Editor's Note: The European Society for Medical Oncology (ESMO) Congress is one of the most highly anticipated academic events in global oncology, where the presentation of every major study has the potential to reshape the clinical treatment landscape. Iza-bren (BL-B01D1/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 evaluating iza-bren in patients with HR-positive/HER2-negative advanced breast cancer who had previously received endocrine therapy and one to two lines of chemotherapy was presented as a late-breaking abstract (LBA), demonstrating impressive results.On the strength of its compelling efficacy data, the full results of PANKU-Breast01 were 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.
Oncology Frontier invited Professor Yehui Shi of Tianjin Medical University Cancer Institute and Hospital to provide an in-depth interpretation of the efficacy findings from PANKU-Breast01, the mechanistic advantages of bispecific ADCs, and the clinical positioning of iza-bren in the later-line treatment of HR-positive/HER2-negative advanced breast cancer, with the aim of offering insights for clinical practice.
Oncology Frontier: One of the most striking findings from PANKU-Breast01 is that it achieved impressive results even in patients with high-risk, difficult-to-treat disease: median PFS doubled to 8.2 months, while the confirmed objective response rate (cORR) also doubled, reaching 40.5%. What clinical value and practical significance do you believe these results have, given the high-risk characteristics of the enrolled population?
Professor Yehui Shi: The patient population enrolled in PANKU-Breast01 had typical high-risk, difficult-to-treat characteristics. All participants had previously received CDK4/6 inhibitors; 71.6% had liver metastases at baseline; 8.4% were at particularly high risk of early recurrence, with disease progression occurring within six months after completion of neoadjuvant or adjuvant chemotherapy; and nearly 30% had received two lines of chemotherapy for advanced disease. Overall, these patients had extensive prior treatment exposure, high tumor burden, and aggressive disease. They closely resemble the most challenging patients encountered in later-line clinical practice, making the study results highly relevant to real-world treatment.
This efficacy breakthrough is supported by the differentiated mechanism of action of the EGFR×HER3 bispecific ADC. Conventional single-target ADCs face clear efficacy limitations in patients with treatment-resistant disease in later lines of therapy. These limitations are associated with heterogeneity in tumor antigen expression, treatment-induced downregulation of antigen expression, and compensatory activation of bypass pathways.
Iza-bren simultaneously targets two key receptors in the ERBB family and addresses resistance through multiple mechanisms:
- Dual-target recognition helps overcome tumor heterogeneity. Even if expression of one antigen is downregulated, the other target can still mediate drug internalization and payload delivery, reducing the risk of antigen-mediated escape.
- Dual-target binding enhances drug internalization and payload delivery. It can induce receptor crosslinking and clustering, increasing clathrin-mediated co-internalization and facilitating more efficient delivery of the cytotoxic payload into tumor cells, thereby strengthening the antitumor effect.
- Simultaneous blockade of two signaling pathways helps limit resistance. It inhibits downstream proliferative signaling and reduces resistance mediated by compensatory activation of bypass pathways.
- The novel topoisomerase I inhibitor payload, Ed-04, provides an additional mechanism for overcoming resistance. It has no cross-resistance with conventional chemotherapy agents such as taxanes and anthracyclines. It also exhibits a pronounced bystander effect, enabling it to penetrate the tumor stroma and kill neighboring tumor cells with low antigen expression, further addressing tumor heterogeneity.
From a clinical perspective, these findings directly address the urgent needs of patients receiving later-line treatment. For patients with liver metastases or rapidly progressing disease, an objective response rate of 40.5% means that tumor burden can be reduced quickly, helping relieve tumor-related symptoms and potentially avoiding the need for frequent treatment changes over a short period.
The median PFS of 8.2 months doubles the duration of disease control for this challenging patient population. This allows patients to maintain disease stability for a longer period and provides valuable time and flexibility for planning subsequent treatment throughout the course of their disease. In doing so, iza-bren helps address an important unmet need for effective treatment options in this population.
Oncology Frontier: We noted that PANKU-Breast01 enrolled patients across different levels of HER2 expression (IHC 0, 33.7%; IHC 1+, 38.4%; and IHC 2+/ISH-negative, 27.9%) and prospectively incorporated HER2 expression as a stratification factor in randomization. By contrast, the benefit of HER2-targeted ADCs in this population depends on highly accurate pathological assessment. From the perspective of clinical decision-making, what impact could iza-bren’s efficacy, which is independent of HER2 expression levels, have on clinical practice?
Professor Yehui Shi: PANKU-Breast01 prospectively incorporated HER2 expression status as a randomization stratification factor, ensuring comprehensive coverage of the full spectrum of HER2-negative disease. The prespecified subgroup analysis demonstrated consistent and significant PFS benefits across all HER2 expression subgroups: the HR was 0.41 (95% CI, 0.28–0.62) in the HER2 IHC 0 subgroup, 0.53 (95% CI, 0.36–0.76) in the IHC 1+ subgroup, and 0.32 (95% CI, 0.19–0.53) in the IHC 2+/ISH-negative subgroup. These findings confirm that the antitumor activity of iza-bren does not depend on HER2 expression levels.
The fundamental reason for this HER2-independent efficacy is that iza-bren targets EGFR and HER3. Its antitumor activity is entirely independent of HER2 pathway expression, making its mechanism fundamentally different from that of HER2-targeted ADCs.
For HER2-targeted ADCs to work, tumor cells must express a sufficient level of HER2 antigen on their surface. This requires pathologists to interpret immunohistochemistry results with great precision: they must distinguish between the boundaries of IHC 0, IHC 1+, and IHC 2+ expression, while also incorporating ISH results to determine amplification status. Accurate assessment of very low HER2 expression presents an additional challenge. Furthermore, pathological interpretation is inherently subject to a degree of subjectivity, and borderline cases can frequently create uncertainty when clinicians make treatment decisions.
Iza-bren moves entirely beyond this framework. Its two targets are widely co-expressed on HR-positive/HER2-negative breast cancer cells, and its activity is not constrained by HER2 expression levels. Consequently, this level of detailed HER2 stratification is not required for treatment selection.
The practical advantages for clinicians are straightforward:
First, it substantially simplifies the clinical decision-making process. Once a patient has been diagnosed with HR-positive/HER2-negative advanced breast cancer, iza-bren can be considered as a treatment option without repeatedly waiting for detailed HER2 expression results. This can shorten the time between diagnosis and the initiation of effective treatment, which is particularly valuable for patients whose disease is progressing rapidly.
Second, it changes the way clinicians approach treatment sequencing. Previously, when selecting a later-line ADC for patients with HER2-negative breast cancer, clinicians would first ask, “What is the patient’s HER2 expression level?” In the future, greater emphasis can be placed on the patient’s overall clinical condition, the efficacy of the drug itself, and its tolerability, without allowing fine distinctions in HER2 expression to constrain treatment choices.
Oncology Frontier: Beyond its doubled efficacy and ability to benefit the full spectrum of HER2-negative patients, we also noted the favorable safety profile of iza-bren: the treatment discontinuation rate was only 1.6%, and the incidence of interstitial lung disease (ILD) was just 1.1%. How do you assess the clinical significance of the safety findings from this study?
Professor Yehui Shi: The therapeutic safety window is essential to realizing the full efficacy of an ADC. According to the study data, iza-bren has a clearly characterized and predictable adverse-event profile, consistent with findings from earlier studies, with no new safety signals observed.
Adverse events were primarily hematologic toxicities that can be managed and controlled in clinical practice. The treatment discontinuation rate due to treatment-related adverse events was 1.6%, comparable to the 1.0% observed in the investigator’s choice chemotherapy group.
The incidence of ILD, a particular concern in clinical practice, was only 1.1%. All cases were Grade 1–2 events, with no Grade 3 or higher cases and no fatal ILD reported.
Compared with certain single-target ADCs, iza-bren also demonstrates notable safety advantages. Its incidence of ILD is substantially lower than that reported with ADCs carrying a DXd payload. In addition, its permanent treatment discontinuation rate is lower than that of most currently approved single-target ADCs.
The combination of potent efficacy, manageable safety, and the potential for long-term treatment tolerability has important implications for both clinical practice and patient outcomes.
For clinicians, a clearly characterized and manageable safety profile reduces the complexity of treatment management and increases confidence and predictability in clinical decision-making. It supports patients in receiving sustained treatment at the appropriate dose, helping ensure that the substantial PFS benefit can be fully realized. Established adverse-event management strategies also lower the barriers to adoption in primary and community healthcare institutions, facilitating broader clinical implementation.
For patients, the lower incidence of severe adverse events reduces the physical burden associated with treatment and helps preserve quality of life during disease control. The low discontinuation rate supports treatment continuity and reduces the likelihood of premature interruption due to intolerance, allowing patients to derive the full survival benefit of therapy. Furthermore, stable disease control and a good overall physical condition provide a stronger foundation and a wider window of opportunity for subsequent sequential therapies. This is consistent with the central goal of comprehensive advanced cancer management: achieving a balance between prolonging survival and maintaining quality of life.
Summary
PANKU-Breast01 is the first and, to date, only Phase III clinical study of the world’s first approved bispecific ADC, iza-bren, to meet its primary endpoint in the treatment of HR-positive/HER2-negative breast cancer.
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 has also been accepted. Its development across solid tumor indications continues to advance, with an increasingly comprehensive treatment portfolio taking shape.
We look forward to the early approval of iza-bren for its breast cancer indications and its eventual entry into international markets, bringing the benefits of Chinese-originated innovation to breast cancer patients in China and around the world.
Professor Yehui Shi
