Izalontamab (SI-B001), a novel EGFR/HER3 bispecific monoclonal antibody, was well-tolerated and exhibited preliminary antitumor activity in previously treated patients with locally advanced or metastatic epithelial tumors, according to results of a phase 1/1b study (NCT04603287).1

With a median follow-up of 27.5 months, the most common treatment-related adverse events among 60 enrolled patients were rash (42%), paronychia (25%), and infusion-related reactions. Rashes were reported to be mild, generally grade 1 or grade 2 events. In terms of pharmacokinetics, the agent demonstrated nonlinearity, and no dose-limiting toxicities were observed.

“This phase [1] study demonstrates that izalontamab, a novel EGFR/HER3 bispecific antibody, can be safely administered with an acceptable toxicity profile in patients with advanced epithelial tumors,” said authors Xue et al in Clinical Cancer Research.1

Early efficacy signals were also observed among the 57 efficacy-evaluable patients, with a confirmed objective response rate of 4%. This included 2 confirmed partial responses in 2 patients with non–small cell lung cancer (NSCLC) and head and neck cancer squamous cell carcinoma. Eighteen patients, including 17 patients with NSCLC and 1 patient with colorectal cancer, had stable disease.

These encouraging results support the advancement of izalontamab for further clinical evaluation at the established recommended phase 2 dose of 9 to 19 mg/kg weekly.

Izalontamab is also the backbone of the bispecific antibody-drug conjugate (ADC) izalontamab brengitecan (iza-bren; BL-B01D1), which earned FDA breakthrough designation in EGFR-positive NSCLC earlier this year. A recent presentation at the 2025 European Society for Medical Oncology (ESMO) Congress reported superior overall response rate with iza-bren compared with chemotherapy in nasopharyngeal cancer (54.6% vs 27%) in an ongoing phase 3 trial (NCT06118333).

“These findings also provide insights into further development of the ADC [iza-bren], which shares the same antibody but adds a cytotoxic payload,” added the authors.1

Study Design and Patient Characteristics

The multicenter, open-label, single-arm phase 1 study aimed to characterize the safety, tolerability, and pharmacokinetics of izalontamab, consisting of dose-escalation and dose-expansion stages.2 A total of 60 adult patients with advanced unresectable or metastatic solid tumors who had failed standard treatment were enrolled. Over 3 tumor types were represented in the population: NSCLC (n = 49), nasopharyngeal cancer (n = 6), head and neck cancer squamous cell carcinoma (n = 3), among other types (n = 2). Eighteen patients had EGFR mutations.

The dose-escalation stage involved accelerated titration followed by a 3+3 design. Next, the dose-expansion stage evaluated 5 dose levels of izalontamab: 6.0, 9.0, 12.0, 16.0, and 21.0 mg/kg. All patients received intravenous izalontamab weekly or every 2 weeks for 28 mg/kg in a 4-week cycle.

Biomarker analyses were also performed to examine EGFR and HER3 expression in available pretreatment tumor tissues by immunohistochemistry assay.

Other Studies of Izalontamab

A randomized phase 3 trial (NCT06382129) is underway and recruiting patients. This study is evaluating the efficacy and safety of izalontamab in combination with docetaxel in advanced or metastatic EGFR wild-type NSCLC following treatment failure with anti–PD-1/PD-L1 monoclonal antibodies and platinum-based chemotherapy.3 The trial aims to enroll 680 patients and is slated to complete in mid-2026.

REFERENCES1. Xue J, Ma Y, Zhao Y, et al. 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. Clin Cancer Res. 2025;31(21):4438-4445. doi:10.1158/1078-0432.ccr-25-02062. A study of SI-B001, an EGFR/HER3 bispecific antibody, in locally advanced or metastatic epithelial tumors. ClinicalTrials.gov. Updated September 26, 2025. Accessed November 5, 2025. https://clinicaltrials.gov/study/NCT046032873. A study comparing BL-B01D1 with docetaxel in patients with unresectable locally advanced or metastatic EGFR wild-type non-small cell lung cancer. ClinicalTrials.gov. Updated May 2, 2025. Accessed November 5, 2025. https://www.clinicaltrials.gov/study/NCT06382129