Background
Registrational phase 1/2 single-arm; advanced ROS1 fusion-positive NSCLC; cohorts by prior ROS1 TKI/chemo exposure. ROS1+ N=127 (TKI-naive n=71; 1 prior TKI/no chemo n=56). Repotrectinib is a next-gen ROS1 TKI designed for resistance mutations and CNS disease.
Results
Interventions and follow up: Treatment: repotrectinib 160 mg PO daily x14d, then 160 mg PO BID (RP2D).
Primary endpoint: confirmed ORR by BICR per RECIST v1.1.
mFollow up: ~24.0mo (TKI-naive), ~21.5mo (pretreated).
Results: TKI-naive (n=71): ORR 79% (95% CI 68–88), mDOR 34.1mo, mPFS 35.7mo, mOS NE.
Prior 1 TKI/no chemo (n=56): ORR 38% (95% CI 25–52), mDOR 14.8mo, mPFS 9.0mo, mOS 25.1mo.
ROS1 G2032R (n=17): ORR 59% (95% CI 33–82).
CNS: intracranial responses in 7/8 TKI-naive and 5/12 previously treated patients with measurable brain metastases.
Primary endpoint: confirmed ORR by BICR per RECIST v1.1.
mFollow up: ~24.0mo (TKI-naive), ~21.5mo (pretreated).
Results: TKI-naive (n=71): ORR 79% (95% CI 68–88), mDOR 34.1mo, mPFS 35.7mo, mOS NE.
Prior 1 TKI/no chemo (n=56): ORR 38% (95% CI 25–52), mDOR 14.8mo, mPFS 9.0mo, mOS 25.1mo.
ROS1 G2032R (n=17): ORR 59% (95% CI 33–82).
CNS: intracranial responses in 7/8 TKI-naive and 5/12 previously treated patients with measurable brain metastases.
Adverse events
Most common (any grade, pooled n=426): dizziness 58%, dysgeusia 50%, paresthesia 30% — largely manageable with dose modification.
Grade ≥3: 29%; most common anemia and CK increase (4% each).
Notable: TRAE discontinuation 3%; no treatment-related deaths.
Grade ≥3: 29%; most common anemia and CK increase (4% each).
Notable: TRAE discontinuation 3%; no treatment-related deaths.
Conclusions
Repotrectinib produced high, durable systemic and intracranial responses in ROS1+ NSCLC regardless of prior TKI, with activity against G2032R; toxicity mainly low-grade neurologic.
Key Limitations
Single-arm, no head-to-head comparison vs existing ROS1 TKIs, ORR surrogate; small cohorts (rare fusion); very small CNS-evaluable subsets limit intracranial precision.
Clinical Context
Supported FDA traditional (not accelerated) approval of repotrectinib in November 2023 for locally advanced/metastatic ROS1+ NSCLC in TKI-naive and pretreated patients; regarded as a preferred first-line ROS1 TKI given durable responses and CNS activity.