The 2026 ESMO Congress brought major advances to the forefront of oncology. Iza-bren (BL-B01D1/伦康依隆妥单抗), the world's first-in-class and first approved EGFR×HER3 bispecific antibody–drug conjugate (ADC), made a striking appearance with data from its pivotal Phase III PANKU-Breast01 study. The study presented its prespecified interim analysis results in full for the first time in a late-breaking abstract (LBA).Led by Academician Binghe Xu of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, the study enrolled patients with unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer who had previously received endocrine therapy and one to two lines of chemotherapy. The results showed that iza-bren achieved a median progression-free survival (mPFS) of 8.2 months, doubling the 4.0 months observed with treatment of physician’s choice (TPC), and reduced the risk of disease progression or death by 59%. The confirmed objective response rate (cORR) also doubled, reaching 40.5%, with consistent benefits across subgroups irrespective of HER2 expression levels.
At a time when later-line treatment options for HR-positive/HER2-negative breast cancer are becoming increasingly diverse but also more complex, these findings offer compelling evidence for some of the most challenging patients in clinical practice—those with difficult-to-treat disease and the greatest need for more effective therapies. The innovative dual-target mechanism of iza-bren also introduces a new approach to clinical decision-making in HR-positive/HER2-negative metastatic breast cancer (mBC).
On the strength of its outstanding efficacy, the full PANKU-Breast01 study was published simultaneously in the prestigious international journal The Lancet (impact factor: 109). More than 200 years after the journal’s founding, iza-bren became the first innovative Chinese drug in the field of breast cancer to be published in the journal’s main edition.
Against this backdrop, Oncology Frontier invited Academician Binghe Xu, the principal investigator (PI) of PANKU-Breast01, to discuss the study’s progress. The interview explores the rationale behind the study design, the innovation of its dual-target mechanism, its efficacy and safety findings, and the implications for clinical decision-making in HR-positive/HER2-negative advanced breast cancer. Academician Xu also shares his perspectives on the clinical prospects of iza-bren and directions for future research.
The Central Challenge in an Increasingly Complex Treatment Landscape: Moving from “Having Treatment Options” to “Accessing More Effective Therapies”
HR-positive/HER2-negative breast cancer is the most prevalent molecular subtype of breast cancer. Over the past decade, treatment options have expanded considerably. Endocrine therapy combined with CDK4/6 inhibitors has become an important first-line standard for advanced disease, while PI3K/AKT pathway inhibitors, selective estrogen receptor degraders (SERDs), and single-target ADCs have subsequently emerged, further improving patient outcomes.
However, a growing number of treatment options does not necessarily mean that clinical needs have been fully met. In real-world practice, some patients continue to face considerable treatment challenges. Visceral metastases, including liver metastases, high tumor burden, and rapid disease progression can occur together, making subsequent treatment decisions increasingly complex. Even after failure of CDK4/6 inhibitor-based therapy and subsequent chemotherapy, some patients still do not achieve satisfactory tumor responses or durable disease control.
How to further improve response rates, prolong PFS, and maintain treatment tolerability has therefore become a central unmet need in the later-line treatment of HR-positive/HER2-negative advanced breast cancer.
Academician Xu explained that it was precisely this real-world clinical challenge that shaped the design of PANKU-Breast01. Rather than taking the easier route of selecting low-risk patients to generate favorable-looking data, the study was designed to address the needs of patients encountered in everyday clinical practice. Its findings are intended to provide robust evidence to guide treatment decisions.
High-Level Clinical Evidence: Doubling Efficacy and Demonstrating Broad Patient Benefit in a Real-World-Like Population
PANKU-Breast01 was a multicenter, randomized, open-label Phase III registration study involving 383 patients with unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer who had previously received endocrine therapy and one to two lines of chemotherapy. Patients were randomized 1:1 to receive either iza-bren or standard chemotherapy selected by the investigator (TPC). The primary endpoint was PFS assessed by blinded independent central review (BICR).
The study population had substantial clinical complexity. In the iza-bren group, 64.2% of patients had an ECOG performance status of 1; 80% had previously received neoadjuvant or adjuvant therapy, and 80% had received prior anthracyclines. Liver metastases were present in 71.6% of patients. In addition, 17.4% had de novo metastatic breast cancer, while 8.4% experienced disease progression within six months after completing neoadjuvant or adjuvant treatment.
Notably, despite the challenging characteristics of this population—including early high-risk disease, aggressive tumor biology, extensive prior treatment in the advanced setting, and compromised performance status—PANKU-Breast01 achieved the breakthrough finding of doubling median PFS.
According to BICR assessment, median PFS was 8.2 months (95% CI, 6.9–8.6) in the iza-bren group, twice the 4.0 months (95% CI, 2.9–4.3) observed in the TPC group. This represented a 59% reduction in the risk of disease progression or death (HR=0.41; 95% CI, 0.33–0.53; P<0.0001).
These findings demonstrate not only a statistically significant improvement but also clinically meaningful disease control for patients who continue to face treatment challenges after endocrine therapy, CDK4/6 inhibitors, and chemotherapy.
PANKU-Breast01 also demonstrated PFS benefits with iza-bren across different HER2 expression subgroups. The prespecified subgroup analysis showed PFS hazard ratios of 0.41, 0.53, and 0.32 in the HER2 IHC 0, IHC 1+, and IHC 2+/ISH-negative subgroups, respectively. These findings prospectively support the conclusion that the efficacy of iza-bren does not depend on HER2 pathway expression.
The benefits were equally compelling in terms of tumor response. The confirmed objective response rate (cORR) in the iza-bren group reached 40.5%, twice the 20.2% observed with chemotherapy. The disease control rate (DCR) was 86.3%, significantly higher than the 63.7% in the control group. Tumor shrinkage in target lesions was observed in 77.9% of patients, with a median reduction in tumor size of 37.4%. The complete response (CR) rate was 3.9%. Median duration of response (mDOR) increased from 4.2 months in the control group to 6.9 months with iza-bren, demonstrating the combined clinical value of deeper tumor responses and more durable disease control.
The overall toxicity profile of iza-bren was clearly characterized and manageable. The most common treatment-related adverse events were hematologic toxicities, for which established clinical management pathways are available. These events can generally be controlled through standard supportive care and appropriate dose modifications. The treatment discontinuation rate due to treatment-related adverse events was only 1.6%, substantially lower than the rates reported with many single-target ADCs. The incidence of interstitial lung disease (ILD), a major concern in clinical practice, was only 1.1%, with all cases limited to Grade 1–2. These findings provide a favorable safety foundation for sustained treatment.
Academician Binghe Xu’s Perspective: A Milestone Breakthrough—How Bispecific Molecular Design Could Reshape the Treatment Paradigm
Academician Binghe Xu: The success of PANKU-Breast01 represents much more than a positive Phase III result. It marks a milestone in the translation of the world’s first-in-class EGFR×HER3 bispecific ADC from concept to clinical application.
Over the past decade, single-target ADCs have helped advance cancer treatment beyond the conventional use of cytotoxic agents toward targeted drug delivery. However, the spatial and temporal heterogeneity of solid tumors, dynamic changes in target antigen expression, and complex regulation of resistance signaling networks remain important factors limiting drug efficacy.
Iza-bren optimizes the drug’s mechanism of action across three dimensions.
First, dual-target recognition may broaden coverage of heterogeneous tumor cell populations. EGFR and HER3 both belong to the ERBB receptor family, and their associated signaling networks are involved in tumor cell proliferation, survival, and treatment resistance. By simultaneously recognizing EGFR and HER3, iza-bren may increase the likelihood of identifying tumor cells with different antigen-expression profiles, offering a new strategy for addressing tumor heterogeneity.
Second, dual-receptor binding provides a new mechanistic approach to optimizing intracellular drug delivery. Dual-target binding and receptor crosslinking may influence the internalization process and facilitate drug delivery into tumor cells, creating conditions that could improve the activity of the cytotoxic payload.
Third, the coordinated design of the linker and payload further expands its antitumor potential. Iza-bren incorporates a cleavable linker and a novel topoisomerase I inhibitor payload, Ed-04, with a drug-to-antibody ratio (DAR) of 8. Linker stability, payload-release characteristics, and the membrane permeability of the payload collectively influence drug delivery in vivo and antitumor activity. The potential bystander effect may also broaden cytotoxic activity against neighboring tumor cells with low target-antigen expression.
From dual-target recognition and intracellular delivery to payload release and tumor cell killing, iza-bren demonstrates a coordinated approach to molecular design in bispecific ADC development. This not only expands the design possibilities for ADCs but also provides new research directions for addressing the challenges of drug delivery and tumor heterogeneity in complex solid tumors.
The PANKU-Breast01 study provides compelling clinical evidence that ADC treatment for breast cancer need not remain confined to the traditional single-target, biomarker-selected model. Through its novel mechanism of dual-target binding and simultaneous blockade of two signaling pathways, the study prospectively demonstrated consistent and significant benefits from bispecific ADC therapy in later-line HR-positive/HER2-negative breast cancer, regardless of HER2 expression levels.
From the perspective of clinical practice, these findings may reshape the underlying logic of treatment decision-making. Historically, later-line treatment selection for HR-positive/HER2-negative breast cancer has largely been guided by HER2 expression levels. PANKU-Breast01 demonstrated a doubling of mPFS (8.2 vs. 4.0 months; HR=0.41), a doubling of cORR (40.5% vs. 20.2%), and target-lesion tumor shrinkage in 77.9% of patients. These results support a new approach centered on the efficacy data of bispecific ADC therapy.
This could not only improve diagnostic and treatment efficiency and broaden access to effective therapy, but also provide high-risk patients with substantial tumor burden and an urgent need for symptom control with a better opportunity to achieve longer survival and improved quality of life.
The positive results in this particularly challenging population—patients previously treated with CDK4/6 inhibitors and multiple lines of therapy—reflect Chinese investigators’ deep understanding of unmet clinical needs and demonstrate the strength of original innovation from China.
China has moved from conducting clinical research on innovations originating elsewhere to leading the development of globally first-in-class therapies that may open new directions in breast cancer treatment. The presentation of PANKU-Breast01 as an ESMO late-breaking abstract also marks an important step in the evolution of Chinese breast cancer clinical research, from following international advances toward helping lead the field globally.
Summary and Outlook
With its innovative EGFR×HER3 dual-target molecular design, iza-bren offers a new treatment option for patients with HR-positive/HER2-negative breast cancer. As the world’s first approved bispecific ADC, it has the potential to reshape the oncology treatment landscape and usher breast cancer therapy into a new era of bispecific ADCs.
Of particular note, information published by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) on October 21, 2026, indicated that the new drug application (NDA) for iza-bren in unresectable or metastatic HR-positive/HER2-negative breast cancer previously treated with endocrine therapy and at least one line of chemotherapy in the advanced disease setting had been formally accepted.
We look forward to the approval of this indication and its incorporation into authoritative clinical guidelines in China and internationally. These developments could bring longer survival and better quality of life to breast cancer patients in China and around the world.
Academician Binghe Xu
