Editor's Note: In the field of breast cancer treatment, the rapid development of antibody-drug conjugates (ADCs) is gradually changing the traditional treatment landscape, bringing more hope to patients. The presentation of the DB-06 and OptiTROP-Breast01 studies at the 2024 ASCO conference has elevated the application of ADC drugs in breast cancer treatment to a new level. At the 2024 BOC/BOA conference, Oncology Frontier invited Professor Ying Fan from the Cancer Institute & Hospital  Chinese Academy of Medical Sciences to provide an in-depth interpretation of these two research advances and discuss the latest developments in ADC drug treatment for HER2-low breast cancer and triple-negative breast cancer (TNBC).

Comparing DB-06 and DB-04 Studies

Oncology Frontier: The DB-04 study brought a milestone change to the treatment landscape of HER2-low breast cancer. Could you introduce the differences and similarities in the patient populations and study designs between the DB-06 and the first HER2-low patient-targeted DB-04 study?

Professor Ying Fan: Although both DB-06 and DB-04 are randomized controlled studies mainly targeting HR+/HER2- advanced breast cancer patients, there are some differences in the enrolled populations and clinical trial designs. The data reported at the 2024 ASCO meeting show that DB-06 enrolled patients who had not received chemotherapy at the metastatic stage and had undergone ≥2 lines of endocrine therapy ± targeted therapy at the advanced stage or had received one line of endocrine therapy (if patients progressed within ≤6 months after first-line endocrine therapy + CDK4/6 inhibitors at the advanced stage or within ≤24 months after adjuvant endocrine therapy). Enrolled patients were randomly (1:1) divided into two groups, one treated with T-DXd and the other receiving the physician’s choice of chemotherapy (TPC).

The previously announced DB-04 study enrolled HR+ or HR-, HER2-low expression, unresectable and/or metastatic breast cancer (mBC) patients who had previously received one or two lines of chemotherapy.

Therefore, the first difference between the DB-06 and DB-04 studies is that the DB-06 study enrolled patients who had not received chemotherapy at the advanced stage, and these patients were at an earlier disease stage compared to those in the DB-04 study. The second difference is that the DB-06 study included some patients with HER2 ultra-low expression, aiming to further explore the therapeutic efficacy of T-DXd in this subgroup. In contrast, the DB-04 study enrolled only HER2-low expression patients but included a small portion of HR-/HER2-low expression patients, which is another significant difference between the two studies’ patient populations. However, the sample sizes of these subgroups in both studies are relatively small and are not the primary study endpoints.

Significance of DB-06 Study Results

Oncology Frontier: The DB-06 study further explored HER2-low patient populations, enrolling patients at earlier lines of treatment. What is the significance of the study results, and what impact will they have on breast cancer treatment?

Professor Ying Fan: As I mentioned earlier, the DB-06 clinical study enrolled patients at earlier lines of treatment, specifically those who had not received chemotherapy at the advanced stage. The study results demonstrated that T-DXd treatment for HR+/HER2- advanced breast cancer patients who had not received chemotherapy was significantly superior to traditional chemotherapy (primary endpoint BICR-assessed PFS for HER2-low patients: 13.2 vs. 8.1 months; HR 0.62, 95% CI: 0.51-0.74, P < 0.0001), highlighting the therapeutic advantage of ADC drugs.

As more ADC drugs emerge and research data are published, we may see ADC drugs fully replace traditional chemotherapy drugs in the future. Additionally, with more ADC treatment options available, strategizing the use of ADC drugs becomes a new challenge and consideration following the publication of the DB-06 study results.

Moreover, the DB-06 study is the first to explore the efficacy of anti-HER2 ADC drugs in HER2 ultra-low expression patients. Although the sample size for HER2 ultra-low expression patients is relatively small (153 cases), the study preliminarily showed similar clinical benefits to those seen in HER2-low expression patients. More data and real-world clinical evidence are needed to confirm whether anti-HER2 ADC drugs can be used for HER2 ultra-low expression patients in the future. Accurately diagnosing HER2 ultra-low expression patients is also a future challenge we must address.

Impact of OptiTROP-Breast01 Study on Chinese Patients

Oncology Frontier: ADC drugs are playing an increasingly important role in breast cancer treatment. At this year’s ASCO conference, Academician Xu Binghe reported on the first Chinese-developed Trop-2 ADC, Lucansatuzumab (SKB264), for locally recurrent or metastatic TNBC, phase III clinical trial OptiTROP-Breast01 data. As a study participant, could you discuss the significance of the OptiTROP-Breast01 study data for Chinese patients?

Professor Ying Fan: First, congratulations to Academician Xu Binghe and his team for presenting the OptiTROP-Breast01 study at the 2024 ASCO conference. The study data are indeed very encouraging for researchers in China. The OptiTROP-Breast01 clinical study results are very impressive. This study enrolled advanced TNBC patients who had undergone multiple lines of treatment, requiring that patients had received at least two lines of standard chemotherapy and had failed taxane therapy. A total of 263 patients were enrolled and randomly assigned (1:1) to the Lucansatuzumab group and the physician’s choice of chemotherapy (TPC) group. The primary study endpoint was PFS assessed by an independent review committee (BICR), with secondary endpoints including overall survival (OS), objective response rate (ORR), and investigator-assessed PFS.

The study results showed that BICR-assessed mPFS extended from 2.5 months in the TPC group to 6.7 months in the Lucansatuzumab group (HR 0.32, 95% CI: 0.22-0.44, P < 0.00001). Although OS data are still immature, they already show a significant improvement over the control group. This indicates very promising clinical research results, confirming for the first time that Lucansatuzumab provides significant clinical benefits compared to other physician-chosen chemotherapy regimens. We look forward to this drug being approved and marketed in China soon to benefit more Chinese patients.

Additionally, the success of this study is also significant for China. First, Lucansatuzumab is a Chinese-developed Trop-2 ADC drug, filling the domestic gap in original Trop-2 ADC drugs and showcasing China’s drug innovation capabilities. Second, the OptiTROP-Breast01 study was conducted specifically for Chinese patients, with clinical data more suitable for Chinese patients, offering more treatment options. Moreover, the treated patients not only showed remarkable efficacy, but their adverse reactions were also manageable. Therefore, Lucansatuzumab is a highly anticipated and more suitable Trop-2 ADC for Chinese patients, and its approval and marketing will significantly impact domestic clinical treatment.

Professor Ying Fan

• Director of the Breast Cancer Department, Cancer Hospital of the Chinese Academy of Medical Sciences
• Chief Physician, Master’s Supervisor, Peking Union Medical College eight-year program, Ph.D.
• Visiting Scholar at the Royal Marsden Hospital/ICR, UK (2008-2009)
• Deputy Director and Secretary General of the Clinical Research Innovation Development Committee of the Chinese Medical Education Association
• Deputy Director of the Youth Committee of the Beijing Breast Disease Prevention and Treatment Society
• Deputy Director of the Youth Committee of the Beijing Cancer Prevention and Treatment Research Society
• Deputy Director of the Breast Cancer Professional Committee of the Beijing Chronic Disease Prevention and Health Education Research Association
• Deputy Director of the Central Nervous System Metastatic Tumor Multidisciplinary Integration Professional Committee of the Beijing Integrated Medicine Society