Editor's Note: At the 2024 ASCO Conference, the progress in breast cancer ADC (antibody-drug conjugate) research was remarkable. T-DXd demonstrated excellent efficacy in HER2-positive breast cancer, significantly extending patient survival and reinforcing the concept of using the best drugs first. In HR-positive and triple-negative breast cancer, Dato-DXd showed good safety and efficacy, laying the foundation for future combination therapy regimens. Additionally, domestic ADC drugs like ARX788 and SKB264 provided new treatment options for breast cancer patients. In this article, Dr. Songqing Ye from Fujian Provincial Hospital provides an in-depth analysis of the latest research findings on ADC drugs in HER2-positive, HR-positive, and triple-negative breast cancer presented at the 2024 ASCO Conference. 01 HER2-Positive Advanced Breast Cancer
Advanced breast cancer is often considered incurable, and one of the treatment goals is to extend patient survival. Overall survival (OS) is the “gold standard” in clinical oncology research, although OS is increasingly difficult to observe due to the introduction of new drugs, complex treatment options, and longer patient survival. However, the DB-03 study presented at this year’s ASCO showed a significant OS improvement with T-DXd compared to T-DM1, despite one-third of patients in the T-DM1 group crossing over to T-DXd. Historically, OS in second- and later-line treatments for HER2-positive breast cancer ranges from 20-30 months. The DB-03 study showed a median OS of 52.6 months with T-DXd, breaking the survival ceiling for similar treatments and approaching the 57.1 months OS observed in the first-line CLEOPATRA study, greatly improving the prognosis for patients with HER2-positive advanced breast cancer and supporting the concept of using the best drugs first.
Having shown excellent efficacy in the second line, how does T-DXd perform in the first line? The DB-07 study was the first to report data on T-DXd as a first-line treatment for HER2-positive metastatic breast cancer, with T-DXd monotherapy and T-DXd + pertuzumab showing impressive efficacy and safety. Although the median progression-free survival (PFS) has not been reached, the ORR in the T-DXd + pertuzumab group was 84%, compared to the 80.2% ORR in the CLEOPATRA study with dual-targeted therapy combined with docetaxel, raising expectations for the results of the phase III DB-09 confirmatory clinical trial.
This conference also presented a deep response analysis from the DB-01, DB-02, and DB-03 studies, showing that patients with good baseline characteristics (e.g., ECOG PS 0, non-visceral metastasis, <3 metastatic lesions) and fewer treatment lines are more likely to achieve complete response (CR) with T-DXd. In the combined analysis, 125 patients (15.0%) achieved CR, with a CR rate of 21.1% in second-line treatment. Patients achieving CR with T-DXd had better PFS and OS, confirming that T-DXd provides durable disease control and translates into extended PFS and OS, especially for those achieving CR. Although responders had a longer treatment duration, safety was generally manageable, with no increase in the proportion of patients experiencing treatment-emergent adverse events (TEAEs) over time. These results further support the widespread use of T-DXd in HER2+ metastatic breast cancer (mBC) patients.
Following T-DM1 and T-DXd, domestic HER2 ADCs are also emerging rapidly. For example, the phase III ACE-Breast-02 study with ARX788 offers a new treatment option for HER2+ advanced breast cancer patients in later lines, though its ocular toxicity management should be noted.
02 HR-Positive Breast Cancer
HR-positive breast cancer generally has a better prognosis and longer survival, making patients’ quality of life especially important. Patient-reported outcomes (PROs) are widely used to assess quality of life. The ASCO conference updated the PRO results from the TB-01 study, analyzing the efficacy and safety of Dato-DXd versus chemotherapy in HR+/HER2- advanced breast cancer (post-endocrine therapy failure and 1-2 lines of chemotherapy). Most treatment-related adverse events (TRAEs) in the Dato-DXd group were grade 1-2 and manageable, with fewer than half the incidence of ≥grade 3 TRAEs compared to the chemotherapy group. Oral mucositis was the only high-incidence event at 6%, with other TRAEs at 1%-2%. Fewer dose reductions or discontinuations due to TRAEs highlight Dato-DXd’s potential as a preferred treatment option in clinical practice and a foundation for future combination therapies.
In HR+/HER2- breast cancer, the SACI-IO clinical study of ADC combined with immunotherapy showed that SG combined with pembrolizumab did not significantly improve efficacy compared to SG alone. Subgroup analysis indicated a trend of benefit in PFS and OS for PD-L1-positive patients, though not statistically significant. OS data remain immature and require further follow-up. The safety profile of SG combined with pembrolizumab was consistent with the expected safety of both drugs, with no new safety signals reported. There may be intrinsic subtypes within HR+/HER2- advanced breast cancer that benefit from immunotherapy, necessitating further exploration of predictive factors for ADC combined immunotherapy strategies.
03 Triple-Negative Breast Cancer (TNBC)
TNBC lacks clear targets, making traditional chemotherapy the primary treatment option. The advent of immunotherapy and ADCs has revolutionized the treatment landscape. This conference presented the OptiTROP-Breast01 phase III study of the domestically developed Trop-2 ADC SKB264 for second-line and later TNBC treatment in China. The results showed that SKB264 significantly improved median PFS compared to physician’s choice chemotherapy, reaching 6.7 months, with overall safety being clinically manageable. SKB264 will be a new option for second-line and later treatment of advanced TNBC, and we look forward to its early approval in China to benefit more patients.
The BEGONIA study showed that the Dato-DXd + durvalumab (anti-PD-L1) combination achieved an ORR of 79% as first-line treatment for advanced TNBC, an excellent benefit. The innovative I-SPY2.2 study presented at this year’s ASCO explored Dato-DXd combined with durvalumab in early TNBC, achieving good efficacy in immune+ predictive subtype patients, with a pCR rate of 65% in the immune+ subtype model, providing evidence for IO+ADC combined therapy. Could ADC combined with immunotherapy replace preoperative immunochemotherapy in the future? We look forward to the phase III TB-04 study results comparing Dato + Durva versus paclitaxel + carboplatin + pembrolizumab as preoperative treatment. Additionally, two phase II studies of SG combined with other targeted drugs were presented, suggesting that ADC+ might become the mainstream treatment for TNBC in the future.
The ASCO conference demonstrated the continued robust development momentum of ADCs in breast cancer. We look forward to these new ADC drugs and therapies entering clinical practice soon to benefit many breast cancer patients.
Dr. Songqing Ye
- Chief Physician, Breast Surgery, Fujian Provincial Hospital
- Deputy Director of the Department (in charge of daily work)
- Member of the Breast Cancer Professional Committee, China Anti-Cancer Association
- Member of the Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Member of the Breast Cancer Group, Chinese Medical Doctor Association
- Deputy Director of the Yangtze River Academic Breast Alliance
- Deputy Director of the Breast Disease Branch, Fujian Medical Association
- Editorial Board Member of “Gland Surgery” and Guest Editorial Board Member of “Chinese Journal of Breast Disease”
