FDA Grants Breakthrough Designation to Repotrectinib for Pretreated, ROS1+ Metastatic NSCLC

The FDA has granted a breakthrough therapy designation to repotrectinib for the treatment of patients with ROS1-positive metastatic non–small cell lung cancer who have been previously treated with one ROS1 TKI and have not received prior platinum-based chemotherapy.

The FDA has granted a breakthrough therapy designation to repotrectinib for the treatment of patients with ROS1-positive metastatic non–small cell lung cancer (NSCLC) who have been previously treated with one ROS1 TKI and have not received prior platinum-based chemotherapy.1

“We are excited to receive our third breakthrough therapy designation and eighth overall FDA regulatory designation for repotrectinib in an indication where there are no approved targeted therapies,” Mohammad Hirmand, MD, chief medical officer of Turning Point Therapeutics Inc., stated in a 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.”

Repotrectinib, a next-generation ROS1 and TRK TKI, previously received two breakthrough therapy designations for patients with ROS1-positive metastatic NSCLC who have not received a ROS1 TKI, and patients with advanced solid tumors that have an NTRK gene fusion who have progressed after treatment with one or two prior TRK TKIs, with or without prior chemotherapy, and have no satisfactory alternative treatments.

The most recent designation is based on pooled efficacy data from approximately 50 patients enrolled in the phase 1 and phase 2 portions of the TRIDENT-1 trial (NCT03093116), which includes 6 expansion cohorts:

  • Expansion 1 cohort: ROS1 TKI–naïve ROS1-positive NSCLC
  • Expansion 2 cohort: ROS1-positive NSCLC with 1 prior ROS1 TKI and 1 platinum-based chemotherapy regimen
  • Expansion 3 cohort: ROS1-positive NSCLC with 2 prior ROS1 TKIs
  • Expansion 4 cohort: ROS1-positive NSCLC with 1 prior ROS1 TKI
  • Expansion 5 cohort: TRK TKI–naïve NTRK-positive solid tumors
  • Expansion 6 cohort: TRK TKI–pretreated NTRK-positive solid tumors

Each cohort is being evaluated for the primary end point of objective response rate (ORR) in phase 2, with secondary end points of duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival, and intracranial ORR.

In phase 1 of the trial, investigators evaluated dose-limiting toxicities and established the recommended phase 2 dose of repotrectinib (160 mg once daily for 14 days followed by 160 mg twice daily if tolerated) in TKI-naïve and -refractory patients with advanced ALK/ROS1/NTRK-positive solid tumors. Secondary end points included safety, pharmacokinetics, and preliminary antitumor efficacy.2

Interim data from the expansion 4 cohort showed that of 5 patients with ROS1-positive NSCLC who received prior treatment with 1 TKI without chemotherapy, 4 patients had a complete response (CR) to repotrectinib.3 The ORR in this patient population was 67% (95% CI, 22%-96%) and the DOR ranged from 1.0+ months to 5.7+ months. All patients who achieved a CR remained in response at the time of the data cutoff.

Pooled safety data from phase 1 and 2 across all cohorts (n = 185) indicated that repotrectinib was well tolerated in patients with ROS1 fusion–positive advanced NSCLC.4 Most treatment-related adverse events (TRAEs) were grade 1 or grade 2, and none were above grade 3. Notably, most treatment-emergent AEs (TEAEs) were only grade 1 (79%). The most common TEAE occurring in at least 15% of patients was low-grade dizziness (58.4%), which did not lead to treatment discontinuation.

Dose reductions occurred in 17.8% of patients because of TEAEs, and 8.6% of patients discontinued treatment because of TEAEs.

Enrollment across all six cohorts of the study remains open and continues to progress steadily.


  1. 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 May 11, 2022. https://bit.ly/3wiwZVv
  2. 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.
  3. 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 May 11, 2022. https://bit.ly/3iV1w3h
  4. 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