January 31, 2021 - Repotrectinib, a next-generation ROS1 and TRK TKI, has demonstrated encouraging objective responses with acceptable tolerability in patients with ROS1 fusion–positive non–small cell lung cancer.
Repotrectinib (TPX-0005), a next-generation ROS1 and TRK TKI, has demonstrated encouraging objective responses with acceptable tolerability in patients with ROS1 fusion–positive non–small cell lung cancer (NSCLC), according to updated preliminary results from the phase 2 expansion 1 (EXP-1) cohort of the ongoing phase 1/2 TRIDENT-1 clinical trial (NCT03093116) presented during the the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer.1
“Preliminary TRIDENT-1 data are very encouraging and support repotrectinib as a potential best-in-class treatment in ROS1-positive advanced NSCLC,” Byoung Chul Cho, MD, PhD, stated during a presentation of the data given.
Earlier interim data from a cohort of 11 patients in phase 1 of the TRIDENT-1 trial were reported in August 2020 and showed an objective response rate (ORR) of 91% (95% CI, 59%-100%) overall and 86% among patients who were ROS1 TKI–naïve and received the recommended phase 2 dose of repotrectinib. The median duration of response in this cohort was 23.1 months (95% CI, 5.6 to not reached [NR]). The median progression-free survival was 24.6 months (95% CI, 7.2 to NR).2
The EXP-1 cohort includes 55 patients with ROS1 TKI–naïve ROS1 fusion–positive advanced NSCLC. Patients in this cohort are a median of 58 years old (range, 30-76). Sixty percent of the population has an ECOG performance status of 1, and 20% had prior chemotherapy use. In phase 1 of the TRIDENT-1 study, this cohort achieved an ORR of 86% (95% CI, 42%-100%). Preliminary phase 2 data were evaluable in 15 patients whose data cutoff date was December 31, 2020.
Based on 2 post-baseline scans, Cho explained the clinical activity in the form of tumor shrinkage was observed in all patients who were treated with repotrectinib. The confirmed ORR in the EXP-1 cohort is 93% (95% CI, 93%-100%). As of data cutoff, a 16th patient from EXP-1 had an unconfirmed partial response, awaiting confirmation based on a second post-baseline scan. When pooled with data from 7 patients treated in phase 1, the confirmed ORR for the cohort is 91% (95% CI, 71%-99%).
Pooled data from phases 1 and 2 for the EXP-1 cohort (n = 22) show that 2 phase 1 patients remain on treatment, as well as 14 phase 2 patients. Of the patients who were treated with repotrectinib in phase 1, 57% remained on treatment for more than 30 months. The median time on treatment was 30.9 months (range, 10.9-37.3) in phase 1 and 5.3 months (range, 3.7+ to 10.9+) for the ongoing phase 2 portion of the study.
Combined safety data for patients treated in phases 1 and 2 across all cohorts (n = 185) show repotrectinib to be well tolerated in patients with ROS1 fusion–positive advanced NSCLC. The majority of the treatment-related adverse events (TRAEs) observed so far were grade 1 or grade 2, and none were above grade 3. In fact, most of the treatment-emergent AEs (TEAEs) were only grade 1 (79%). The most common TEAE (≥15% of patients) was low-grade dizziness (58.4%). Dizziness did not lead to treatment discontinuation in any patient.
Dose reductions were performed for 17.8% of patients due to TEAEs. In addition, 8.6% of patients discontinued treatment due to TEAEs.
The open-label, multi-center, first-in-human TRIDENT-1 study continues to evaluate treatment with repotrectinib in patients with ROS1 fusion–positive advanced NSCLC, as well as NTRK fusion–positive disease. The study includes 6 EXP cohorts who are being assessed for the primary end point of ORR, as well as secondary end points including DOR, clinical benefit rate, PFS, overall survival, and intracranial ORR.
As part of the ROS1 fusion–positive population, the EXP-2 cohort includes 60 patients who are previously treated with 1 ROS1 TKI and platinum-based chemotherapy. A portion of this cohort (n = 5) had an ORR of 40% (95% CI, 5%-58%) in the phase 1 portion of the study. The 40 patients in EXP-3 are previously treated with 2 ROS1 TKIs and no chemotherapy. In phase 1, the EXP-3 cohort also had an ORR of 40% (95% CI, 5%-58%), according to data from 5 of the patients. The last cohort of patients with ROS1 fusion–positive disease are from EXP-4 and are a group of 60 individuals who received 1 prior ROS1 TKI and no prior chemotherapy. Phase 1 data from 6 patients from EXP-4 showed an ORR of 67% (95% CI, 22%-96%).
Two cohorts of patients with NTRK fusion are included in TRIDENT-1. The 55 patients in EXP-5 are naïve to TRK TKIs and thus far, no response data have been reported for these patients. EXP-6 includes 40 patients who are pretreated with TRK TKI(s). In phase 1, the EXP-6 cohort had an ORR of 50% (95% CI, 12%-88%), according to data from 6 of the patients.
Currently, TRIDENT-1 is recruiting patients with either ROS1 fusion– or NTRK fusion–positive advanced NSCLC from 90 sites around the world. During his WCLC presentation, Cho explained that “consistent with phase 1 data, updated phase 2 data continue to support strong clinical activity in [patients with] TKI-naive ROS1-positive NSCLC.” The preliminary results from TRIDENT-1 led the FDA to grant repotrectinib a Breakthrough Therapy Designation, which may expedite the development of the drug and the regulatory review an application for FDA approval of repotrectinib as treatment of ROS1-positive metastatic NSCLC.1,3