Designed to be Different.
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 structure is believed to enable 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.
The Patient Need
In 2020, lung cancer was the leading cause of cancer-related deaths globally, including many forms of oncogenic driven NSCLC. Despite new targeted therapies for the treatment of NSCLC, there continues to be a growing number of acquired resistant mutations in patients with previously treated TKIs, particularly solvent-front mutations. Existing TKIs can show susceptibility to acquired mutations, and toxicities that can limit duration of treatment. There continues to be a high unmet medical need to develop novel therapies that overcome intrinsic and acquired resistance, treat brain metastases, and prolong duration of response, with a more tolerable overall safety profile.
Repotrectinib’s Development Designations
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.