Background
Phase 2 single-arm registrational trial (eNRGy); N=204 advanced/metastatic NRG1 fusion-positive solid tumors (predominantly NSCLC and pancreatic cancer) after prior systemic therapy. Zenocutuzumab is a bispecific HER2/HER3 antibody.
Interventions and follow up
Treatment: Zenocutuzumab 750 mg IV every 2 weeks (no control arm)
Primary endpoint: objective response rate (independent review)
mFollow up: 7.1mo
Primary endpoint: objective response rate (independent review)
mFollow up: 7.1mo
Results
ORR (overall): 30%
mPFS: 6.8mo, 95%CI 5.5-9.1
NSCLC ORR: 35%
NSCLC mDOR: 17.1mo
mPFS: 6.8mo, 95%CI 5.5-9.1
NSCLC ORR: 35%
NSCLC mDOR: 17.1mo
Adverse events
GI: diarrhea 18%; nausea 11%
Constitutional: fatigue 12%
Infusion: infusion-related reactions 14%
Constitutional: fatigue 12%
Infusion: infusion-related reactions 14%
Conclusions
Zenocutuzumab produced durable responses in NRG1 fusion-positive NSCLC and pancreatic cancer with a manageable toxicity profile.
Key Limitations
Single-arm, no comparator; small NRG1 fusion-positive population; short median follow-up; ORR/DOR surrogate endpoints.
Clinical Context
FDA accelerated approval (BIZENGRI, zenocutuzumab-zbco) December 2024 for advanced NRG1 fusion-positive NSCLC and pancreatic adenocarcinoma after prior systemic therapy, based on ORR and DOR. First targeted therapy for this rare driver.
References