Repotrectinib continues to demonstrate durable efficacy in patients with ROS1+ NSCLC

With 14 months of minimum follow-up in the pivotal phase I/II TRIDENT-1 trial, repotrectinib continued to demonstrate durable efficacy in patients with ROS1+ non-small-cell lung cancer (NSCLC), including intracranial activity, in both the cohort of patients who are TKI-naïve and those who receive one prior TKI and no chemotherapy. Furthermore, safety in patients treated at the recommended phase II dosing was manageable, consistent with previous reports in all treated patients.

Although the standard-of-care ROS1 tyrosine kinase inhibitors (TKIs) such as crizotinib and entrectinib are effective, their durability of response is sometimes limited due to acquired ROS1 resistance mutations (such as G2032R). Repotrectinib is a next-generation ROS1 and TRK TKI with a compact macrocyclic structure designed to improve durability of benefit by decreasing the potential of developing ROS1 resistance mutations, circumventing known ROS1 resistance mutations, displaying favourable characteristics for enhanced intracranial activity. In the pivotal phase I/II TRIDENT-1 trial, repotrectinib demonstrated durable clinical activity in both TKI-naïve and TKI-pretreated patients with ROS1 fusion-positive (ROS1+) advanced NSCLC. At WCLC, a clinical update from the TRIDENT-1 trial with a median follow-up of 21.5 to 24 months was presented.

Study design

Patients with ROS1+ advanced NSCLC were assigned to 4 cohorts by treatment history: ROS1 TKI-naïve, one prior ROS1 TKI and one prior platinum-based chemo, two prior ROS1 TKIs and no prior chemo and one prior ROS1 TKI and no prior chemo. The recommended phase II dosing (RP2D) of repotrectinib was 160 mg QD for 14 days, followed by 160 mg BID. The phase II primary endpoint was confirmed objective response rate (cORR) by Blinded Independent Central Review (BICR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), intracranial ORR, cORR in TKI-pretreated patients with ROS1 G2032R NSCLC, and safety. Efficacy analyses included patients with ≥14 months follow-up. Safety assessments included patients treated at RP2D across all study cohorts.

Results

After a median follow-up of 24.0 months, patients in the ROS1 TKI naïve cohort treated at the RP2D (N= 63), had a cORR of 78% and a median DOR, median PFS and median OS that were not reached. For those pretreated with one prior ROS1 TKI and no prior chemo (N= 53), the cORR was 38%, median DOR was 14.8 months, median PFS was 9.0 months and median OS was 20.5 months (median follow-up of 21.5 months). The intracranial ORR per BICR for patients who were TKI-naïve (N= 9) was 89%, for those with one prior TKI and no chemo (N=13) the intracranial ORR was 38%. In an analysis of time to first intracranial progression only, none occurred within 18 months of repotrectinib treatment in both TKI naïve and TKI pretreated patients. Furthermore, no TKI-naïve patients who progressed on repotrectinib developed an on-target resistance mutation. Among TKI-pretreated patients with baseline G2032R mutation (N= 17), the cORR was 59%, median DOR was 7.6 months and median PFS was 9.2 months.

Among patients receiving repotrectinib at RP2D (N= 426), treatment-emergent adverse events (TEAEs) occurred in 422 (99%), most commonly dizziness (62%). Grade ≥3 TEAEs occurred in 216 (51%) and were considered treatment-related in 122 (29%). TEAEs led to dose reduction and treatment discontinuation in 38% and 7% of patients, respectively.

Conclusion

IN TRIDENT-1, with a median follow-up of over 20 months, repotrectinib continued to demonstrate durable clinical activity in patients with ROS1+ NSCLC. Repotrectinib led to durable intracranial responses, and may have delayed or prevented the development of brain lesions in patients without baseline brain metastases. Repotrectinib safety in patients treated at the RP2D was manageable and consistent with previous reports in all treated patients. These results demonstrate the potential of repotrectinib as a new standard of care option for TKI-naïve and TKI-pretreated patients with ROS1+ locally advanced or metastatic NSCLC.

Reference

Cho B.C., et al. Repotrectinib in Patients with ROS1 Fusion-positive (ROS1+) NSCLC: Update from the Pivotal Phase 1/2 TRIDENT-1 Trial. Presented at WCLC 2023; Abstract OA03.06.