Background: NTRK1, 2 and 3 gene fusions occur across a wide array of tumor types and can lead to constitutively-active TRKA, B, and C kinases. LOXO-101 is an orally bioavailable, potent, ATP-competitive, selective pan-TRK inhibitor. Here, we report response and durability data for patients with NTRK fusions enrolled in an ongoing Phase I dose escalation trial. Updated pharmacokinetic (PK) and safety data for all 41 enrolled patients (pts) are also reported.

Methods: This is an ongoing, open-label, multicenter, 3+3 dose escalation Phase I study. LOXO-101 is administered orally as a one- or twice-daily dose for continuous 28-day cycles. Response is measured by RECIST guideline, version 1.1, criteria. Plasma is obtained for PK analysis on Cycle 1 Day 1 and Day 8. Safety information is collected on all patients and adverse events are reported regardless of their attribution to the study drug.

Results: As of February 16, 2016, 41 pts with solid tumors refractory to available therapies have been enrolled, including seven pts with NTRK fusions across five different tumor types: sarcoma (1), papillary thyroid cancer (1), mammary analog secretory carcinoma (MASC) of the salivary glands (3), non-small cell lung cancer (1) and GI stromal tumor (1). Collectively, these seven patients harbor gene fusions involving both NTRK1 and NTRK3, with a variety of fusion partners. Six of the seven patients with NTRK fusions were evaluable for response evaluation at the time of data cutoff, and all six have demonstrated a clinical response to LOXO-101. Five of the six patients have achieved confirmed RECIST partial responses, while the sixth patient has exhibited a 21% tumor regression. All seven patients remain on study with no evidence of progressive disease. For these seven patients, duration of therapy ranges from one to thirteen cycles. No objective anti-tumor activity has been observed in treated patients without an NTRK fusion.

In total, 41pts have been treated on the Phase I study, across five dose levels (50mg QD, 100mg QD, 200mg QD, 100mg BID, and 150mg BID). 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. LOXO-101 has been well tolerated. The maximum tolerated dose has not been reached, and the most common adverse events are Grade 1 and 2 fatigue (29%), dizziness (24%) and nausea (20%).

Conclusions: LOXO-101 has been well tolerated and has shown promising and broad anti-tumor activity in patients with NTRK fusions. All patients with NTRK fusions have experienced objective tumor reductions, with 5/6 (83%) exhibiting confirmed RECIST partial responses. All of these patients remain on study without disease progression. These data suggest that a LOXO-101 dose of 100mg BID is well-tolerated and capable of inducing durable disease control in patients with NTRK gene fusions, supporting the design of the ongoing LOXO-101 Phase 2 basket trial.

Citation Format: David S. Hong, Anna F. Farago, Marcia S. Brose, Howard A. Burris, Afshin Dowlati, Todd M. Bauer, Matthew Taylor, Alice T. Shaw, Adriana Estrada-Bernal, Anh T. Lee, Nisha Nanda, Michael C. Cox, Robert C. Doebele. Clinical safety and activity from a phase I study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT008.