patients with TRK fusion-positive primary central nervous system tumors. The Phase 1 1/2 SCOUT trial (NCT02637687) evaluated 36 patients younger than 21 years with advanced solid tumors, and the Phase 2 NAVIGATE basket study (NCT02576431) included 19 patients 12 years and older with advanced TRK fusion-negative solid tumors. A total of 55 patients with TRK fusion-positive primary central nervous system tumors were included in this analysis.

atIn the SCOUT trial, a "wait and see" approach is allowed. According to the trial protocol, patients without signs of on-treatment disease progression were allowed to discontinue larotrectinib treatment and were actively monitored for progression. If progression occurs, investigators will assess response to retreatment with larotrectinib. ORR as assessed by the IRC according to the Neuro-Oncology Response Evaluation Criteria served as the primary endpoint of the investigation. Secondary endpoints include DOR, progression-free survival (PFS), overall survival (OS) and safety.

2. Other efficacy data

In pediatric patients (n=18) with HGG, 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%). In pediatric patients with LGG (n=12), the ORR was 42% (95% CI, 15%-72%), including best overall response of PR (42%), SD (50%), and PD (8%). The 24-week DCR was 92% (95% CI, 62%-100%).

In 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, the median follow-up was 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, the median follow-up was 5 months, the median progression-free survival was 3 months (95% CI, 2-12), and the 3-year progression-free survival rate was 0.

RegardingOS, in the pediatric population, with a median follow-up of 46 months, the median OS (95% CI, 33-NE) was not reached, and the 3-year OS rate was 64% (95% CI, 46%-81%). In the adult population, the median follow-up was 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 in adult patients was 11 months (95% CI, NE-NE; median follow-up, NE), and the 3-year DOR rate was 0%.

3.“Wait and see” and safety investigation results

atIn the SCOUT study, 4 LGG patients and 1 HGG patient entered the "wait and see" period. The median duration of this period was 20 months (range 4-29). One LGG patient was withdrawn from the "wait and see" analysis due to noncompliance with required tumor evaluation visits. Importantly, none of the five patients in this analysis had documented progression and were alive at the data cutoff date.

In the "watchful waiting" population, best response before or at the time of discontinuation of larotrectinib was pathological CR (n=1; median treatment time before first "watchful waiting period", 11 months [range, 11-11] ), PR (n=1, median treatment time after the first "observation period," 27 months [range, 27-27]), and SD (n=3; median treatment time before the first "observation period," 28 months [range, 23-31]).

Regarding safety,Treatment-related adverse reactions (TRAEs) occurred in 58.2% of patients, mainly grade 1/2, although 9.1% of patients experienced grade 3/4 TRAEs, including increased gamma-glutamyl transferase levels, hyperglycemia, hypernatremia, hyponatremia, decreased neutrophil count, and increased aminotransferase levels. The researchers noted that no patients discontinued treatment due to TRAEs. However, treatment discontinuations unrelated 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 14.5% required dose adjustments due to TRAEs.

References:https://www.onclive.com/view/larotrectinib-induces-rapid-durable-responses-in-pediatric-patients-with-trk-fusion-cns-tumors