Pre-NDA Meeting Held With FDA to Discuss Repotrectinib for ROS1+ Advanced NSCLC


A pre–new drug application meeting was held with representatives from Turning Point Therapeutics, Inc. and the FDA to discuss repotrectinib as a potential therapeutic option for patients with ROS1-positive advanced non–small cell lung cancer.

A pre–new drug application (NDA) meeting was held with representatives from Turning Point Therapeutics, Inc. and the FDA to discuss repotrectinib as a potential therapeutic option for patients with ROS1-positive advanced non–small cell lung cancer (NSCLC).1

The clinical-stage precision oncology company shared that they received positive feedback from the regulatory agency regarding the planned patient follow-up within the ROS1-positive, advanced NSCLC cohorts of the ongoing phase 1/2 TRIDENT trial (NCT03093116). Specifically, at the time of the application submission, the company will share findings from those with ROS1-positive disease who are TKI-naïve and TKI-pretreated and who have at least 6 months of follow-up from the time of their first post-baseline scan.

“We continue to be encouraged by our collaborative meetings with the FDA,” Mohammad Hirmand, MD, chief medical officer of Turning Point Therapeutics, Inc., stated in a press release. “The planned NDA 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.”

Repotrectinib is a next-generation ROS1 and TRK TKI that was granted a breakthrough therapy designation from the FDA in May 2022.2 The designation was supported by pooled efficacy findings from approximately 50 patients who were enrolled to either phase of the TRIDENT-1 trial, which was comprised of 6 expansion cohorts.

Patients with ROS1-positive NSCLC who were naïve to ROS1 TKIs, received 2 prior ROS1 TKIs, or 1 prior ROS1 TKI comprised expansion cohorts 1, 2, and 3, respectively. Those with NTRK-positive solid tumors who were naïve to TRK TKIs or who previously received TRK TKIs were included in expansion cohorts 5 and 6, respectively.

The primary end point in each cohort for the phase 2 portion of the research is objective response rate (ORR). Secondary end points include duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival, and intracranial ORR.

Dose-limiting toxicities were evaluated in the phase 1 portion of the trial. Investigators established 160 once daily for 14 days followed by 160 twice daily if tolerated as the recommended phase 2 dose of repotrectinib in TKI-naïve and -refractory patients who had advanced ALK/ROS1/NTRK-positive solid tumors.3

Interim data from expansion cohort 4 showed that in patients with NSCLC and ROS1 positivity who previously received 1 TKI without chemotherapy, repotrectinib elicited an ORR of 67% (95% CI, 22%-96%); notably, 4 of the 5 patients who received treatment achieved a complete response (CR).4 The DOR to treatment ranged from 1.0+ months to 5.7+ months. Moreover, all patients who experienced a CR continued to respond at the time of data cutoff.

Repotrectinib was also noted to have favorable tolerability, according to pooled safety findings from both phases of the trial spanning cohorts (n = 185).5 Most of the treatment-related adverse effects experienced with the agent were grade 1 or 2.

Seventy-nine percent of treatment-emergent adverse effects (TEAEs) were grade 1 in severity. Low-grade dizziness was the most common TEAE experienced by those who received repotrectinib, and it occurred in 58.4% of patients.

Moreover, 17.8% of patients required dose reductions, and 8.6% discontinued treatment due to toxicities.


  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. Turning Point Therapeutics granted breakthrough therapy designation for repotrectinib treatment in patients with one prior ROS1 tyrosine kinase inhibitor and no prior chemotherapy. News release. Turning Point Therapeutics. May 10, 2022. Accessed July 28, 2022.
  3. Lin J, Kim D, Drilon A, et al. Safety and preliminary clinical activity of repotrectinib (TPX-0005), a ROS1/TRK/ALK inhibitor, in advanced ROS1 fusion-positive NSCLC. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26; Toronto, Canada. Abstract OA02.02.
  4. Turning Point Therapeutics reports early interim data from registrational phase 2 trident-1 study of repotrectinib, provides regulatory update. News release. Turning Point Therapeutics. August 19, 2020. Accessed July 28, 2022.
  5. Cho BC, Doebele RC, Lin JJ, et al. Phase 1/2 TRIDENT-1 study of repotrectinib in patients with ROS1+ or NTRK+ advanced solid tumors. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract MA11.07
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