Editor's Note: The European Society for Medical Oncology (ESMO) Congress is one of the most prestigious academic events in global oncology, where the presentation of every major study has the potential to reshape the clinical treatment landscape. Iza-bren (伦康依隆妥单抗) is the world's first approved EGFR×HER3 bispecific antibody–drug conjugate (ADC). At this year's congress, the pivotal Phase III PANKU-Breast01 study, led by Academician Binghe Xu of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, was presented as a late-breaking abstract (LBA). The study evaluated iza-bren in 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, and demonstrated highly encouraging results. The full study was 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.At the ESMO-CSCO forum, “Exploring the Pathway to Global Oncology Drug Development,” jointly organized by Chinese and international experts, Professor Shusen Wang of Sun Yat-sen University Cancer Center, one of the principal investigators (PIs) at a participating center in PANKU-Breast01, also delivered a focused presentation on the development of innovative breast cancer drugs in China. He highlighted the PANKU-Breast01 and PANKU-Breast02 studies of iza-bren, emphasizing the rapid progress of innovative Chinese ADCs and their expanding development across breast cancer subtypes. Oncology Frontier invited Professor Shusen Wang to provide an in-depth interpretation of PANKU-Breast01, with the aim of offering insights for clinical practice.
Oncology Frontier: Historically, treatment options for later-line HR-positive/HER2-negative breast cancer have been relatively limited, with chemotherapy serving as the conventional approach. HER2-targeted ADCs subsequently became available, but their use was restricted to patients with HER2-low expression. The PANKU-Breast01 study demonstrated that the EGFR×HER3 bispecific ADC doubled mPFS from 4 months to 8.2 months, while also doubling the confirmed objective response rate (cORR), achieving a disease control rate (DCR) of 86.3%, and showing low rates of ILD and treatment discontinuation. From the perspective of clinical practice, could these findings change the standard of care in later-line treatment? What distinguishes iza-bren from previously available ADC regimens?
Professor Shusen Wang: In recent years, the treatment of advanced HR-positive/HER2-negative breast cancer has undergone remarkable progress. A range of therapeutic options has emerged, including TROP2-targeted ADCs, HER2-targeted ADCs, AKT inhibitors, and novel selective estrogen receptor degraders (SERDs). The development of ADCs has been particularly notable, establishing a stratified treatment landscape in which different therapies can be sequenced across multiple lines. Nevertheless, for patients with difficult-to-treat disease who have received multiple prior therapies, the clinical benefits offered by existing options remain subject to clear limitations.
In HR-positive/HER2-negative breast cancer, the selection of ADCs has long relied heavily on HER2 expression as a key stratification factor. Their clinical application also depends on accurate pathological assessment, and borderline cases can lead to uncertainty in treatment decisions. Furthermore, specific adverse events associated with certain ADCs, particularly interstitial lung disease (ILD), remain important clinical concerns.
The differentiated advantages of iza-bren are primarily reflected in two key areas: clinical applicability and safety and tolerability.
First, its efficacy is not restricted by HER2 expression, enabling treatment across the full spectrum of HER2-negative disease. Thanks to its EGFR×HER3 dual-target mechanism, the antitumor activity of iza-bren does not depend on HER2 expression. There is no need to distinguish between HER2 IHC 0, IHC 1+, or IHC 2+/ISH-negative status; patients across the full spectrum of HER2-negative disease can derive consistent benefit. This avoids the treatment decision-making difficulties associated with heterogeneity in HER2 pathological assessment and substantially simplifies the evaluation and selection of later-line therapies.
Second, its adverse-event profile is clearly characterized and predictable, with a particularly low risk of ILD. The incidence of ILD with iza-bren was only 1.1%, with all cases limited to Grade 1–2. The treatment discontinuation rate due to adverse events was also comparable to that in the chemotherapy group. This is directly associated with the drug’s precision-delivery design incorporating a highly stable linker. The lower risk of adverse events not only reduces the complexity of treatment management for clinicians but also supports patients’ ability to remain on treatment over the long term, allowing the substantial efficacy benefit to translate into meaningful clinical outcomes.
Furthermore, the fact that iza-bren maintains efficacy among the leading treatment options even in difficult-to-treat patients with poorer baseline prognostic characteristics further reinforces its clinical value. For patients with liver metastases, high tumor burden, or rapidly progressing disease, its stronger tumor-shrinking effect and longer disease control may help stabilize the condition quickly, relieve symptoms, and provide more time and flexibility for subsequent treatment.
Taken together, its advantages in efficacy, patient coverage, and safety may help shift later-line treatment for HR-positive/HER2-negative breast cancer away from a model based primarily on HER2-stratified drug selection toward more effective and convenient treatment options, substantially optimizing the overall later-line treatment landscape.
Oncology Frontier: Iza-bren is the world’s first approved EGFR×HER3 bispecific ADC. Unlike conventional single-target ADCs, it simultaneously targets two members of the ERBB receptor family. From a mechanistic perspective, how does this dual-target design achieve deeper tumor shrinkage, benefits across a broader patient population, and a more manageable safety profile? Which clinical challenges associated with single-target ADCs does it overcome?
Professor Shusen Wang: The emergence of iza-bren has brought bispecific ADCs beyond the conceptual stage and into the realm of demonstrated Phase III clinical benefit. As the world’s first EGFR×HER3 bispecific ADC, iza-bren is not simply a combination of two individual targeting components. Rather, its innovative molecular architecture incorporates a comprehensive, end-to-end mechanistic design that delivers three interconnected advantages: deeper tumor shrinkage, broad patient benefit, and manageable safety.
The broad patient benefit stems from the complementary biology of its two targets. EGFR and HER3 both belong to the ERBB receptor family and are widely co-expressed in HR-positive/HER2-negative breast cancer. EGFR serves as a key hub for transmitting proliferative signals, whereas HER3 is an important mediator of compensatory resistance under treatment pressure. Their biological functions are complementary.
With this dual-target design, tumor cells need to express only one of the two antigens to be recognized by the drug. Even if expression of one target is downregulated, the other can still mediate ADC internalization and payload delivery, fundamentally reducing the risk of antigen-mediated treatment escape. Because the drug’s activity is anchored to the EGFR and HER3 pathways rather than being directly dependent on HER2 expression, it can cover the full spectrum of HER2-negative disease, from HER2 IHC 0 to IHC 2+/ISH-negative, moving beyond the strict dependence of single-target ADCs on a specific level of antigen expression.
The deeper tumor-shrinking effect results from the combined enhancement of delivery efficiency and cytotoxic activity. Dual-target binding can induce receptor crosslinking and clustering, enhancing clathrin-mediated co-internalization and enabling more cytotoxic payload to be delivered precisely into tumor cells.
The payload, Ed-04, is a novel topoisomerase I inhibitor with no cross-resistance to conventional chemotherapy and favorable membrane permeability. Through the bystander effect, it can also target neighboring tumor cells with low antigen expression. Together with a design featuring a highly uniform drug-to-antibody ratio (DAR), these properties help ensure potent tumor-shrinking activity.
Meanwhile, simultaneous blockade of both pathways can inhibit heterodimer formation and compensatory bypass signaling, delay the emergence of resistance, and further prolong disease control.
The manageable safety profile is supported by meticulous optimization of the molecular structure. Iza-bren employs a differentiated binding design, with high affinity for EGFR and lower affinity for HER3, helping reduce off-target binding to normal tissues. It also incorporates a highly stable, cleavable tetrapeptide linker that remains stable in the peripheral circulation, minimizing premature payload release and enabling targeted release within tumor-cell lysosomes.
This precision-delivery design increases local drug concentrations within tumors while reducing the risk of systemic toxicity. It provides the key molecular basis for the low treatment discontinuation rate and low incidence of ILD observed with iza-bren.
Overall, the dual-target design represents a comprehensive advancement across target recognition, payload delivery, and the therapeutic safety window. It systematically addresses the clinical limitations of single-target ADCs, including restricted patient coverage, prominent resistance risks, and significant off-target toxicity associated with certain drugs.
Oncology Frontier: Iza-bren previously achieved positive results for both co-primary endpoints, PFS and OS, in the pivotal Phase III PANKU-Breast02 study in triple-negative breast cancer. At this year’s ESMO Congress, it also achieved a Phase III breakthrough in HR-positive/HER2-negative breast cancer. As a pioneer in bispecific ADC development, what future research directions do you believe are worth exploring for iza-bren in breast cancer?
Professor Shusen Wang: Iza-bren has now achieved positive Phase III results in the later-line treatment of two major breast cancer subtypes: triple-negative breast cancer and HR-positive/HER2-negative breast cancer. In addition, substantial clinical evidence has been generated across other solid tumors, including nasopharyngeal carcinoma, esophageal squamous cell carcinoma, non-small cell lung cancer, and urothelial carcinoma. These findings provide strong validation of the broad antitumor activity of the EGFR×HER3 bispecific ADC platform and establish a solid evidence base for further exploration across breast cancer subtypes.
From the perspective of evolving clinical treatment strategies, moving treatment into earlier lines of therapy will be one of the most important directions for future research in breast cancer.
For HR-positive/HER2-negative disease, treatment could gradually move into the setting following failure of CDK4/6 inhibitor therapy but before the initiation of chemotherapy. Research could explore combinations with endocrine therapy or endocrine-targeted agents to delay the need for chemotherapy and improve patients’ treatment experience and quality of life.
For triple-negative breast cancer, the global multicenter Phase III first-line study IZABRIGHT-Breast01, which is evaluating treatment in patients unsuitable for PD-(L)1 inhibitor therapy, is already underway. Future research could further expand into first-line combinations with immunotherapy, with the aim of raising the potential benefit achievable in the first-line advanced disease setting.
Exploring combination strategies is another important direction, with the central aim of delaying treatment resistance and optimizing long-term treatment approaches. Building on the pharmacological characteristics of EGFR×HER3 bispecific ADCs, different combination strategies can be tailored to individual breast cancer subtypes.
In triple-negative breast cancer, combining iza-bren with immune checkpoint inhibitors may help regulate the tumor immune microenvironment and strengthen antitumor immune responses, potentially identifying more effective first-line treatment strategies.
In HR-positive/HER2-negative disease, combinations with agents targeting the endocrine signaling pathway may provide synergistic suppression of tumor proliferation signals, delay the development of resistance, and extend the overall duration of disease control, offering patients a broader range of treatment options.
As clinical evidence continues to accumulate, the value of bispecific ADCs may expand beyond palliative treatment of advanced disease toward curative-intent treatment in early-stage breast cancer. For patients with high-risk early breast cancer, the potent tumor-shrinking activity of iza-bren could be explored in the neoadjuvant setting to rapidly reduce tumor burden and increase the pathological complete response rate, potentially creating opportunities for curative surgery in some patients whose tumors were initially inoperable.
In the adjuvant setting, it could be investigated as postoperative consolidation therapy for high-risk patients, with the aim of further reducing the risk of long-term recurrence and strengthening the treatment strategy across the entire course of breast cancer.
Further research is also needed to refine biomarker assessment and identify patient populations most likely to benefit. Although iza-bren can deliver benefits across a broad patient population without requiring target-based patient selection, a more detailed understanding of the relationship between EGFR and HER3 expression levels and treatment efficacy would be valuable. Combining these findings with tumor molecular characteristics and resistance patterns could help identify patient populations with particularly favorable outcomes. This would not only make treatment more precisely tailored to individual patients but also provide clearer direction for the development of future combination strategies and the investigation of resistance mechanisms.
Summary
PANKU-Breast01 is the Phase III clinical study of iza-bren in HR-positive/HER2-negative breast cancer that met its primary endpoint. Its results were presented as an LBA at ESMO and published simultaneously in the leading international journal The Lancet (impact factor: 109). More than 200 years after its founding, The Lancet has published the first innovative Chinese drug in the field of breast cancer in its main edition: iza-bren.
At the ESMO-CSCO forum, “Exploring the Pathway to Global Oncology Drug Development,” Professor Shusen Wang also highlighted the impressive findings from PANKU-Breast01 in HR-positive/HER2-negative breast cancer and PANKU-Breast02 in triple-negative breast cancer. He emphasized that China is transitioning from being a participant in global drug development to becoming a source of innovation in breast cancer therapeutics and clinical evidence generation. Innovative concepts led by Chinese researchers can address practical clinical needs while achieving precise targeting at the biological level. Iza-bren is an outstanding example of this progress.
Importantly, on October 21, the marketing application 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 was formally accepted by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA).
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 had also previously been accepted. The drug’s development across solid tumor indications continues to advance steadily and expand into new treatment settings.
We look forward to the approval of its breast cancer indications and its eventual introduction to international markets, bringing the benefits of Chinese-originated innovation to breast cancer patients both in China and around the world.
Professor Shusen Wang
