Larotrectinib (1223403-58-4) is a potent (IC50’s < 11 nM) inhibitor of tropomyosin receptor kinases A, B, and C (TrkA, B, and C).1 It is >100 fold selective against a panel of 229 kinases. Larotrectinib markedly attenuated bone cancer pain and significantly blocked the formation of neuroma-like structures and the sprouting of sensory nerve fibers. Larotrectinib caused substantial tumor regression in various cancers displaying TRK gene fusions.2-4 Larotrectinib is the first tissue agnostic drug approved by the FDA.
1) Ghilardi et al. (2010), Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation, and bone cancer pain; Mol. Pain, 6 87
2) Doebele et al. (2015), An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101; Cancer Discov., 5 1049
3) Landman et al. (2018), Rapid response to Larotrectinib (LOXO-101) in Adult Chemotherapy-Naïve Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion; Clin. Breast Cancer, 18 e267
4) Drilon et al. (2018), Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children; N. Engl. J. Med., 378 731