Editor's Note: The annual meeting of the European Society for Medical Oncology (ESMO) is one of the most authoritative academic gatherings in global oncology. The presentation of key research findings continues to drive advances in clinical practice and reshape treatment paradigms. At the 2026 ESMO Congress, the PANKU-Breast01 study, led by Academician Binghe Xu of the Chinese Academy of Engineering and the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, was presented as a Late-breaking Abstract (LBA).Unlike conventional single-target ADCs directed solely against HER2, iza-bren (BL-B01D1), the world’s first-in-class, first approved, and most clinically impactful ADC, is a bispecific ADC with a novel mechanism of action. Its study results were simultaneously published in full in the flagship edition of The Lancet (impact factor: 109). Notably, this is the first study of an innovative Chinese drug in the breast cancer field to appear in the journal’s main edition in its more than 200-year history. This is not simply another conventional ADC; through a novel mechanism based on dual-target synergy, it fundamentally reshapes the treatment paradigm for later-line HR+/HER2− breast cancer.
PANKU-Breast01 was designed to evaluate the efficacy and safety of iza-bren in patients with unresectable locally advanced, recurrent, or metastatic HR+/HER2− breast cancer whose disease had progressed after at least one prior line of chemotherapy. To explore the clinical value and practical implications of this study, Oncology Frontier invited Professor Quchang Ouyang of Hunan Cancer Hospital to discuss three key topics: the clinical value of deep tumor shrinkage, the mechanisms through which bispecific ADCs may overcome treatment resistance, and the differentiated advantages of this approach in later-line treatment. His insights are presented in the context of the available clinical evidence.
Oncology Frontier: The tumor-shrinkage results from PANKU-Breast01 are particularly impressive: the confirmed objective response rate (cORR) reached 40.5%, twice that of the chemotherapy group; 77.9% of patients experienced a reduction in target lesion size, with a median tumor shrinkage of −37.4%; and median duration of response (mDoR) was extended to 6.9 months. For patients with advanced breast cancer, particularly those with a high tumor burden or visceral metastases, what is the practical clinical significance of achieving “greater, deeper, and more durable tumor shrinkage”?
Professor Quchang Ouyang: We can see that PANKU-Breast01 enrolled patients with unresectable locally advanced or metastatic HR+/HER2− breast cancer who had previously received endocrine therapy and one to two lines of chemotherapy. Patients at this stage generally share several characteristics: high-risk disease from an early stage, aggressive tumor biology, multiple prior lines of treatment in the advanced setting, and relatively poor performance status. In this setting, the objective response rate with conventional later-line chemotherapy is usually below 25%, with limited tumor shrinkage and short response duration, while patients also face a substantial toxicity burden. Therefore, the key clinical priorities are to rapidly control disease progression, relieve tumor-related symptoms, and preserve patients’ quality of life as much as possible.
It is precisely against this background of high-risk, difficult-to-treat disease that the higher tumor response rates and more durable responses achieved with iza-bren take on greater clinical significance.
Higher tumor response rates. The confirmed objective response rate reached 40.5%, approximately twice that of the chemotherapy group, while 77.9% of patients experienced a reduction in target lesion size. This indicates that even among patients with disease resistant to multiple prior lines of treatment, nearly 80% experienced disease control and more than 40% achieved substantial tumor regression. This can effectively control tumor progression and is particularly important for patients who have significant baseline symptoms or rapidly progressing disease.
Substantial reduction in tumor burden. Median tumor shrinkage reached −37.4%. Such a profound reduction in tumor burden can directly alleviate compression and invasion of surrounding tissues by the tumor, rapidly relieving tumor-related symptoms such as distension, pain, and pressure caused by liver and lung metastases or mediastinal lymph node metastases, as well as pain associated with bone metastases. This can help improve patients’ physical condition and ability to perform daily activities at an early stage.
Stable and sustained efficacy. Median duration of response reached 6.9 months, compared with 4.2 months in the chemotherapy group. With more durable tumor responses, patients can benefit from a longer period of treatment without disease progression, while reducing the physical strain and psychological burden associated with frequent changes in treatment regimens.
From the perspective of subsequent treatment planning, deep and durable tumor regression may create opportunities for local interventions, such as palliative surgery or palliative radiotherapy, in selected patients who were initially unsuitable for such interventions. These approaches may further consolidate disease control. At the same time, sustained responses may delay the need to initiate more intensive later-line treatments, preserving additional treatment options and patients’ physical reserves and ability to tolerate subsequent therapy.
Particularly noteworthy is that, despite achieving deep tumor shrinkage, the rate of treatment discontinuation due to treatment-related adverse events was only 1.6%. The incidence of interstitial lung disease (ILD) was only 1.1%, with all cases being mild Grade 1–2 events. The treatment therefore achieves deep tumor shrinkage while remaining suitable for long-term use, which is crucial for patients with advanced breast cancer who require prolonged disease management.
The PANKU-Breast02 study, conducted in patients with advanced triple-negative breast cancer (TNBC), a more difficult-to-treat subtype, also demonstrated substantial tumor shrinkage with iza-bren: 77.3% of patients experienced tumor shrinkage, median tumor shrinkage reached −44.6%, and the confirmed objective response rate was 51.7%. All these efficacy measures were significantly better than those in the chemotherapy group. The consistent tumor-shrinkage benefits observed across two different breast cancer subtypes provide strong evidence of the reproducibility of iza-bren’s tumor-shrinking activity.
Oncology Frontier: From resistance to endocrine therapy and CDK4/6 inhibitors to resistance to multiple lines of chemotherapy, the challenge of treatment resistance in later-line HR+/HER2− breast cancer urgently needs to be addressed. As the world’s first bispecific ADC, why can iza-bren’s unique mechanism of action effectively overcome resistance to multiple prior lines of treatment compared with conventional single-target ADCs? And why is its efficacy not restricted by HER2 expression levels?
Professor Quchang Ouyang: The difficulty of overcoming treatment resistance in later-line advanced HR+/HER2− breast cancer essentially reflects the combined effects of tumor heterogeneity and compensatory signaling pathways. Single-target ADCs have three inherent limitations. First, target downregulation or loss: tumor cells can evade recognition and internalization by single-target ADCs by reducing target protein expression, preventing effective delivery of the cytotoxic payload. Second, intratumoral heterogeneity in antigen expression: different cell populations within the same lesion may express different levels of the target antigen. Cells with low expression can escape drug-mediated killing and proliferate, forming resistant clones. Third, compensatory activation of bypass pathways: after a single target is blocked, tumor cells can activate proliferation and survival signals through other receptor pathways, resulting in diminished treatment efficacy.
Iza-bren addresses these limitations systematically through three dimensions: target coverage, pathway inhibition, and payload activity. This is what fundamentally distinguishes it from single-target ADCs and is also the key reason why its efficacy is not restricted by HER2 expression levels.
First, dual-target recognition expands coverage of tumor heterogeneity. EGFR and HER3 both belong to the ErbB receptor family and have complementary functions. EGFR is a central hub mediating tumor growth signals, with multiple proliferation- and survival-promoting signals converging at this receptor and being transmitted downstream. Although HER3 lacks intrinsic kinase activity, it can form heterodimers with EGFR and serve as a key mediator of compensatory resistance under treatment pressure.
The dual-target design enables the drug to recognize both antigens. Even if expression of one antigen is downregulated, the other can still mediate ADC internalization and delivery of the cytotoxic payload, substantially reducing the likelihood of “single-target escape.” Therefore, patients do not need to be selected according to HER2 expression status. Tumors expressing either EGFR or HER3 can potentially be recognized and targeted for killing, making the potential treatment population broader.
Second, simultaneous inhibition of two pathways suppresses compensatory activation. EGFR and HER3 jointly regulate downstream proliferation and survival pathways, including RAS/RAF/MEK/ERK and PI3K/AKT. Simultaneous blockade of both targets can more comprehensively interrupt tumor signal transduction and inhibit compensatory activation of bypass pathways at the source. Compared with single-target ADCs, this may enable more durable tumor control.
Third, a novel payload offers a distinct mechanism of action without cross-resistance. Iza-bren carries the novel topoisomerase I inhibitor Ed-04, whose mechanism of action is entirely different from that of commonly used chemotherapy agents such as taxanes and anthracyclines. It therefore retains cytotoxic activity against tumor cells that have developed resistance to multiple lines of chemotherapy. In addition, its favorable membrane permeability enables a bystander effect, allowing it to kill neighboring tumor cells with heterogeneous antigen expression and further expand its activity across heterogeneous tumor populations.
These mechanistic advantages have been supported by findings from multiple clinical studies. In a Phase Ib clinical study involving patients with HR+/HER2− breast cancer who had received multiple prior lines of treatment, cORR reached 37.3% and median progression-free survival (mPFS) was 7.0 months, providing preliminary evidence of the efficacy of this mechanism in a population with multiple forms of treatment resistance. The Phase III PANKU-Breast01 study further confirmed these findings: mPFS reached 8.2 months, doubling that of the chemotherapy group, with consistent benefits across all subgroups. These results validate the breakthrough clinical value of bispecific ADCs in a large patient population.
Findings across different molecular subtypes further support the robustness of the drug’s mechanism of action. In the Phase III PANKU-Breast02 study in advanced TNBC, mPFS was 8.5 months versus 3.1 months in the chemotherapy group, while cORR was 51.7% versus 20.5%, respectively. Iza-bren has demonstrated significant efficacy in both HR+/HER2− breast cancer and TNBC. This suggests that the underlying principle by which its dual-target design addresses treatment resistance can apply across different breast cancer subtypes, providing more substantial clinical evidence to support its application.
Conclusion
As the world’s first-in-class and first approved bispecific ADC, iza-bren has already been approved in China for two indications: later-line treatment of recurrent or metastatic nasopharyngeal carcinoma and treatment of recurrent or metastatic esophageal squamous cell carcinoma.
On October 21, 2026, information published by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration showed that the marketing application for iza-bren (BL-B01D1) for HR+/HER2− breast cancer had been formally accepted. The proposed indication is for patients with unresectable locally advanced, recurrent, or metastatic HR+/HER2− breast cancer whose disease has progressed after at least one prior line of chemotherapy. This marks the second breast cancer indication for which a marketing application for iza-bren has been accepted by the CDE, following TNBC.
From nasopharyngeal carcinoma to esophageal cancer, and from TNBC to HR+/HER2− breast cancer, iza-bren is progressively translating the innovative advantages of its novel dual-target mechanism—demonstrating that it is “not simply another ADC”—into tangible benefits for patients. As clinical evidence in breast cancer continues to accumulate and additional indications move toward approval, iza-bren is poised not only to offer a new option for later-line treatment of advanced breast cancer, but also to help move breast cancer treatment beyond the era of “single-target approaches and narrowly selected populations” and into a new era of bispecific ADC therapy characterized by “dual-target recognition and broader patient coverage.”
Professor Quchang Ouyang
