Efficacy, safety and pharmacokinetics (PK) of zurletrectinib, a next-generation pan-TRK inhibitor, in pediatric and adolescent patients (pts) with NTRK fusion-positive (NTRK+) solid tumors.

10048 Background: NTRK gene fusions are significant oncogenic drivers in pediatric tumors (e.g. infantile fibrosarcoma). Zurletrectinib is a highly selective next-generation TRK inhibitor. Preclinical data of zurletrectinib showed strong activity against resistant mutations, e.g., G595R. Promising efficacy was observed in a phase I/II clinical trial (NCT04685226). The pivotal phase II clinical trial (NCT05745623) is currently ongoing. Here we report an integrated analysis by combining pediatric and adolescent pts from the two clinical trials. Methods: Eligible pts with locally advanced or metastatic solid tumor harboring NTRK fusions, who failed from standard of care or for whom there was currently no effective therapy were included in the efficacy analysis. Adolescent pts (12-18 years) received zurletrectinib tablet at fixed dose, and pediatric pts ( < 12 years) received zurletrectinib orally disintegrating tablet (ODT) based on body surface area (BSA). The primary endpoint was confirmed objective response rate (ORR) per independent review committee (IRC). Tumor responses were assessed by IRC and investigators per RECSIT1.1 and RANO (BM) criteria. Treatment-emergent adverse events (TEAEs) were evaluated and graded according to CTCAE v5.0. Results: As of 23 Nov 2024, 18 pts in total were enrolled, including 8 pediatric pts and 10 adolescent pts. Median age was 5.0 (range: 3-9) and 13.5 (range: 12-15) respectively. ECOG performance status was between 0-1. Among the 18 pts, 6 TRK inhibitor treatment-naïve pts with central lab confirmed NTRK+ were efficacy evaluable. The confirmed ORR assessed by IRC was 100% (95% CI 54.1, 100.0). All of the pts achieved partial response (PR) at the 1 st tumor assessment and maintained the remission as of the cutoff date. Median time to response were 1.0 month (95% CI: 0.99, NE) in adolescent pts and 0.9 (95% CI: 0.89, NE) month in pediatric pts. It is worth noting that one pediatric patient who progressed on prior first-generation TRK inhibitor achieved complete response after receiving zurletrectinib. The most common treatment related adverse events (TRAEs) were ALT increased (n = 8) and anemia (n = 6), the majority of which were Gr 1 or 2. There were no TRAEs leading to dose reduction or discontinuation, and no serious TRAEs were reported. PK results indicated that zurletrectinib PK profiles in pediatrics and adolescents at the recommended phase 2 dose (RP2D) were similar to that in adults. Conclusions: The integrated analysis demonstrated that zurletrectinib had significant efficacy and good safety profile in pediatric and adolescent pts with NTRK+ solid tumors. Zurletrectinib also showed the potential to overcome the resistance to 1 st generation TRK inhibitors. These findings support zurletrectinib is a better treatment option for NTRK+ pediatric and adolescent pts. Clinical trial information: NCT04685226 .