Abstract 52: Antitumor activity of entrectinib, a highly potent pan-TRK, ROS1, and ALK inhibitor, in NTRK-fusion positive acute myeloid leukemia
Authors: Fagan Patrick , Barrera Maria , Walsh Colin , Murphy Danielle , Silverman Ian , Shoemaker Robert , Wei Ge , Hornby Zachary , Li Gary , Smith Kristen M. 
Published: August 2018

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and comprises a heterogeneous group of diseases. A number of recurrent leukemogenic gene mutations or chromosomal rearrangements have been identified and clinically validated in AML. However, nearly 50% of AML patient samples lack any known canonical AML driver mutations. Advances in molecular diagnostics have resulted in the identification of novel and actionable gene mutations or chromosomal rearrangements in a subset of these AML samples. The ETV6-NTRK3 fusion gene is one such rearrangement identified in samples from patients with AML. Fusion of ETV6 to the tyrosine kinase domain of TRKC (encoded by NTRK3) results in constitutive activation of the TRKC kinase, and ETV6-TRKC fusion protein expression has been shown to be sufficient for leukemogenesis. Constitutive activation of TRK family tyrosine kinases has also been detected in a wide range solid tumor and hematologic malignancies including lung, colorectal, salivary gland, sarcoma, thyroid, glioblastoma, melanoma, anaplastic large cell lymphoma, and Philadelphia-like acute lymphoblastic leukemia.

Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent, and selective kinase inhibitor with low nanomolar potency against TRKA/B/C, ROS1 and ALK kinase activities (encoded by NTRK1/2/3, ROS1, and ALK genes, respectively). In these studies, we have demonstrated sensitivity to entrectinib in AML cell lines with endogenous expression of the ETV6-NTRK3 fusion gene. Entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with sub-nanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein, as well as phosphorylation of known TRKC downstream signaling effectors, was inhibited by entrectinib treatment in a dose-dependent manner. Sensitivity to entrectinib was dependent on expression of the TRKC fusion protein. In xenograft models, entrectinib treatment at clinically relevant doses resulted in tumor regression, which was accompanied by elimination of residual cancer cells from the bone marrow.

The clinical relevance of activated oncogenic tyrosine kinases resulting from chromosomal rearrangements has been validated by the efficacy of selective tyrosine kinase inhibitors. Entrectinib is currently the subject of STARTRK-2, an ongoing global phase 2 basket study enrolling patients across multiple tumor histologies containing TRK, ROS1, or ALK fusions. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with NTRK rearranged acute myeloid leukemia and provide a rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.

Citation Format: Patrick Fagan, Maria Barrera, Colin Walsh, Danielle Murphy, Ian Silverman, Robert Shoemaker, Ge Wei, Zachary Hornby, Gary Li, Kristen M. Smith. Antitumor activity of entrectinib, a highly potent pan-TRK, ROS1, and ALK inhibitor, in NTRK-fusion positive acute myeloid leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 52.