A randomized, active-controlled phase 3 study of ivonescimab + FOLFOX versus bevacizumab + FOLFOX as first-line treatment of metastatic colorectal cancer (mCRC): HARMONi-GI3.

TPS3682 Background: Fluorouracil (5-FU)-based chemotherapy plus an anti–vascular endothelial growth factor (VEGF) or anti–epidermal growth factor receptor (EGFR) therapy is recommended as first-line treatment for many patients with mCRC; however, prognosis is still poor, with a 5-year survival rate of <30%. The investigational, anti–programmed cell death protein 1 (PD-1)- and VEGF-bispecific antibody ivonescimab is approved in China for non-small cell lung cancer (NSCLC) and is currently being evaluated as monotherapy or in combination with chemotherapy in global phase 3 clinical trials for NSCLC, and in other tumor types including colorectal cancer. Methods: HARMONi-GI3 (NCT07228832) is a randomized, active-controlled, double-blind, multiregional, phase 3 trial to compare the efficacy and safety of ivonescimab + 5-FU, oxaliplatin, and leucovorin (mFOLFOX6) versus bevacizumab + mFOLFOX6 in patients with mCRC who are not candidates for surgical resection, have not previously received systemic therapy for metastatic disease, and have an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients with microsatellite instability-high or mismatch repair deficient disease, and with BRAF V600E mutation or dihydropyrimidine dehydrogenase deficiency, will be excluded. Approximately 600 patients will be randomly assigned (1:1) to receive ivonescimab 20 mg/kg + mFOLFOX6 or bevacizumab + mFOLFOX6 every 2 weeks for up to 4 months, followed by maintenance with ivonescimab + 5-FU and leucovorin or bevacizumab + 5-FU and leucovorin until disease progression, intolerable toxicity, or initiation of new anti-tumor therapy. Randomization will be stratified according to geographic region (East Asia, Europe, North America), liver metastases at study entry (absence or presence), and rat sarcoma virus tumor mutational status (RAS; mutant or wild-type). The hypothesis of this study is that ivonescimab + mFOLFOX6 has superior efficacy to bevacizumab + mFOLFOX6 in patients with mCRC who have not previously received systemic therapy for metastatic disease, as determined by progression-free survival (PFS). The primary endpoint is PFS (assessed by independent radiology review committee per Response Evaluation Criteria in Solid Tumors, v1.1). Secondary endpoints are overall survival, objective response rate, duration of response, safety, pharmacokinetics of ivonescimab + mFOLFOX6, and immunogenicity. All patients will have regular tumor evaluations every 8 weeks until week 48, then every 12 weeks until disease progression, loss to follow-up, death, withdrawal, or study closure. HARMONi-GI3 is currently recruiting participants. Clinical trial information: NCT07228832 .