FDA Grants Breakthrough Therapy Designation to Repotrectinib for ROS1+ Metastatic NSCLC
Breakthrough therapy designation has been granted to repotrectinib by the FDA for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer.
The FDA has granted breakthrough therapy designation (BTD) to repotrectinib (TPX-0005) for treatment use in patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have previously been treated with a ROS1 tyrosine kinase inhibitor and who have not received prior platinum-based chemotherapy, according to Turning Point Therapeutics, Inc.1
The BTD is supported by efficacy analyses of the TRIDENT-1 trial (NCT03093116) which included approximately 50 patients pooled from the phase 1 and phase 2 portions of the study.
“We are excited to receive our third BTD and eighth overall FDA regulatory designation for repotrectinib in an indication where there are no approved targeted therapies,” said Mohammad Hirmand, MD, chief medical officer, in the press release. “We are encouraged by the continued momentum in TRIDENT-1 with enrollment targets achieved in cohorts EXP-1, EXP-4 and EXP-6. We look forward to continuing to progress repotrectinib toward registration with our first pre-NDA meeting with the FDA to discuss the topline data by blinded independent central review from the ROS1-positive advanced NSCLC cohorts of the TRIDENT-1 study expected later this quarter.”
TRIDENT-1 is an open-label, multicenter, ongoing registrational trial observing the effects of repotrectinib among several cohorts. Enrollment is open to patients aged 12 years and older with a histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor that harbors an ALK, ROS1, neurotrophic tyrosine receptor kinase (NTRK) 1, NTRK2, or NTRK3 gene rearrangement by protocol specified tests.2
To be included in the trial, patients are required to have an ECOG performance status of 0-1, at least 1 measurable target lesion according to RECIST v1.1, and a life expectancy of at least 3 months. Additionally, prior cytotoxic chemotherapy and immunotherapy is allowed, and resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy is required.
Phase 1 consists of the dose escalation part of the study which will examine several primary end points including the first cycle dose-limiting toxicities, the maximum tolerated dose, the biologically effective dose, and the recommended phase 2 dose of repotrectinib to be given to adult patients with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
The phase 2 portion of the study aims to determine the confirmed overall response rate of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Secondary end points of the trial include the duration of response, time to response, progression-free survival, overall survival and clinical benefit rate of repotrectinib in each expansion cohort of advanced solid tumors that harbor one of the previously stated gene rearrangements.
Repotrectinib is a next-generation ROS1/TRK TKI that binds inside ATP pockets in the presence of mutations.
Repotrectinib has previously been granted 2 BTDs. The first for patients with ROS1-positive metastatic NSCLC who have not been treated with a ROS1 tyrosine kinase inhibitor, and the second for patients with advanced solid tumors that have a NTRK gene fusion, have progressed following treatment with 1 or 2 prior TRK tyrosine kinase inhibitors, with or without prior chemotherapy, and have no satisfactory alternative treatments.
Four fast track designations have also been granted to repotrectinib for various cancer types including patients with ROS1-positive advanced NSCLC who are ROS1 TKI naïve, ROS1-positive advanced NSCLC patients who were previously treated with 1 prior line of platinum-based chemotherapy and 1 prior ROS1 TKI, ROS1-positive advanced NSCLC patients pretreated with 1 ROS1 TKI without prior platinum-based chemotherapy, and NTRK-positive patients who have advanced solid tumors that have progressed following treatment with at least 1 prior line of chemotherapy and 1 or 2 prior TRK TKIs and have no satisfactory alternative treatments. Additionally, orphan drug designation was granted to repotrectinib in 2017.
