Reference Detail

Ref Type

PMID

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NTRK2 rearrange	Advanced Solid Tumor	predicted - sensitive	Entrectinib	Clinical Study	Actionable	In a clinical study, Rozlytrek (entrectinib) treatment resulted in objective response in 75% (3/4) of patients with advanced solid tumors harboring rearrangement in NTRK1, NTRK2, or NTRK3 genes (AACR Apr 2016, Abstract # CT007).	detail...
NTRK1 rearrange	Advanced Solid Tumor	predicted - sensitive	Entrectinib	Clinical Study	Actionable	In a clinical study, Rozlytrek (entrectinib) treatment resulted in objective response in 75% (3/4) of patients with advanced solid tumors harboring rearrangement in NTRK1, NTRK2, or NTRK3 genes (AACR Apr 2016, Abstract # CT007).	detail...