Editor’s Note:
The mid-term analysis results of the DESTINY-Breast04 (DB-04) study were striking, quickly influencing international guidelines such as NCCN and ESMO, and obtaining approvals for indications related to HER2 low expression both domestically and internationally. At the 2023 ESMO Congress held recently, the DB-04 study presented updated survival data with a median follow-up of 32 months, demonstrating sustained survival benefits, good safety, and tolerability, further solidifying T-DXd as a new standard for advanced HER2-low expression breast cancer. Prof. Ying Fan from the Cancer Hospital of the Chinese Academy of Medical Sciences, provides an introduction and commentary on the study as follows.
Study Introduction
Background:
In traditionally defined HER2-negative metastatic breast cancer (mBC), approximately 60% exhibit HER2 low expression (HER2-Low, i.e., IHC 1+ or IHC 2+/ISH-). HER2-Low expression mBC is usually treated as HER2-mBC, and after first-line CDK4/6 combined endocrine therapy, there is no standard second-line treatment. Previous HER2-targeted treatment studies for breast cancer patients with HER2 low expression have been unsuccessful, and the current domestically available endocrine combined targeted treatment for patients with mPFS is only 4.2 to 5.7 months. Ongoing studies related to other targeted/endocrine treatments show mPFS of around 7 months, while chemotherapy only provides 3 to 4 months of mPFS benefit. There is still a significant unmet clinical need for new drugs in this patient population.
T-DXd is a novel antibody-drug conjugate (ADC) targeting HER2, with strong drug activity and low cross-resistance, a high drug-to-antibody ratio, good circulation stability, and drug advantages such as selectively cleavable linkers and bystander effects from drug membrane permeability. The DB-04 study is the first phase III trial to investigate ADC treatment for HER2-low expression advanced breast cancer and has yielded positive results. The initial mid-term analysis (median follow-up of 18.4 months) showed significant prolongation of the primary endpoint: PFS in HR+ patients in the T-DXd group (BICR assessment: 10.1 vs. 5.4 months; HR 0.51, P <0.001). Key secondary endpoints: PFS in all patients (BICR assessment: 9.9 vs. 5.1 months; HR 0.50, P <0.001); HR+ patients (23.9 vs. 17.5 months; HR 0.64, P = 0.0028) and all patients (23.4 vs. 16.8 months; HR 0.64, P = 0.0010) all showed significant extensions. Exploratory endpoints: PFS (BICR assessment: 8.5 vs. 2.9 months; HR 0.46) and OS (18.2 vs. 8.3 months; HR 0.48) in HR- patients showed benefits as well.
Methods:
Patients enrolled in the study had HER2 low expression, were ineligible for surgery, and/or had metastatic breast cancer after 1-2 lines of advanced chemotherapy, with HR+ patients being endocrine therapy-resistant. Patients were randomly assigned to receive T-DXd (5.4 mg/kg Q3w) or physician’s choice of chemotherapy (TPC, capecitabine, eribulin, ixabepilone, paclitaxel, or albumin-bound paclitaxel). The primary endpoint was blinded independent central review (BICR)-assessed PFS in HR+ patients; key secondary endpoints included BICR-assessed PFS in all patients, and overall survival (OS) in HR+ and all patients; other secondary endpoints included investigator-assessed PFS, BICR and investigator-assessed objective response rate (ORR), BICR-assessed duration of response (DOR), safety, and reported outcomes in HR+ patients.
This report includes the extended survival analysis with a median follow-up of 32.0 months, covering updated overall survival (OS) for key endpoints in both HR+ and all patients, as well as secondary endpoints like investigator-assessed progression-free survival (PFS) and safety.
Results:
The OS benefits in the HR+ cohort and all patients remained consistent with the initial mid-term analysis results. In the HR+ cohort, patients in the T-DXd group had a 31% reduction in the risk of death compared to the TPC group (23.9 vs. 17.6 months; HR 0.69). The 2-year OS rates for the two groups were 49.0% and 35.1%, and the 3-year OS rates were 26.5% and 16.9%, respectively. In all patients, the T-DXd group also showed a 31% reduction in the risk of death (22.9 vs. 16.8 months, HR 0.69), with 2-year OS rates of 47.3% and 32.0%, and 3-year OS rates of 26.2% and 16.3%, respectively.
The subgroup analysis of OS for both the HR+ cohort and all patients indicates consistent benefits across all subgroups.
In the HR+ cohort, the T-DXd group showed a 63% reduction in the risk of progression and death (investigator-assessed: 9.6 vs. 4.2 months, HR 0.37). The 2-year progression-free survival (PFS) rate for the T-DXd group reached 15.4%. In all patients, the T-DXd group exhibited a 64% reduction in the risk of progression and death (investigator-assessed: 8.8 vs. 4.2 months, HR 0.36), with a 2-year PFS rate of 14.5%.
In the exploratory analysis of the HR- cohort, patients in the T-DXd group experienced a 71% reduction in the risk of progression and death (investigator-assessed: 6.3 vs. 2.9 months, HR 0.29), with a 1-year progression-free survival (PFS) rate of 25.3%. The risk of death was reduced by 42% (17.1 vs. 8.3 months, HR 0.58), and the 2-year overall survival (OS) rate reached 32.6%.
在HR+队列中，T-DXd仍可延长PFS2（15.8 vs 10.5个月，HR 0.51）；在所有患者中，同样显示T-DXd可延长PFS2（15.4 vs 9.7个月，HR 0.51），使患者获得持续获益。T-DXd经治后不影响患者后续治疗选择，两组的后续治疗大致相似，常见后续抗癌治疗为化疗（～68%）、内分泌治疗（～30%）、靶向治疗（～38%）；TPC组后续接受ADC治疗的比例高于T-DXd组。
The median duration of treatment for the T-DXd group and the TPC group was 8.2 months and 3.5 months, respectively. The incidence of Grade ≥3 treatment-emergent adverse events (TEAEs) during treatment was lower in the T-DXd group compared to the TPC group (54.4% vs. 67.4%). The rate of TEAEs leading to dose reduction was also lower in the T-DXd group than in the TPC group (24.0% vs. 37.8%). Common TEAEs leading to dose reduction in the T-DXd group included nausea (4.6%) and decreased platelet count (3.0%), while in the TPC group, they included decreased neutrophil count (10.5%) and hand-foot syndrome (5.2%).
Since the initial mid-term analysis, there have been no new cases of interstitial lung disease (ILD) or non-infectious pneumonia added. The incidence of any-grade ILD/non-infectious pneumonia in the T-DXd group is 12.1%, with the majority being Grade 1-2. There were four cases each of Grade 3 and Grade 5 ILD/non-infectious pneumonia (both 1.1%).
The updated data presented above indicates that T-DXd, used in patients with HER2 low expression who have undergone at least one line of chemotherapy, continues to provide benefits in terms of both progression-free survival (PFS) and overall survival (OS) during longer follow-up. The updated OS data further solidify the position of T-DXd as the standard treatment for HER2 low expression. The study’s long-term safety and tolerability support T-DXd as a new standard of care for patients in this category.
Expert Commentary
The initial mid-term analysis results of the DB-04 study were impressive, not only offering ADC treatment with dual benefits in PFS and OS for HER2 low expression patients but also establishing a new standard of care for advanced HER2 low expression breast cancer patients. Based on the results of the DB-04 study, international guidelines such as NCCN and ESMO have designated T-DXd as the preferred option for second-line/advanced treatment after progression in HR+/HER2- breast cancer. The Chinese Guidelines for the Diagnosis and Treatment of Advanced Breast Cancer (2022 Edition) (ABCC Guidelines) also recommend T-DXd for the treatment of HR+/HER2- breast cancer patients with HER2 low expression.
The ESMO update on the DB-04 study includes critical data with a median follow-up of 32 months, covering key secondary endpoints such as OS in the HR+ cohort and all patients, as well as secondary endpoint investigator-assessed PFS and safety data. The results demonstrate that, with prolonged follow-up, T-DXd continues to provide sustained and statistically significant clinical improvements in survival compared to the TPC group for HER2 low expression mBC. Regardless of HR status, T-DXd treatment showed survival benefits.
At the 2023 ESMO Congress, the median PFS data for the investigator-assessed HR- subgroup were reported as follows: T-DXd vs. TPC – 6.3 months vs. 2.9 months, HR 0.29. The initial BICR-assessed HR- subgroup median PFS data presented at the 2022 ASCO Congress were: T-DXd vs. TPC – 8.5 months vs. 2.9 months, HR 0.46. Although there are slight differences in absolute benefits between the two assessments, the relative benefits remain consistent. Considering the reasons for different evaluation criteria (BICR or investigator assessment) is a normal phenomenon in clinical research. Previous data suggested that T-DXd benefits different expression subgroups and patients with brain metastases. The DESTINY-Breast04 study further reported data for patients with ER-negative and ER low expression subgroups, indicating that T-DXd benefits are unrelated to ER expression levels. Results from the DEBBRAH study and the DAISY study also suggest that T-DXd provides benefits for patients with brain metastases, providing more treatment options for this patient population.
The data from this extended follow-up demonstrate the sustained survival benefits of T-DXd, further solidifying its position as the preferred standard of care for patients in this category. The China National Medical Products Administration (NMPA) approved T-DXd for use in July of this year for the treatment of unresectable or metastatic HER2 low expression (IHC 1+ or IHC 2+/ISH-) breast cancer in adults who have received at least one systemic therapy in the metastatic stage or have relapsed within 6 months after completing adjuvant chemotherapy. This indication includes all HER2 low expression patients, regardless of HR status. The benefits of T-DXd treatment are consistent for both HR+ and HR- patients, and T-DXd’s mechanism of action is independent of HR status, aligning with international and domestic guideline recommendations. Furthermore, the safety and tolerability of T-DXd in the extended follow-up data are consistent with previous findings, especially with no new interstitial lung disease (ILD) or non-infectious pneumonia events reported.
In addition to the survival data updates, this ESMO Congress also presented a subgroup analysis of baseline brain metastasis patients in the DB-04 study. The study included 35 asymptomatic patients with stable brain metastases at baseline (24 in the T-DXd group and 11 in the TPC group). With a median follow-up of 32 months, the intracranial objective response rate (ORR) was 25.0% for the T-DXd group and 0% for the TPC group, clinical benefit rate (CBR) was 58.3% and 18.2%, and disease control rate (DCR) was 75.0% and 63.6%, respectively. The BICR-assessed CNS-PFS for the T-DXd group was 9.7 months, and the median OS was 16.7 months.
In summary, the results of the extended follow-up in the DB-04 study demonstrate that T-DXd, used for treating HER2 low expression mBC patients, provides sustained benefits in terms of both PFS and OS. The favorable safety and tolerability profile of T-DXd solidify its position as a new standard of care for patients in this category. These data validate current guideline recommendations and indications both domestically and internationally, highlighting that the efficacy of T-DXd is not influenced by HR status. On the other hand, the extended follow-up analysis of the brain metastasis subgroup in the DB-04 study addresses a research gap for such patients. Despite the relatively small sample size, T-DXd shows superior intracranial and extracranial disease control compared to TPC, achieving consistent efficacy and survival benefits in line with the overall HER2 low expression population.
References:
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Cancer Hospital, Chinese Academy of Medical Sciences
Doctor of Medicine, Chief Physician of Internal Medicine, Master’s Supervisor
Visiting Scholar at the Royal Marsden Hospital/ICR in the United Kingdom (2008-2009)
Deputy Director and Secretary-General of the Clinical Research and Innovation Development Professional Committee of the China Medical Education Association
Deputy Chair of the Youth Committee of the Tumor Drug Clinical Research Professional Committee of the China Anti-Cancer 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 Control Research Association
Secretary-General of the Chinese Academy of Cancer Health Management
Member of the Tumor Chemotherapy Professional Committee of the China Anti-Cancer Association
Member of the Youth Committee of the Chinese Society of Clinical Oncology (CSCO)
Author of numerous articles published in domestic and international journals such as JAMA Oncology and Annals of Oncology.
