Pre-NDA Meeting With FDA May Lead ROS1 NSCLC Indication for Repotrectinib

A pre-NDA meeting with the FDA discussed planned patient follow-up for patients with ROS1+ advanced non-small cell lung cancer in cohorts of the ongoing TRIDENT-1 study of repotrectinib.

The FDA agreed to a plan to receive data about patients within ROS1-positive tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated advanced non–small cell lung cancer (NSCLC) cohorts of the ongoing phase 1/2 TRIDENT-1 study (NCT03093116) of repotrectinib (TPX-0005) during a pre-new drug application meeting, according to Turning Point Therapeutics, Inc.1

In the meeting, the FDA and Turning Point Therapeutics, Inc. discussed the planned new drug application for repotrectinib and proposed patient follow-up in ROS1-positive advanced NSCLC cohorts of the study. Provided data will be for this patient population with at least 6 months of follow-up from the first post-baseline scan at the time of new drug application submission.

Repotrectinib is a potential best-in-class, next-generation ROS1 TKI which works to target the ROS1 and TRK oncogenic drivers of both NSCLC and advanced solid tumors. The TKI binds inside ATP pockets in the presence of mutations.

Previously this TKI received 2 breakthrough therapy designations with the first for the treatment of patients with NTRK-positive TKI-pretreated advanced solid tumors in October 2021, and the second in May 2022, for the treatment of patients with ROS1-positive metastatic NSCLC.

“We continue to be encouraged by our collaborative meetings with the FDA,” said Mohammad Hirmand, MD, chief medical officer, in the press release. “The planned new drug application submission represents an important milestone for our company. The unmet need in ROS1-positive advanced NSCLC patients is significant, and we continue to believe that repotrectinib could offer a best-in-class profile for the treatment of these patients.”

In the open-label, multicenter, ongoing, registrational TRIDENT-1 trial, approximately 50 patients were pooled from the phase 1 and phase 2 portions of the study to examine the effects of repotrectinib among several cohorts.2

In order to be enrolled in the trial, patients must be aged 12 years and older with a histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by protocol specified tests. Further, patients must have an ECOG performance status of 0-1, at least 1 measurable target lesion according to RECIST v1.1, and a life expectancy of 3 months or greater. Having prior cytotoxic chemotherapy and immunotherapy is acceptable, and patients must have resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy.

Within phase 1, the dose-escalation portion of the study, primary end points consist of determining the first cycle dose-limiting toxicities, the maximum tolerated dose, the biologically effective dose, and the recommended phase 2 dose of repotrectinib which will then 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 will find the confirmed overall response rate of repotrectinib in each expansion cohort of advanced solid tumors that harbor either an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Secondary end points of the TRIDENT-1 trial are 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.

  1. Turning point therapeutics provides regulatory update for repotrectinib for the treatment of ROS1+ advanced NSCLC. News release. Turning Point Therapeutics, Inc. July 27, 2022. Accessed July 28, 2022.
  2. A study of repotrectinib (TPX-0005) in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1). Updated July 11, 2022. Accessed July 28, 2022.
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