Phase 2 study of larotrectinib in children with newly diagnosed infantile fibrosarcoma (IFS): Children's Oncology Group (COG) ADVL1823 cohort A

10008 Background: NTRK1/2/3 gene fusions (TRK fusions) occur in a range of pediatric cancers and are the canonical molecular alterations in IFS. Larotrectinib is a highly selective TRK inhibitor that is FDA-approved for TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. ADVL1823 (NCT03834961) evaluated larotrectinib in children with newly diagnosed TRK fusion positive solid tumors in two histology-based cohorts. Cohort A enrolled patients with IFS and is the focus of this analysis. Methods: Newly diagnosed patients ≤30 years old with unresectable or metastatic IFS and a locally identified NTRK gene fusion were eligible for Cohort A utilizing a Simon 2-stage design. Patients received larotrectinib at a dose of 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles until disease progression, unacceptable toxicity, the tumor becoming surgically resectable following a minimum of 6 cycles of therapy, or completion of 12 cycles (for those with CR) or 26 cycles (for those with PR) of therapy. The primary endpoint was the centrally confirmed objective response rate within 6 cycles according to RECIST 1.1; response assessment occurred every 2 cycles for the first 6 cycles. The data cutoff was December 31, 2022. Results: Between October 2019 and May 2022, 18 patients with IFS were enrolled from 14 centers. The median age was 2 months (range <1 month to 4.6 years). NTRK fusions included presumed/confirmed ETV6: NTRK3, n=15, NTRK3 (partner unconfirmed), TMP3: NTRK1 and DCTN1: NTRK1, n=1 each, and were identified by FISH (n=8), NGS (n=7), and PCR (n=3). 17 of 18 patients (94%) demonstrated confirmed objective responses (16 PR and 1 CR,) resulting in closure to enrollment after meeting the pre-specified efficacy threshold. The only patient without confirmed response demonstrated 79% tumor reduction after cycle 2, but no confirmatory scan was obtained within the first 6 cycles. No patient discontinued therapy within the first 6 cycles due to disease progression or toxicity. Four (22%) patients had dose limiting toxicities: 2 neutropenia (both CTCAE V5 grade (G)4) and 1 each G3 AST increase and G3 weight loss. All patients resumed therapy following a dose reduction. Treatment-related grade ≥ 3 toxicities occurred in 7 patients, most commonly neutropenia (n=5, 3 G3, 2 G4). Conclusions: Larotrectinib is highly active and well tolerated in newly diagnosed patients with IFS. Enrollment of this very rare molecularly defined patient population was feasible within the COG. Ongoing follow-up will evaluate durability of response after treatment discontinuation at protocol specified response-adapted timepoints with or without surgical resection of tumor. Clinical trial information: NCT03834961 .