Repotrectinib (TPX-0005)

Our lead drug candidate, repotrectinib (TPX-0005), is an orally administered TKI (tyrosine kinase inhibitor) being evaluated in an ongoing Phase 1/2 trial called TRIDENT-1 for both TKI-naïve and TKI-pretreated patients with ROS1+ advanced NSCLC and NTRK+ advanced solid tumors.

Mechanism of Action
Repotrectinib is a small (low molecular weight), macrocyclic tyrosine kinase inhibitor of ROS1, TRK and ALK. Repotrectinib was designed to efficiently bind with the active kinase conformation and avoid steric interference from a variety of clinically resistant mutations. The compact and rigid three-dimensional structure enables repotrectinib to precisely and efficiently bind deep into the ATP binding pocket of the kinase, and potentially circumvent the steric interference that results in resistance to bulkier kinase inhibitors, especially the solvent-front and gatekeeper mutations of ROS1, TRK and ALK kinases.

Medical Need

Currently, there are no approved TKIs that can overcome solvent-front mutations that arise in ROS1 or TRK kinases.

An estimated 1.8 million people are projected to die of lung cancer in 2018, the leading cause of cancer-related deaths globally. Despite new targeted therapies for the treatment of NSCLC, there continues to be a growing number of acquired resistant mutations in patients previously treated with TKIs, particularly solvent-front mutations. The most common of the solvent-front mutation for the ROS1 kinase, G2032R, was reported in 2017 from a single institution in 41% of patients who experienced progressive disease while taking crizotinib (Gainor, et al. JCO Prec Oncol. 2017). In addition, emerging solvent-front mutations, such as TRKA G595R, TRKC G623R and TRKC G623E, have been reported in NTRK+ solid tumors after treatment with larotrectinib and current investigational agent entrectinib.

Given the incidence of these resistant mutations, there continues to be a high unmet medical need to develop novel therapies that can overcome intrinsic and acquired resistance, such as the development of solvent-front mutations.

Turning Point Therapeutics has been granted Breakthrough Therapy designation by the Food and Drug administration (FDA) for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have not been treated with a ROS1 tyrosine kinase inhibitor (TKI-naïve). Repotrectinib has also been granted three Fast Track designations by the FDA in ROS1-positive NSCLC patients who are TKI-naïve, ROS1-positive NSCLC patients who have been previously treated with one prior platinum chemotherapy and one prior ROS1 TKI, and NTRK-positive patients with advanced solid tumors who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK TKIs.

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