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Elective discontinuation following response to larotrectinib (Vitrakvi) was shown to be safe and feasible in pediatric patients with TRK fusion–positive infantile fibrosarcoma or other soft tissue sarcomas, according to data from the phase 1/2 SCOUT trial (NCT02637687) that were presented at the 2025 ESMO Sarcoma and Rare Cancers Annual Congress.1
At a data cutoff of July 20, 2023, and median follow-up of 41 months, all 47 patients were alive. The median time to discontinuation was 15 months (range, 3-65). Thirty-four percent of patients (n = 16) who discontinued larotrectinib had subsequent progression. The median time from discontinuation to progression was 3 months (range, 1-35).
“Larotrectinib demonstrated robust, durable responses and favorable safety in pediatric patients with TRK fusion sarcomas who had a drug holiday. These data suggest that patients with completely resected localized tumors can discontinue larotrectinib” Claudia Blattmann, MD, lead study author and medical director of the Department of Oncology, Hematology, and Immunology at Olgahospital in Stuggart, Germany, and coauthors, said in the presentation.
NTRK gene fusions are oncogenic drivers of several malignancies, including infantile fibrosarcoma, presenting in up to approximately 70% of cases and other pediatric sarcomas. In 2018, larotrectinib, the first-in-class, highly selective TRK inhibitor, received the second tissue-agnostic FDA approval in oncology, for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion.2
The present study was performed to better understand outcomes in pediatric patients with TRK fusion–positive sarcomas who electively discontinued the agent while in response.1
The trial enrolled pediatric patients up to 21 years of age with advanced solid tumors. Patients received a maximum dose of 100 mg/m2 of larotrectinib twice daily. Patients in the dose-escalation cohort received between 9.6 and 120 mg/m2 of larotrectinib twice daily based on target dosing calculation tables per protocol. All patients were actively followed for progression, and those who re-started larotrectinib due to progression were re-evaluated by investigators for response per RECIST 1.1.
The primary end points were time to discontinuation, time from discontinuation to progression, and time from progression to resumption of treatment. The secondary end point was safety.
Of the 99 pediatric patients who were enrolled, 47 patients with TRK fusion–positive sarcoma were allowed to discontinue larotrectinib in the absence of on-treatment disease progression.
Baseline characteristics indicated that the median age was 0.9 years (range, 0-13). Most patients were male (53%), had an ECOG performance status of 0 (83%), and infantile fibrosarcoma (64%) as opposed to other soft tissue sarcomas (36%). Only NTRK1 (36%) and NTRK3 (64%) gene fusions were represented in the study population. The median number of prior lines of therapy was 1 (range, 0-3). Prior lines of therapy included surgery (28%), radiotherapy (2%), and systemic therapy (55%). The best response to prior systemic therapy included complete response (CR; 2%), partial response (PR; 9%), stable disease (SD; 28%), progressive disease (9%), or other (9%). Forty-five percent of patients did not receive prior systemic therapy.
By the data cutoff, 64% of patients with infantile fibrosarcoma and 36% with other soft tissue sarcomas discontinued larotrectinib and entered the wait-and-see period in the absence of on-treatment progression. Fifty-three percent of patients discontinued treatment after achieving CR, which included 10 surgical patients with pathological CR (pCR), 38% with PR, and 9% with SD. Forty-five percent of patients electively discontinued larotrectinib after surgery, which took place up to 1 week after discontinuation, and 55% did not undergo surgery.
Investigators also evaluated time to discontinuation and progression in the surgical (n = 21) and non-surgical (n = 26) subgroups, whose follow-up ranged from 36 months to 41 months.
Within the non-surgical population, the median time to discontinuation was 20 months (range, 11-65). Twelve patients progressed, and the median time from discontinuation to progression was not reached (NR; range, 1-59).
The surgical population was further stratified by best response before or at the time of stopping larotrectinib. Patients whose best response was pCR (n = 10) had a median time to discontinuation 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 either R0 (n = 1), R1 (n = 8), or R2 (n = 1) resection, the median times to discontinuation were 22 months (range, 22-22), 8 months (range, 4-26), and 6 months (range, 6-6), respectively. One patient each with R1 and R2 resection experienced disease progression, and the median times from discontinuation to progression were NR (range, 1-78) and 1 month (range, 1-1), respectively.
Additional results indicated that 4 patients who underwent surgery and 12 who did not experienced disease progression. The median time from discontinuation to progression was NR in both the surgical and non-surgical groups. Ten patients with infantile fibrosarcoma and 6 with other soft tissue sarcomas had disease progression. The median time from discontinuation to progression was also NR in both histologic groups.
Best response after progression and resumption of treatment was also evaluated. Of the 16 patients who discontinued larotrectinib and had subsequent progression, all resumed treatment with the agent. Eleven patients had response to re-treatment, including 5 CRs, 6 PRs, and 4 cases of SD. Response was undefined in 1 patient who had re-started treatment and then underwent surgery.
Within the non-surgical cohort (n = 26), 12 patients had progressed and resumed treatment. Best responses after re-treatment included 4 CRs, 4 PRs, 3 cases of SD, and 1 response that was undefined. Within the surgical cohort (n = 21), best responses after re-treatment were 1 CR and 1 PR in the pCR population (n = 10), 1 PR in the R1 population (n = 8), and 1 case of SD in the R2 population (n = 1).
Regarding safety, treatment-related adverse effects (TRAEs) were mostly grade 1 or 2. Grade 3/4 TRAEs occurred in 34% of patients, the most common of which was neutrophil count decrease (any grade, 29.8%; grade ≥3, 19.1%). Other TRAEs were vomiting (any grade, 10.6%; grade ≥3, 2.1%), cough (any grade, 4.3%), increased aspartate aminotransferase (any grade, 48.9%), increased alanine aminotransferase (any grade, 44.7%; grade ≥3, 2.1%), diarrhea (any grade, 10.6%), anemia (any grade, 21.3%), constipation (any grade, 14.9%), blood alkaline phosphatase increase (any grade, 19.1%; grade ≥3, 6.4%), leukocyte count decrease (any grade, 25.5%), weight increase (any grade, 14.9%; grade ≥3, 6.4%), nausea (any grade, 21.3%), headache (10.6%), urinary tract infection (any grade, 2.1%), dry skin (any grade, 2.1%), platelet count decrease (any grade, 10.6%), hypoglycemia (any grade, 2.1%), lymphocyte count decrease (any grade, 17%), and pain in extremity (any grade, 2.1%).
No patients discontinued larotrectinib because of a TRAE.
Disclosures: Blattman had nothing to report.
References
Blattmann C, Mascarenhas L, Orbach D, et al. Treatment discontinuation outcomes in paediatric patients with TRK fusion sarcomas treated with larotrectinib. ESMO Open. 2025;10(suppl 3):104376. doi:10.1016/j.esmoop.2025.104376
FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Updated December 14, 2018. Accessed March 27, 2025. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions