Editor's Note: The European Society for Medical Oncology (ESMO) Congress is one of the most influential academic events in global oncology, where the presentation of each major study has the potential to reshape the clinical treatment landscape. Iza-bren (伦康依隆妥单抗), a globally pioneering, first-in-class bispecific antibody–drug conjugate (ADC) and the first of its kind to receive regulatory approval worldwide, has demonstrated significant clinical impact. At this year's congress, the interim analysis results of its pivotal Phase III PANKU-Breast01 study were presented as a late-breaking abstract (LBA). The study evaluated patients with unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer who had received prior endocrine therapy and one to two lines of chemotherapy. The results were also published simultaneously in The Lancet (impact factor: 109), making iza-bren the first innovative Chinese drug in the field of breast cancer to be published in the journal's main edition in its 200-year history.This is not simply another ADC. With its innovative EGFR×HER3 dual-target design and novel mechanism of action, iza-bren is a bispecific ADC that overcomes the limitations of conventional breast cancer ADCs that rely on HER2 expression. Its compelling clinical data, demonstrating a doubling of progression-free survival (PFS) and substantial tumor shrinkage, are redefining the clinical decision-making framework for HR-positive/HER2-negative advanced breast cancer and ushering in a new era of bispecific ADC therapy.
Oncology Frontier invited Professor Qingyuan Zhang of the Harbin Medical University Cancer Hospital to provide an in-depth interpretation of the key findings and clinical implications of this landmark study.
Oncology Frontier: The PANKU-Breast01 study showed that median PFS (mPFS) in the iza-bren group reached 8.2 months, twice the 4.0 months observed in the chemotherapy control group, representing a 59% reduction in the risk of disease progression or death (HR=0.41). Notably, these results were achieved in a difficult-to-treat population characterized by early high-risk disease, aggressive tumor biology, multiple prior lines of treatment for advanced disease, and relatively poor performance status. What do these findings mean for clinical practice?
Professor Qingyuan Zhang: The mPFS of 8.2 months achieved with iza-bren, doubling that observed with chemotherapy, is an extremely encouraging breakthrough, particularly in such a high-risk, difficult-to-treat population.
Let us first examine the baseline characteristics of the enrolled patients. All patients (100%) had previously received CDK4/6 inhibitors, 71.6% had liver metastases, nearly 30% had already received two lines of chemotherapy for advanced disease, and 80% had previously received (neo)adjuvant therapy and anthracyclines. These are among the most challenging patients encountered in clinical practice after multiple lines of treatment, with very limited conventional treatment options.
In this population, the mPFS achieved with conventional chemotherapy is generally only around four months. Iza-bren doubled this figure to 8.2 months, reducing the risk of disease progression or death by 59%.
What makes these results even more remarkable is that they are not simply impressive figures obtained from a highly selected population. Rather, the study population closely reflects the patients we encounter in real-world clinical practice. A total of 64.2% of patients had an ECOG performance status of 1, indicating some degree of functional impairment, while a high proportion had visceral metastases at baseline and substantial tumor burden. Achieving a doubling of PFS under these challenging circumstances demonstrates that the efficacy of iza-bren is tangible and can be reproduced in the types of patients treated in everyday clinical practice.
Oncology Frontier: We also noted that all prespecified subgroups demonstrated a highly consistent trend toward benefit. Regardless of HER2 expression level, the number of prior chemotherapy lines, or the presence or absence of liver metastases, the direction of benefit remained consistent. What is the underlying mechanism behind this pattern of consistent efficacy across the overall population and subgroups? What does it mean for clinical decision-making?
Professor Qingyuan Zhang: This is precisely the most important mechanistic breakthrough of iza-bren as a dual-target ADC: its design moves beyond the conventional ADC approach of relying on the expression of a single target.
Why are single-target ADCs limited? Tumor cells can escape treatment through antigen downregulation and heterogeneous antigen expression. When the expression of a particular target decreases or disappears, the drug can no longer bind effectively, and its therapeutic effect may consequently be lost.
Iza-bren, however, is designed to target both EGFR and HER3. It can bind to two antigens belonging to the ERBB receptor family. As long as tumor cells express either one of these targets, they can be recognized, internalize the ADC, and receive its cytotoxic payload.
The characteristics of these two targets are also important. EGFR is broadly expressed in HR-positive/HER2-negative breast cancer and serves as a key hub driving tumor growth. HER3, meanwhile, is an important mediator of compensatory resistance under treatment pressure. The two targets therefore have complementary functions: one provides broad target availability, while the other addresses mechanisms of treatment escape. By targeting both simultaneously, iza-bren addresses the fundamental limitation of single-target ADCs, in which treatment efficacy may be compromised when expression of the target antigen decreases. This also helps explain why the study demonstrated consistent subgroup benefits regardless of HER2 expression status.
In clinical practice, this mechanism brings about three fundamental changes.
First, treatment decisions become simpler. Physicians no longer need to wait for HER2 test results or question whether a patient’s HER2 expression is sufficient to qualify for ADC treatment. Patients with HR-positive/HER2-negative disease who require later-line treatment may be considered for this approach, offering an ADC treatment option even to patients with IHC 0 tumors.
Second, the timing of treatment becomes more flexible. The benefit was consistent regardless of whether patients had received one or two prior lines of chemotherapy. Physicians therefore do not have to be constrained by the assumption that treatment must be reserved for a particular line of therapy, allowing greater flexibility in sequencing treatment.
Third, physicians can prescribe treatment with greater confidence. One of the greatest concerns for clinicians is that, although overall study results may be favorable, an individual patient might belong to a subgroup that does not benefit. The consistent benefit observed across all subgroups means that physicians do not need to assume in advance that a particular patient will be an exception, making treatment decisions more confident.
In short, the characteristic of delivering consistent benefits across subgroups without depending on a specific biomarker is not an outcome artificially produced by subgroup analysis. It is fundamentally rooted in the dual-target mechanism. In the future, this may help shift clinical decision-making away from an approach based primarily on molecular classification before selecting treatment and toward one that places greater emphasis on clinical efficacy data when determining treatment strategies.
Oncology Frontier: In addition to its efficacy and broad patient coverage, the safety profile also appears noteworthy. The discontinuation rate due to treatment-related adverse events was only 1.6%, while the incidence of interstitial lung disease (ILD) was just 1.1%, with all cases limited to Grade 1–2. ILD has long been a major concern in the clinical use of ADCs. How would you assess this safety profile, and what does it mean for patients receiving long-term treatment?
Professor Qingyuan Zhang: Overall, the adverse-event profile of iza-bren is clearly characterized, predictable, and manageable. It is consistent with the safety findings of previous studies, and no new safety signals have emerged.
The most common adverse events are hematologic toxicities, such as neutropenia and anemia. These are familiar toxicities in clinical practice and can generally be managed effectively through supportive care with growth factors, treatment delays, or dose modifications.
ILD is understandably one of the adverse events of greatest concern. In this study, its incidence was only 1.1%, and all cases were Grade 1–2, with no severe cases reported. This is a favorable finding for an ADC, and it should help reassure both physicians and patients.
A manageable safety profile ultimately translates into tangible benefits for patients in several ways.
First, patients can remain on treatment for longer. The median treatment duration was 7.3 months in the iza-bren group, compared with only 4.3 months in the chemotherapy group. A low discontinuation rate means that patients can continue to benefit from treatment, allowing the improvement in PFS to translate into meaningful clinical outcomes.
Second, quality of life can be better maintained. The incidence of patient-experienced adverse events, such as nausea, diarrhea, and stomatitis, was relatively low. Patients therefore do not have to endure an excessive treatment burden, which is consistent with the goal of advanced cancer care: controlling disease while preserving quality of life.
Third, the clinical management burden is reduced. The absence of particularly difficult-to-manage toxicities means that physicians do not need to devote extensive time and resources to handling complex adverse events, potentially improving the efficiency of clinical care.
Summary
PANKU-Breast01 is the pivotal Phase III study of iza-bren, the first globally approved EGFR×HER3 bispecific ADC, in patients with HR-positive/HER2-negative breast cancer. Its significance extends far beyond a positive clinical trial result. With its novel EGFR×HER3 dual-target mechanism, iza-bren overcomes the limitations of conventional single-target ADCs that depend on HER2 expression. Its robust clinical data, demonstrating a doubling of PFS, substantial tumor shrinkage, and a manageable safety profile, have the potential to reshape the later-line treatment landscape for advanced HR-positive/HER2-negative breast cancer.
Importantly, the marketing application for iza-bren in the treatment of unresectable or metastatic HR-positive/HER2-negative breast cancer previously treated with endocrine therapy and at least one line of chemotherapy for advanced disease has been formally accepted by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA). This represents the drug’s fourth indication submitted for regulatory review in China.
To date, iza-bren has received approval for two indications: later-line treatment of recurrent or metastatic nasopharyngeal carcinoma and recurrent or metastatic esophageal squamous cell carcinoma. Its marketing application for triple-negative breast cancer has also been accepted. From nasopharyngeal carcinoma to esophageal cancer, and from triple-negative to HR-positive/HER2-negative breast cancer, this innovative Chinese bispecific ADC is progressively translating its novel mechanism of action into potential benefits for patients worldwide.
ADC therapy for breast cancer is moving beyond the era of single-target approaches that require careful patient selection and into a new era of bispecific ADCs designed to address a broader patient population. Robust Phase III evidence from studies such as PANKU-Breast01 is helping lay the foundation for this transformation.
Professor Qingyuan Zhang
