Introduction: Larotrectinib is a first-in-class, CNS-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved by the US Food and Drug Administration and European Medicines Agency for the treatment of adult and pediatric patients with tumor agnostic indication for TRK fusion-positive cancer. Larotrectinib produced an objective response rate (ORR) of 79% in 159 patients with TRK fusion-positive cancer across various tumor types (Hong DS et al. Lancet Oncol. 2020). Here we report the efficacy and safety of larotrectinib in the six patients from the NAVIGATE phase II study (NCT02576431) with TRK fusion-positive breast cancer. Methods: Data were obtained for patients with breast cancer harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and treated with larotrectinib in the NAVIGATE study. All patients received 100 mg twice daily on a continuous 28-day schedule. Responses were investigator-assessed per RECIST v1.1 (data cut-off: July 15, 2019). Results: A total of 6 patients with TRK fusion breast cancer were included: 3 with secretory carcinomas, 2 with triple-negative breast cancer (TNBC), and 1 with ER+/HER2− disease. The median age was 49 years (range 32-65). One of the patients with secretory breast cancer was male. All of the secretory cases and 1 TNBC patient harbored an ETV6-NTRK3 fusion, 1 TNBC patient had an LMNA-NTRK1 fusion, and the ER+/HER2− patient had a TPM3-NTRK1 fusion. Four patients had received ≥3 prior systemic therapies. The majority of patients had metastatic disease (n=5); 1 patient had locally advanced disease. The ORR was 83% (95% confidence interval [CI] 36-100) with 5 partial responses, while the ER+/HER2− patient had progressive disease. One of the TNBC patients had brain metastasis with complete resolution of CNS disease while on therapy. The median time to response was 1.7 months (range 0.9-1.9) and the duration of treatment ranged from 0.9 to 12+ months, with 4 patients (3 secretory and 1 TNBC) continuing on therapy at time of data cut. Median duration of response was not reached (95% CI 8.2-NE). Median progression-free survival was 9.1 months (95% CI 1.0-NE). Median overall survival was not reached at a median follow-up of 7.4 months. Four of the 6 patients had worst-grade adverse events (AEs) Grade 1-2; the most common Grade 1-2 AEs were dizziness and nausea. One patient had Grade 3 hepatocellular injury and Grade 4 hepatitis that were related to larotrectinib. There were no discontinuations due to AEs. Conclusion: Larotrectinib demonstrated an ORR in breast cancer patients similar to the ORR reported for larotrectinib across all tumor types, which supports the routine testing for NTRK gene fusions in patients with breast cancer regardless of histology.

Citation Format: Ezra Y. Rosen, Antoine Italiano, Dejan Juric, John A. Reeves, Laura Dima, Nicoletta Brega, Alexander Drilon. Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-06.