Iza-Bren Shows Preliminary Efficacy, Safety in Heavily Pretreated HER2–/HER2-low Breast Cancer

Advanced/Metastatic Breast Cancer | Image Credit:

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The potential first-in-class EGFR- and HER3-directed bispecific antibody-drug conjugate (ADC) izalontamab brengitecan (iza-bren; BL-B01D1) demonstrated preliminary responses and a manageable safety profile regardless of HER2 expression in heavily pretreated patients with advanced or metastatic HER2-negative or HER2-low breast cancer, according to initial data from a phase 1 study (NCT05470348) presented during the 2025 ESMO Breast Congress.1

At a median follow-up of 11.7 months, the overall response rate (ORR) among all efficacy-evaluable patients who had received at least 1 dose of iza-bren at 2.5 mg/kg (n = 121) was 42.1%, and the confirmed ORR was 36.4%. Complete responses (CRs) and partial responses (PRs) were achieved in 51 patients, and 44 had confirmed CRs/PRs. Best overall responses also included stable disease (n = 46) and progressive disease (n = 13); responses were not evaluable in 11 patients. The disease control rate (DCR) was 80.2%, and the median duration of response (DOR) was 9.7 months (95% CI, 5.8-11.7). Notably, patients also achieved a median progression-free survival of 6.9 months (95% CI, 5.5-8.4).

Further evaluation of responses according to HER2 status showed that patients with a HER2 immunohistochemistry (IHC) score of 0 (HER2-zero; n = 55) achieved an ORR of 41.8%, and confirmed ORR of 36.4%, and a DCR of 80.0%. The median DOR was 11.5 months (95% CI, 5.4-not reached [NR]), and the median PFS was 8.3 months (95% CI, 4.8-12.7). Corresponding rates for patients with a HER2 IHC of 1+ or 2+ IHC with a negative in situ hybridization test (HER2-low disease; n = 66) were 42.4%, 36.4%, and 80.3%, respectively. The median DOR for this subgroup was 9.7 months (95% CI, 5.5-NR), and the median PFS was 6.3 months (95% CI, 5.1-8.3).

“Subgroup analysis by HER2 expression [showed that] the preliminary efficacy of [iza-bren] in [patients with] HER2-zero and HER2-low expression [was similar]. [Both subgroups] demonstrated a good depth and favorable duration [of response],” presenting author Yiqun Du, an associate professor in the Department of Medical Oncology at Fudan University in Shanghai, China, stated in a presentation of the data.

Trial Design and Patient Characteristics

This phase 1 dose escalation/expansion study enrolled patients with locally advanced or metastatic breast cancer and other solid tumors with prior exposure to standard therapies. An ECOG performance status of 0 or 1, measurable disease per RECIST 1.1 criteria, and adequate organ and marrow function were also required. Eligible patients were enrolled onto phase 1a of the study, referred to as BL-B01D1-101, and assigned to 1 of 2 cohorts. In cohort A, patients received iza-bren at escalating doses of 2.5 mg/kg, 3.0 mg/kg, or 3.5 mg/kg every 3 weeks on days 1 and 8 of each treatment cycle. Patients in cohort B received either 5.0 mg/kg, 6.0 mg/kg, or 7.0 mg/kg of iza-bren every 3 weeks on day 1 of each treatment cycle. In the dose-expansion portion of the study (phase 1b), patients received the 2.5 mg/kg dose of iza-bren.

The primary end points of the study included dose-limiting toxicities, identification of the maximum tolerated dose or maximum administered dose, and determination of the recommended phase 2 dose. Secondary end points included ORR, DCR, DOR, and safety. PFS, overall survival, biomarker analyses, and neutralizing antibody titer served as exploratory end points.

The current analysis includes data from patients in the HER2-negative breast cancer cohort. The median age for patients in this subgroup treated at the 2.5 mg/kg dose was 54 years (range, 26-75). The majority of patients had an ECOG PS of 1 (88.4%) and HR-positive disease (63.6%). Additionally, brain metastases were present in 8.3% of patients. Treatments previously received by patients included platinum-based therapy (38.8%), paclitaxel (91.7%), anti–PD-L1 therapy (22.3%), CDK inhibitors (43.8%), and ADCs (9.1%).

Most patients were treated with 3 or more prior lines of therapy (65.3%), followed by 2 (19.0%), 1 (14.9%), and no prior lines (0.8%). The respective rates of patients treated with at least 3 lines, 2 lines, 1 line, and no lines of prior chemotherapy were 29.8%, 26.4%, 33.1%, and 10.7%. Regarding HER2 status, 45.5% of patients had HER2 IHC 0+, 28.9% had IHC 1+, and 25.6% had HER2-low disease.

Additional Safety Data and Ongoing Investigations of Iza-bren

The most prevalent treatment-related adverse effects (TRAEs) seen with iza-bren were hematologic AEs, and included anemia (any-grade, 90.1%; grade ≥3, 43.8%), leukopenia (90.1%; 45.5%), neutropenia (86.8%; 54.5%), and thrombocytopenia (71.9%; 30.6%). Non-hematologic AEs were primarily grade 1/2, and comprised nausea (61.2%; 5.0%), stomatitis (52.9%; 3.3%), vomiting (47.9%; 0.8%), asthenia (47.1%; 10.7%), increased aspartate aminotransferase levels (46.3%; 0.0%), increased alanine aminotransferase levels (44.6%; 0.0%), hypertriglyceridemia (37.2%; 1.7%), hypokalemia (37.2%; 5.0%), alopecia (36.4%; 0.0%), and decreased appetite (35.5%; 0.8%).

One treatment-related death due to febrile neutropenia occurred. No patients reported interstitial lung disease, and no new safety signals were observed with iza-bren. Standard supportive measures were used to effectively manage grade 3 or higher TRAEs, leading to a low rate of TRAE-related drug discontinuation (5.0%).

Several studies of iza-bren are ongoing across breast cancer subtypes, including 2 phase 3 trials in triple-negative breast cancer (NCT06382142) and hormone receptor–positive, HER2-negative breast cancer (NCT06343948), and a global phase 2/3 study (NCT06926868). Results from these studies are highly anticipated, Du concluded in his presentation.

Disclosures: Dr Du had no relationships to disclose

Reference

Du Y, Zhang J, Wu J, et al. Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic breast cancer (BC). Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract. 302MO.