Background
Integrated analysis of three single-arm phase I/II trials (ALKA-372-001, STARTRK-1, STARTRK-2); N=161 efficacy-evaluable; locally advanced or metastatic ROS1 fusion-positive NSCLC.
Interventions and follow up
Treatment: Entrectinib 600mg PO daily
Primary endpoints: ORR and duration of response by blinded independent central review
mFollow up: 15.5mo
Primary endpoints: ORR and duration of response by blinded independent central review
mFollow up: 15.5mo
Results
ORR: 67.1%
mDOR: 15.7mo
mPFS: 15.7mo
12-mo PFS: 55%
12-mo OS: 81%; mOS: not reached
Intracranial ORR: 79.2% (patients with baseline CNS mets)
Intracranial mPFS: 12.0mo
mDOR: 15.7mo
mPFS: 15.7mo
12-mo PFS: 55%
12-mo OS: 81%; mOS: not reached
Intracranial ORR: 79.2% (patients with baseline CNS mets)
Intracranial mPFS: 12.0mo
Adverse events
Most common (grade 1-2): Dysgeusia, fatigue, constipation, dizziness, diarrhea, edema
Grade ≥3: Weight increase 10%, anemia, increased creatinine
Neurologic: Cognitive/dizziness/ataxia requiring dose modification in some patients
Discontinuation: ~4% due to AEs
Grade ≥3: Weight increase 10%, anemia, increased creatinine
Neurologic: Cognitive/dizziness/ataxia requiring dose modification in some patients
Discontinuation: ~4% due to AEs
Conclusions
Entrectinib produced durable systemic and intracranial responses in ROS1 fusion-positive advanced NSCLC, supporting its use particularly in patients with CNS metastases.
Key Limitations
Single-arm pooled analysis without comparator; heterogeneous source trials; relatively short follow-up with immature OS; acquired resistance (e.g., G2032R) limits durability.
Clinical Context
FDA approved entrectinib for ROS1-positive metastatic NSCLC (Aug 2019); EMA approved 2020. ESMO lists entrectinib as a preferred first-line ROS1 TKI, favored over crizotinib when CNS disease is present.