Editor's Note: Antibody–drug conjugates (ADCs) have profoundly reshaped the treatment landscape for advanced breast cancer. However, traditional single-target ADCs are vulnerable to antigen downregulation, which can lead to treatment resistance. Iza-kang (izalontamab brengitecan, BL-B01D1/iza-bren), the world's first EGFR × HER3 bispecific ADC developed independently in China, represents a new generation of ADCs.In triple-negative breast cancer (TNBC), the phase III PANKU-Breast02 study demonstrated that iza-bren significantly prolonged median progression-free survival (PFS) compared with chemotherapy in later-line treatment of advanced TNBC, reaching 8.5 months versus 3.1 months (HR = 0.29)—one of the most impressive PFS results reported to date for an ADC in this patient population. Median overall survival (OS) was also positive, at 15.9 months versus 12.5 months, raising the possibility that iza-bren could become a new standard of care [1].
In HR-positive/HER2-negative (HR+/HER2−) advanced breast cancer, a previously reported phase Ib study demonstrated encouraging antitumor activity with iza-bren across different breast cancer subtypes following chemotherapy. Among patients with HR+/HER2− advanced disease, the confirmed objective response rate (cORR) was 37.3%, and median PFS (mPFS) was 7.0 months, indicating promising activity. Subsequent study updates revealed positive results for iza-bren compared with chemotherapy in the phase III PANKU-Breast01 trial in advanced HR+/HER2− breast cancer.
In the latest announcement of the 2026 ESMO Congress’s selected oral presentations, PANKU-Breast01 was selected for a late-breaking abstract (LBA) presentation and is set to be a major highlight. Professor Bo Lan of the Cancer Hospital, Chinese Academy of Medical Sciences, will present the detailed findings at the ESMO Congress on October 23, from 14:35 to 14:45 local time (20:35–20:45 Beijing time), in Alicante Auditorium–Hall 6.
Oncology Frontier has specially invited Professor Fan Wu of Fujian Cancer Hospital to preview LBA50, review the treatment landscape for HR+/HER2− advanced breast cancer, discuss the distinctive mechanisms of bispecific ADCs, and highlight the key findings of PANKU-Breast01. Stay tuned!
Unmet Needs: How ADCs May Break Through the Treatment Challenges in HR+/HER2− Advanced Breast Cancer
For patients with HR+/HER2− advanced breast cancer who are unsuitable for endocrine therapy with or without targeted therapy, ADCs targeting HER2 and TROP2 have already reshaped the treatment landscape. Studies including DESTINY-Breast04 [2], TROPiCS-02 [3], and OptiTROP-Breast02 [4] have shown that these single-target ADCs achieve median PFS ranging from 5.5 to 10.1 months in patients with advanced HR+/HER2− breast cancer previously treated with chemotherapy.
In clinical practice, however, these single-target ADCs primarily rely on a single antigen. Their efficacy may be limited against tumors with heterogeneous antigen expression, and antigen downregulation can facilitate resistance. These limitations represent an inherent challenge for single-target ADCs.
A Dual-Target Approach: EGFR × HER3 Bispecific ADCs Emerge as a Promising Strategy
By targeting two antigens, bispecific ADCs may reduce the risk of tumor escape resulting from the loss or downregulation of a single antigen, potentially overcoming resistance mechanisms associated with single-target ADCs.
EGFR and HER3 both belong to the ERBB receptor family. EGFR is overexpressed in approximately 15%–45% of breast cancers [5,6], while HER3 is expressed in more than 50% [7,8], making both targets widely distributed across breast cancer. In HR-positive breast cancer, HER3 can form heterodimers with HER2 and activate pathways such as PI3K/AKT, contributing to resistance to endocrine therapy and CDK4/6 inhibitors. Cross-signaling through EGFR can also reinforce cell-survival and metastatic phenotypes. Simultaneously targeting both receptors may therefore further enhance antitumor activity.
Iza-kang (izalontamab brengitecan, iza-bren; BL-B01D1), China’s independently developed first-in-class EGFR × HER3 bispecific ADC, incorporates a distinctive molecular design that offers several potential mechanistic advantages.
First, dual-target synergy and precise payload delivery. The drug combines a humanized anti-EGFR IgG1 antibody backbone with an anti-HER3 single-chain variable fragment (scFv) to form a bispecific antibody. This design enables simultaneous binding to EGFR and HER3, potentially blocking upstream oncogenic signaling and limiting compensatory resistance through bypass pathways. More importantly, dual-target binding can induce receptor clustering and synergistically enhance payload delivery, enabling more precise targeting and efficient internalization. It may also offer potential activity in tumors with low or absent HER2 expression.
Second, a cleavable linker and high drug-to-antibody ratio (DAR). The drug uses a proprietary, patented Ac stabilizing linker and a GGFG tetrapeptide linker. This cleavable linker maintains high stability in plasma, helping minimize off-target toxicity. Once the ADC enters tumor cells, lysosomal enzymes cleave the linker to release the payload. A high DAR of approximately 8 substantially increases the effective drug concentration within the tumor, thereby enhancing antitumor activity.
Third, a proprietary, potent payload with a strong bystander effect. The ADC carries Ed-04, a proprietary novel topoisomerase I inhibitor. Compared with the commonly used DXd payload, Ed-04 demonstrates superior antitumor activity and a stronger bystander effect. In the heterogeneous A431 + SW620 tumor model, the Ed-04 payload (red curve) demonstrated greater tumor growth inhibition than the DXd payload (blue curve). This potent bystander effect may enable more effective local killing of heterogeneous tumor cell populations, resulting in stronger antitumor activity.
A Major ESMO LBA50 Presentation: PANKU-Breast01 May Usher in a New Era of Bispecific ADC Therapy for HR+/HER2− Breast Cancer
Building on its mechanistic innovations, iza-bren has achieved a series of advances in breast cancer. A multicenter phase Ib study of iza-bren enrolled 162 patients with locally advanced or metastatic breast cancer who had received prior standard treatment: 41 with HER2-positive disease, 75 with HR+/HER2− disease, and 46 with TNBC. Of these patients, 69.8% had received at least three lines of systemic therapy.
The cORRs in the HER2-positive, HR+/HER2−, and TNBC subgroups were 46.3%, 37.3%, and 34.8%, respectively, while the corresponding mPFS values were 5.8, 7.0, and 5.8 months. Among patients with HR+/HER2− advanced breast cancer who had received one or two lines of chemotherapy, the cORR was 45.7% and mPFS was 8.3 months.
Regarding safety, hematologic toxicities were the most common adverse events. The toxicity profile was well characterized, and clinical experience in managing these events was established. No cases of interstitial lung disease (ILD) were observed [9].
The phase III PANKU-Breast01 study further evaluated iza-bren in patients with HR+/HER2− advanced breast cancer who had previously received endocrine therapy and one or two lines of chemotherapy in the advanced-disease setting. The trial compared the efficacy and safety of iza-bren with physician’s choice of chemotherapy.
On August 26, 2026, Sichuan Biokin Pharmaceutical announced that the study had met its primary endpoint at a prespecified interim analysis, demonstrating a positive PFS result. Detailed data will be presented as an LBA at the upcoming European Society for Medical Oncology (ESMO) Congress. The results are highly anticipated.
Presentation Details
Session: Proffered Paper 1: Breast Cancer, Early and Advanced Stage
Date and Time:
- October 23, 2026, 14:35–14:45 local time
- October 23, 2026, 20:35–20:45 Beijing time
Venue: Alicante Auditorium – Hall 6
Presentation Title: LBA50—PANKU-Breast01: Randomized Phase III Study of Izalontamab Brengitecan (iza-bren) in Previously Treated Unresectable Locally Advanced or Metastatic (LA/M) Hormone Receptor-Positive/HER2-Negative (HR+/HER2−) Breast Cancer (BC)
Presenter: Professor Bo Lan, Cancer Hospital, Chinese Academy of Medical Sciences
From innovation in dual-target mechanisms to the publication of phase III clinical evidence, iza-bren, an ADC independently developed in China, is opening a new era of bispecific ADC therapy for patients with advanced HR+/HER2− breast cancer. Its development could have a profound impact on breast cancer treatment worldwide.
Stay tuned for ESMO LBA50 to learn about the latest developments that may shape treatment strategies for HR+/HER2− advanced breast cancer.
Professor Fan Wu
