Patients with TRK fusion-positive sarcoma may choose to discontinue larotrectinib

Selective discontinuation after response tolarotrectinib is safe and feasible in pediatric patients withTRK fusion-positive infantile fibrosarcoma or other soft tissue sarcomas, according to data from the Phase 1/2 SCOUT trial (NCT02637687) presented at the 2025 ESMO Sarcoma and Rare Cancer Annual Conference. The data cutoff is July 2023, with a median follow-up of 41 months, and all 47 patients are alive. The median time to discontinuation was 15 months (range 3-65). 34% (n=16) of patients who discontinued larotrectinib subsequently progressed. The median time from discontinuation to progression was 3 months (range 1-35).

Larotrectinib demonstrated robust, durable responses and favorable safety profile in pediatric patients with TRK fusion sarcoma on drug holiday These data suggest that larotrectinib can be discontinued in patients with complete localized tumor resection. NTRK gene fusions are oncogenic drivers of several malignancies, including infantile fibrosarcoma, which occurs in approximately 70% of cases, and other pediatric sarcomas. In 2018, larotinib, a first-in-class highly selective TRK inhibitor, received its second tissue-agnostic approval from the FDA in oncology for the treatment of adult and pediatric patients with solid tumors harboring NTRK gene fusions

This study was designed to better understandthe outcomes of children with TRK fusion-positive sarcomas who selectively discontinued the drug in response. The trial enrolled pediatric patients younger than 21 years old with advanced solid tumors. Patients received larotrectinib at a maximum dose of 100 mg/m2 twice daily. Patients in the dose-escalation cohort received larotrectinib at 9.6 to 120 mg/m2 twice daily according to the target dose calculation table for each regimen. All patients were actively followed for progression, and investigators re-evaluated response in patients who restarted larotrectinib due to progression based on RECIST 1.1.

The primary endpoints were time to discontinuation, time from discontinuation to progression, and time from progression to resumption of treatment. The secondary endpoint was safety. Of the 99 pediatric patients enrolled, 47 patients with TRK fusion-positive sarcoma were allowed to discontinue larotrectinib without disease progression on treatment.

As of data cutoff,Sixty-four percent of patients with infantile fibrosarcoma and 36% of patients with other soft tissue sarcomas discontinued larotrectinib and entered a wait-and-see period without treatment progression. Fifty-three percent of patients discontinued treatment after achieving CR, including 10 surgical patients with pathological CR (pCR), 38% of PR patients, and 9% of SD patients. Elective discontinuation of larotrectinib after surgery occurred in 45% of patients, which occurred 1 week after discontinuation, and 55% did not undergo surgery. The researchers also assessed time to discontinuation and progression in surgical (n=21) and nonsurgical (n=26) subgroups, with follow-up ranging from 36 months to 41 months.

In the nonsurgical population, the median time to discontinuation was 20 months (range 11-65). Twelve patients progressed and the median time from discontinuation to progression (NR; range 1-59) was not reached.

The surgical population was further stratified by best response before or while larotrectinib was discontinued. Patients with best response pCR (n=10) had a median time off treatment of 7 months (range 5-22). Two patients progressed, and the median time from discontinuation to progression was NR (range 0-76). For patients whose best response was R0 (n=1), R1 (n=8), or R2 (n=1) resection, the median time to discontinuation was 22 months (range 22-22), 8 months (range 4-26), and 6 months (range 6-6), respectively. One patient each experienced disease progression after R1 and R2 resection, and the median time from discontinuation to progression was NR (range 1-78) and 1 month (range 1-1), respectively.

Additional results showed that 4 patients who underwent surgery and 12 patients who did not experience disease progression. The median time from drug withdrawal to progression was NR in both the surgical and non-surgical groups. Ten patients with infantile fibrosarcoma and six patients with other soft tissue sarcomas had disease progression. In both histological groups, the median time from discontinuation to progression was also NR.

Progression and best response after resumption of treatment were also assessed. Of the 16 patients who discontinued larotrectinib and subsequently progressed, all patients resumed treatment with the drug. Eleven patients responded to re-treatment, including 5 CRs, 6 PR and 4 SD. One patient who restarted treatment and then underwent surgery had an unclear response.

In the nonsurgical cohort (n=26), 12 patients progressed and resumed treatment. Best responses after retreatment included 4 CRs, 4 PRs, 3 SDs, and 1 undefined response. In the surgical cohort (n = 21), best response after retreatment was 1 CR and 1 PR in the pCR population (n = 10), 1 PR in the R1 population (n = 8), and 1 SD in the R2 population (n = 1).

About safety, treatment-related adverse reactions (TRAEs) are mostly grade 1 or 2. Grade 3/4 TRAEs occurred in 34% of patients, the most common of which was decreased neutrophil count. Other TRAEs are vomiting, cough, increased aspartate aminotransferase, increased alanine aminotransferase, diarrhea, anemia, constipation, increased blood alkaline phosphatase, decreased white blood cell count, weight gain, nausea, headache, urinary tract infection, dry skin, decreased platelet count, hypoglycemia, decreased lymphocyte count, and extremity pain.

No patients discontinued larotrectinib due toTRAE.

Reference materials:https://www.onclive.com/view/elective-discontinuation-may-be-possible-with-larotrectinib-in-trk-fusion-positive-sarcomas