Mechanism of Action

Entrectinib has activity against anaplastic lymphoma kinase (ALK), ROS1, and TRKA, TRKB, and TRKC proteins [1-5]. Preclinical studies have demonstrated that entrectinib can cross the blood–brain barrier [3, 6, 7]. On this basis, entrectinib is thought to be able to target brain metastases and primary brain tumours.

The activity of entrectinib across a variety of kinases is shown in the following table, which summarises the IC₅₀ values for entrectinib inhibition of kinase activity [4].

Table 9: Entrectinib Inhibition of Kinase Activity [4]

Target	IC₅₀(nmol/L)
TRKA	1
TRKB	3
TRKC	5
ROS-1	7
ALK	12

Preclinical studies found that entrectinib completely inhibited ALK and STAT3 protein phosphorylation after administration in vivo [4]. In addition, entrectinib induced complete tumour regression in mouse tumour models (including TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumours, and ALK-dependent models from different tissue origins, including a CNS lung cancer metastasis model).

References

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Menichincheri M, Ardini E, Magnaghi P et al. Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor. J Med Chem 2016; 59: 3392-3408.
Ardini E, Menichincheri M, Banfi P et al. Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther 2016; 15: 628-639.
Sartore-Bianchi A, Ardini E, Bosotti R et al. Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. J Natl Cancer Inst 2016; 108.
Drilon A, Siena S, Ou SI et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov 2017; 7: 400-409.
Demetri GD, Paz-Ares L, Farago AF et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) Tumors: Pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Annals of Oncology 2018; 29: mdy424.017-mdy424.017, https://doi.org/410.1093/annonc/mdy1424.1017.