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Authors Alexander Drilon, Filippo G. De Braud, Salvatore Siena, Sai-Hong I. Ou, Manish Patel, Myung-Ju Ahn, Jeeyun Lee, Todd M. Bauer, Anna F. Farago, Stephen V. Liu, Natasha Reddinger, Rupal Patel, David Luo, Edna Chow Maneval, Pratik S. Multani et al
Title Abstract CT007: Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements: Updated phase I results
Journal Vol Issue Date Pages Journal Short Title
Cancer Res 76 14 Suppl
URL https://aacrjournals.org/cancerres/article/76/14_Supplement/CT007/613151/Abstract-CT007-Entrectinib-an-oral-pan-Trk-ROS1
Abstract Text Background: Entrectinib is a potent oral inhibitor of the tyrosine kinases TrkA, TrkB, TrkC (encoded by the genes NTRK1, NTRK2, NTRK3, respectively), ROS1, and ALK with IC50 < 2 nM (biochemical kinase assay). It has been evaluated in two Phase 1 studies (STARTRK-1 and ALKA-372-001) in patients with advanced or metastatic solid tumors harboring NTRK1/2/3, ROS1, or ALK molecular alterations, with or without asymptomatic or controlled CNS disease. Previously, we reported 600 mg daily as the Recommended Phase 2 Dose (RP2D) and an objective response rate of 72% in 18 tyrosine kinase inhibitor (TKI)-naïve patients with NTRK1/2/3 (4), ROS1 (8), or ALK (6) rearrangements treated at or above the RP2D (Siena et al, ESMO 2015). Methods: A 3+3 dose escalation was used to assess safety, pharmacokinetics, and identify the RP2D of entrectinib. Here we provide an update on anti-tumor activity (RECIST v1.1) and safety with continued follow-up of the cohort of patients with gene rearrangements. Results: At a median follow-up of 11 months, 11 of the 18 patients remain on study. Objective responses were observed in 3 of 4 (75%) NTRK1/2/3, 6 of 8 (75%; 1 complete response) ROS1 and 4 of 6 (67%) ALK patients, respectively. Responses were observed in NSCLC, colorectal cancer, mammary analog secretory carcinoma, and other solid tumors, as early as cycle 1 and lasting as long as > 2 years. Notably, a 46-year old male patient with SQSTM1-NTRK1-rearranged NSCLC previously treated with 4 lines of chemotherapy and immunotherapy achieved an overall partial response with a complete response in the brain. He remains on study in response at 10 months. The most common (>10%) treatment-related adverse events (AEs) at the RP2D were fatigue/asthenia (47%), dysgeusia (32%), constipation (26%), dizziness (21%), paresthesia (21%), diarrhea (16%), myalgia (16%), and weight gain (16%). Three treatment-related serious AEs were reported (2 occurred above the RP2D); all resolved with dose modifications. Conclusions: Entrectinib continues to display promising anti-tumor activity in TKI-naive patients across different solid tumor types harboring an NTRK1/2/3, ROS1, or ALK gene rearrangement. Similar patients are now being enrolled in STARTRK-2, a global Phase 2 basket study of entrectinib.

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