Repotrectinib (TPX-0005)

Agent Description

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 non-small cell lung cancer (NSCLC) and NTRK+ advanced solid tumors.

Repotrectinib is a small (low molecular weight), macrocyclic tyrosine kinase inhibitor of ROS1, TRK and ALK.

Mechanism of Action

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 is believed to allow 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.

Classification

Small (low molecular weight), macrocyclic tyrosine kinase inhibitor

Molecular Targets

ROS1, TRK, ALK, JAK, FAK, SRC

Monograph

Two Breakthrough Therapy designations by the U.S. Food and Drug Administration (FDA) in:

Patients with advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with one or two prior TRK tyrosine kinase inhibitors (TKIs), with or without prior chemotherapy, and have no satisfactory alternative treatments; and
Patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have not been treated with a ROS1 TKI.

Four Fast Track designations by the FDA in:

Patients with ROS1-positive advanced NSCLC who have not been previously treated with a ROS1 TKI;
Patients with ROS1-positive advanced NSCLC who have been previously treated with one prior line of platinum-based chemotherapy and one prior ROS1 TKI;
Patients with ROS1-positive advanced NSCLC pretreated with one prior ROS1 TKI without prior platinum-based chemotherapy; and
Patients with advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK TKIs and have no satisfactory alternative treatments.

Repotrectinib was also granted Orphan Drug designation in 2017 for the treatment of advanced NSCLC with adenocarcinoma histology.

Studies of Interest

Non-clinical and Clinical Interests for Repotrectinib: New indications, drug combinations, and ways to differentiate repotrectinib from other ROS1 and TRK inhibitors.

Potential Tumor Types:
Non-small Cell Lung Cancer
Colorectal Cancer (KRAS)
Breast Cancer (SRC)
Head and Neck
NTRK Solid Tumors
CNS Tumors (ALK)
Myeloproliferative Disease (JAK2)

Combinations with agents for the following targets or classes:
EGFRi
MEKi
KRAS
Immunotherapies
Chemotherapies

Utility Optimization:
Tolerability mitigation strategies
Resistance to therapy
Sequencing
Treatment through multiple lines / backbone therapy

Information collaborator would like included in investigator proposals

N/A