Abstract P4-08-29: Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer: an updated analysis

Abstract Background: 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; approval was based on a robust and durable objective response rate in both adult and pediatric patients with various cancers. Here, we report long-term efficacy and safety data in patients with TRK fusion breast cancer (BC). Methods: Patients with TRK fusion BC treated with larotrectinib were identified from 2 clinical trials (NCT02576431 [NAVIGATE] and NCT02637687 [SCOUT]). Most patients received larotrectinib 100 mg twice daily. Responses were assessed by an independent review committee (IRC) per Response Evaluation Criteria in Solid Tumours v1.1. The data cutoff date was July 20, 2023. Results: At data cutoff, 16 patients were identified, 15 of whom were eligible for IRC assessment. Median age was 54 years (range 10–70). At enrollment, 2 (13%) patients had locally advanced disease and 14 (88%) had metastatic disease. Six (38%) patients had secretory carcinoma, 2 of whom were male; 10 (63%) patients had non-secretory carcinoma. NTRK gene fusions were identified by next-generation sequencing (NGS), fluorescence in situ hybridization, and an unknown method in 13 (81%), 2 (13%), and 1 (6%) patients, respectively. Of the 6 patients with secretory carcinoma, 4 had triple-negative BC (TNBC) and 2 had estrogen receptor-positive (ER+) / human epidermal growth factor receptor 2 (HER2) negative tumors. Of the 10 patients with non-secretory carcinoma, 4 had TNBC, 2 had ER+/HER2-equivocal (eq) BC, 2 had ER+/HER2 negative BC, 1 had ER–/HER2eq BC and 1 had ER+/HER2+ BC. Three patients with non-secretory carcinoma had known CNS metastases at baseline. Overall, 4, 2, and 10 patients had 0, 1, or ≥2 lines of prior systemic therapy, respectively; 3 of the patients with secretory carcinoma were treatment-naïve. The overall response rate (ORR) for the IRC-eligible patients (n=15) was 53% (95% confidence interval [CI] 27–79): 4 (27%) patients had complete responses (CRs; including 1 pathological CR [pCR]), 4 (27%) had partial responses (PRs), 3 (20%) had stable disease (SD), and 3 (20%) had progressive disease (PD); response in 1 patient (7%) was not evaluable. ORR for patients with secretory carcinoma (n=6) was 83% (95% CI 36–100): 3 (50%) patients had CRs (including 1 pCR), 2 (33%) had PRs, and 1 (17%) had SD. ORR for patients with non-secretory carcinoma (n=9) was 33% (95% CI 7–70): 1 (11%) patient had a CR, 2 (22%) had PRs, 2 (22%) had SD, and 3 (33%) had PD; response in 1 patient (11%) was not evaluable. In all patients, median time to response was 1.7 months (range 0.9–5.6). Median duration of response (DoR) was not reached (95% CI 7–not estimable [NE]); median follow-up was 43 months. Median progression-free survival (PFS) was 9 months (95% CI 2–NE); median follow-up was 44 months. Median overall survival (OS) was 21 months (95% CI 8–NE); median follow-up was 47 months. The 4-year rates for DoR, PFS, and OS were 73% (95% CI 41–100), 38% (95% CI 13–63), and 38% (95% CI 11–65), respectively. Treatment duration was 0–60+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1/2. Grade 3/4 TRAEs occurred in 3 (19%) patients: hepatic cytolysis and hepatitis, both in 1 patient; paresthesia and thrombocytopenia in 1 patient each. There were no treatment discontinuations due to TRAEs. Conclusions: Larotrectinib demonstrates rapid and durable responses and a favorable safety profile in patients with TRK fusion secretory or non-secretory BC. These results support the wider adoption of NGS panels that include NTRK gene fusions to identify patients who might benefit from TRK inhibitor therapy. Citation Format: Cristiano Souza, Ezra Y. Rosen, Antoine Italiano, Felipe Cruz, Biswajit Dubashi, Mahmut Gumus, Jessica Lin, Maria de Miguel Luken, Daniel Orbach, Sun Young Rha, Domnita-Ileana Burcoveanu, Natascha Neu, Chiara E. Mussi, Lin Shen, Alexander Drilon. Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer: an updated analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-08-29.