Abstract A029: Larotrectinib long-term efficacy and safety in pediatric patients with TRK fusion non-primary CNS tumors: Analysis update

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Abstract Background: NTRK gene fusions are oncogenic drivers across various pediatric and adult tumor types. The prevalence of NTRK gene fusions varies widely, from high (up to 90%) in rare tumors such as infantile fibrosarcoma and secretory carcinoma of the breast to low (<0.5%) in common cancers like non-small cell lung and colorectal carcinoma. Larotrectinib is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer based on a robust and durable objective response rate in both adult and pediatric patients with various tumor types. Here, we report updated data on larotrectinib-treated pediatric patients with TRK fusion non-primary CNS tumors. Methods: This analysis included patients from 2 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE]). Responses were independent review committee-assessed (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). In SCOUT, patients could stop larotrectinib in the absence of on-treatment progression (“wait-and-see”). Responses in patients who were re-treated due to progression were assessed by investigators (RECIST v1.1). Results: Ninety-nine patients with non-primary CNS tumors were eligible for analysis as of July 2024, including 49% with infantile fibrosarcoma, 41% with soft tissue sarcoma, and 9% with other solid tumors. Overall response rate was 86% (95% confidence interval [CI] 77–92). In total, 53 patients had complete responses (CR; including 17 pathological CR), 32 had partial responses (PR), 9 had stable disease (SD), and 3 had progressive disease (PD); responses were undefined in 2 patients. Median time to response was 1.8 months (range 0.9–7.3). Median duration of response was 51 months (95% CI 31-not estimable [NE]). Median progression-free survival and overall survival (OS) were 49 months (95% CI 32–NE) and not reached (NR), respectively. The 5-year OS rate was 87% (95% CI 80–95). Median time to investigator-assessed treatment failure (from larotrectinib initiation to earliest documented on-treatment disease progression, start of other anticancer treatment, or death) was NR. Of 54 patients who entered a first “wait-and-see” period (median duration 33 months [range 1–72]), 18 resumed treatment due to PD. Of these, 11 had a response (6 CR and 5 PR [including 2 pending confirmation]), 5 had SD, 1 was not evaluable, and 1 was undefined. Most treatment-related adverse events (TRAEs) were Grade 1/2. Three patients (3%) discontinued due to a TRAE. Conclusions: Larotrectinib demonstrated rapid and durable responses, extended survival, and favorable safety in pediatric patients with TRK fusion cancer. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions to identify pediatric patients who may benefit from targeted treatment. Citation Format: Leo Mascarenhas, Theodore W. Laetsch, Birgit Geoerger, Steven G. DuBois, Miranda P. Dierselhuis, Catherine M. Albert, Claudia Blattmann, Helen Toledano, Noah Federman, Ramamoorthy Nagasubramanian, Alberto Pappo, Tanya Watt, Domnita-Ileana Burcoveanu, Esther De La Cuesta, Natascha Neu, Daniel H. Orbach, Yizhuo Zhang. Larotrectinib long-term efficacy and safety in pediatric patients with TRK fusion non-primary CNS tumors: Analysis update [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A029.

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