Ensartinib: the unknown TKI

Ensartinib (x396) is a medicine made by Xcovery, a biotech company based in Florida. It works closely with another company called Betta Pharmaceuticals in China for many of its trials.

Currently, there is an eXalt3 (phase 3) clinical trial to compare Ensartinib against Xalkori (not currently recruiting). 

Originally, there was a phase1/2 trial done in US around 2016.  Then, two phase 2 trials were done in China.  In these two (phase 2) trials, one was for patients already been treated with Xalkori and a second trial was for patients with ROS-1 mutation. 

The result was very promising for patients.  There was a paper published in 2018 by Dr. Wakelee, Dr. Lovely, and Dr. Horn; many of these names should be very familiar to our group.  Ensartinib was given at 250mg once per day and most common toxicities were rash (56%), nausea (36%), pruritus or skin sensation that promotes scratching (28%), vomiting (26%), and fatigue (22%).  A response rate of 60% was found and the median progression free survival (mPFS) was 9.2 months.  In TKI naïve patients who have never used any TKI previously, the response rate was 80% and the mPFS was 26.2 months. There was also response observed in CNS penetration at about 64%.  Most of the patient in this trial has already used chemotherapy or another TKI previously.  Some patients had stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). 

Ensartinib also can inhibit other genes (TPM3-TRKA, TRKC, and GOPC-ROS1).  If given at even higher concentraions, ensartinib can theoretically inhibit EphA2, EphA2, EphB2, and c-MET. 

In a recent report given by Dr. Horn to the IASLC World Conference on Lung cancer, the mPFS was 25.8 months compared to Crizotinib at 12.7 months.  Patients were given 225mg per day of Ensartinib.

There was a chart posted previously in our group about the biochemical nature of Ensartinib (see below). It shows the efficiency of binding of Ensartinib at various locations of an aberrant ALK variant.  Green box denotes binding is stronger than is red (less binding).  The letter/number on the left denotes the mutation observed.

A more recent paper was published on the phase 2 trials of ensartinib in Jan 2020.  27 different centers were involved in this study.  About 40 authors from all over China are joined in a herculean effort to study this drug!  156 patients were enrolled.

Therefore, in addition to Crizotinib, Ceretinib, Alectinib and Loraltinib, there will be one more player that is stepping up to be another 1st line ALK TKI.   

 https://clincancerres.aacrjournals.org/content/clincanres/24/12/2771.full.pdf

https://www.sciencedirect.com/science/article/abs/pii/S2213260019302528