Izalontamab (SI-B001), a Novel EGFRxHER3 Bispecific Antibody in Patients with Locally Advanced or Metastatic Epithelial Tumor: Results from First-in-Human Phase I/Ib Study.

PURPOSE: Izalontamab (SI-B001) is a novel EGFR×HER3 bispecific antibody. This first-in-human phase I study presents the safety and pharmacokinetics of izalontamab. PATIENTS AND METHODS: Previously treated patients with locally advanced or metastatic epithelial tumors were enrolled in the dose-escalation or dose-expansion phases. The dose-escalation phase consisted of an accelerated titration and a "3 + 3" design with nine dose levels from 0.4 to 28.0 mg/kg. The dose-expansion phase included five dose levels from 6.0 to 21.0 mg/kg. Izalontamab was administered intravenously weekly or every 2 weeks in a 4-week cycle. Available pretreatment specimens were obtained to explore the relationship between EGFR/HER3 expression and efficacy. RESULTS: Sixty patients were enrolled. Among the 60 enrolled patients, 49 had non-small cell lung cancer (NSCLC), 6 had nasopharyngeal cancer, 3 had head and neck cancer squamous cell carcinoma, and 2 had other types of cancer. The most common treatment-related adverse events were rash (42%), paronychia (25%), and infusion-related reactions (23%). No drug-related death occurred. Izalontamab displayed a nonlinear pharmacokinetic behavior, and clearance at steady state seemed to be approaching a dose-independent value at 6 mg/kg and above. The best response included two confirmed partial responses in patients with NSCLC and head and neck cancer squamous cell carcinoma; 18 patients had stable disease, including NSCLC (n = 17) and colorectal cancer (n = 1). The recommended phase II dose for izalontamab was determined as 9 to 16 mg/kg weekly. CONCLUSIONS: Izalontamab was well tolerated and demonstrated preliminary antitumor activity in patients with locally advanced or metastatic epithelial tumors, supporting it as a promising therapeutic candidate for combination therapies, with a phase III study currently underway.