Background: Gene fusions involving the NTRK1, 2 and 3 genes result in constitutively-active TRKA, -B, and -C kinases that are prevalent in a wide array of tumor types, including lung adenocarcinoma, thyroid, head and neck cancer, sarcoma, and other tumors. LOXO-101 is an orally bioavailable, potent, ATP-competitive, selective inhibitor of TRKA, TRKB, and TRKC being studied in a Phase 1 dose escalation trial. In pre-clinical in vivo xenograft mouse models bearing NTRK-fusions LOXO-101 demonstrated potent tumor growth inhibition and regression. Here, we report updated PK and safety data on 24 patients (pts).

Methods: In this on-going open-label, multicenter, 3+3 dose escalation Phase I study of LOXO-101, 24 pts with solid tumors refractory to standard therapy, normal hematopoietic and major organ function have been enrolled. LOXO-101 is administered orally as a single dose, followed by QD or BID doses for continuous 28-day cycles. Response is measured by RECIST Criteria, version 1.1. Serum is collected for pharmacokinetic analysis on Cycle 1 Day 1 and Day 8. Safety information is collected on all patients and the definition of dose-limiting toxicity applies to adverse events regardless of relationship to investigational product. Nude mice were injected with CUTO3.29 (MPRIP-NTRK1, lung adenocarcinoma) or MO-91 (ETV6-NTRK3, acute myeloid leukemia) cell lines and then administered LOXO-101 orally at 60 or 200mg/kg daily for 2 weeks.

Results: As of September 3, 2015, 24 pts have been treated at each of the first five dose levels (50mg QD, 100mg QD, 200mg QD, 100mg BID, and 150mg BID). LOXO-101 has been well tolerated; the MTD has not been reached and the most common adverse events are Grade 1 and 2 fatigue (42%), dizziness (29%) and anemia (21%). Two pts have had grade 3 AEs leading to dose cohort expansions: elevated AST, grade 3 (Dose Level 150mg BID) and delirium, grade 3 (Dose Level 100mg BID). Each case was subsequently deemed unrelated to study drug by the treating investigator, and the pts remained on study at reduced doses without recurrence.

PK analysis showed maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing. The unbound drug levels of LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at peak concentrations at all dose levels.

All three pts with NTRK-fusions enrolled have achieved a PR: an undifferentiated sarcoma with an LMNA-NTRK1 fusion (59% decrease; 7 cycles+), a c-kit-negative GI Stromal Tumor (GIST) with an ETV6-NTRK3 fusion (30% decrease; 2 cycles+), and a mammary analogue secretory carcinoma of the salivary glands with an ETV6-NTRK3 fusion (64% decrease; 2 cycles+). These patients were treated at either 100 or 150 mg BID. These data are supported by in vivo tumor regression in xenograft mouse models of NTRK1 and NTRK3 fusion bearing tumor cells of different histologies in the presence of clinically achievable concentrations of LOXO-101.

Conclusions: LOXO-101 has been well tolerated and has sufficient systemic exposure for robust tumor responses in 3 of 3 (100%) of NTRK-fusion pts enrolled on study. These data further validate this molecular target as an oncogenic driver across diverse tumor histologies and support the exploration of TRK inhibition in cancer pts with NTRK-fusions.

Citation Format: David S. Hong, Marcia S. Brose, Robert C. Doebele, Alice T. Shaw, Afshin Dowlati, Todd M. Bauer, Anna F. Farago, Adriana Estrada-Bernal, Anh T. Lee, Michael C. Cox, Nisha Nanda, Jennifer A. Low, Howard A. Burris, III. Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR13.