Findings from randomised, phase III DESTINY-Breast04 study show significantly longer progression-free survival (PFS) and overall survival (OS) with trastuzumab deruxtecan than with the physician’s choice of chemotherapy among patients with previously treated HER2-low unresectable or metastatic breast cancer, regardless of hormone receptor (HR) status. These results have the potential to improve the treatment outcome for more than half of patients historically categorised as having HER2-negative breast cancer. The results were presented by Dr. Shanu Modi of the Memorial Sloan Kettering Cancer Center in New York, NY, US at ASCO 2022 Annual Meeting and simultaneously published in The New England Journal of Medicine.
The study team explained that aproximately 60% of HER2-negative metastatic breast cancers express low levels of HER2, defined as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridisation (ISH). HER2-low tumours constitute a heterogeneous population including both HR-positive and HR-negative breast cancers that vary in prognosis and sensitivity to systemic treatments. HER2-directed therapies available until now did not improve clinical outcomes in patients with this subtype.
HER2-low breast cancer is currently treated as HER2-negative (HER2-low and HER2-zero [IHC score of 0]), with patients stratified according to HR status. These patients have limited targeted treatment options after progression during primary therapy and most commonly receive single agent palliative chemotherapy. For patients with HR-positive, HER2-negative metastatic disease, combinations of endocrine therapy and CDK4/6 inhibitors are effective for a median of approximately 2 years, after which resistance often occurs. For patients with HR-negative, HER2-negative metastatic disease, few targeted agents are available, particularly for those without pathogenic BRCA mutations or tumours without PD-L1 expression.
Trastuzumab deruxtecan is an antibody–drug conjugate consisting of a humanised anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload through a tetrapeptide-based cleavable linker. It is approved for the treatment of patients with metastatic HER2-positive breast cancer. Unlike other HER2-targeted therapies, trastuzumab deruxtecan can also effectively target HER2-low tumour cells and can deliver its potent cytotoxic payload through the bystander effect to neighbouring tumour cells heterogeneously expressing HER2.
Phase I and II studies have shown promising results in heavily pretreated patients with HER2-low metastatic breast cancer. In this patient population, the percentage of patients with an overall response has ranged from 37.0% to 37.5%, and the median PFS has ranged from 6.3 to 11.1 months. These findings suggest that the efficacy of trastuzumab deruxtecan exceeds that of available treatments for patients with triple-negative or endocrine-refractory HR-positive breast cancer.
DESTINY-Breast04 is a randomised, two-group, open-label, phase III study that involved patients with HER2-low, unresectable or metastatic breast cancer. Study enrolment was planned for 480 patients with HR-positive disease (immunoreactive for oestrogen or progesterone receptor in ≥1% of tumour-cell nuclei according to local testing) and 60 patients with HR-negative disease. Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel. Randomisation was stratified according to HER2-low status (IHC 1+ versus IHC 2+ and ISH-negative), the number of previous lines of chemotherapy for metastatic disease (one versus two), and HR status (positive [with versus without previous CDK4/6 inhibitor therapy] versus negative).
The primary endpoint was PFS in the HR-positive cohort. The key secondary endpoints were PFS among all patients and OS in the HR-positive cohort and among all patients.
Of 557 patients who underwent randomisation, 494 patients (88.7%) had HR-positive disease and 63 patients (11.3%) had HR-negative disease. In the HR-positive cohort, the median PFS was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice group (hazard ratio for disease progression or death 0.51; p < 0.001), and OS was 23.9 months and 17.5 months (hazard ratio for death 0.64; p = 0.003).
Among all patients, the median PFS was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death 0.50; p < 0.001), and OS was 23.4 months and 16.8 months (hazard ratio for death 0.64; p = 0.001).
Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician’s choice of chemotherapy. Drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan and 0.8% had grade 5 events. The study investigators followed current guidelines for surveillance and management, including proactive monitoring of symptoms and imaging to identify potential cases of interstitial lung disease or pneumonitis, active management with prompt dose interruption, and early institution of glucocorticoid treatment as recommended to manage the risk and minimise serious outcomes.
The authors commented that targeting HER2-low metastatic breast cancer with trastuzumab deruxtecan was superior therapeutic approach in their study to chemotherapy. The risk of disease progression or death was approximately 50% lower, and the risk of death was 36% lower with trastuzumab deruxtecan than with the physician’s choice of chemotherapy, regardless of HR status. The results of the study highlight the clinical relevance in HER2-low patient population and support a need to redefine subgroups within HER2-negative breast cancers.
They also commented that a key consideration in the DESTINY-Breast04 study was the use of conventional HER2 IHC testing and HER2 ISH testing when applicable to identify HER2-low status. The VENTANA HER2/neu (4B5) IUO Assay system with ISH testing when applicable was used to identify patients with HER2-low tumour status. The data from this study will be used to update labeling of the assay to include a predictive claim for patients with HER2-low breast cancer. However, alternative quantitative methods to better select patients may be warranted and the minimum HER2-expression threshold required for trastuzumab deruxtecan activity is currently being determined in ongoing DB-06 and DAISY studies.
Prof. Sara A. Hurvitz of the David Geffen School of Medicine, University of California in Los Angeles, CA, US commented in an accompanied editorial article that consistent benefit was observed with trastuzumab deruxtecan in patients with poor prognostic indicators, including triple-negative cancer. Although the Trop-2–targeted antibody–drug conjugate sacituzumab govitecan has improved outcomes in patients with heavily pretreated triple-negative disease, the median PFS of just under 6 months and OS of approximately 1 year are lower than those reported in the 40 patients with triple-negative disease treated with trastuzumab deruxtecan in DESTINY-Breast04 study (8.5 months and 18.2 months). A randomised study is needed to compare these two agents, and sequencing studies are required to address whether cross-resistance develops among antibody–drug conjugates comprising similar cytotoxic payloads.
However, a critical question generated by DESTINY-Breast04 data is the threshold of HER2 expression needed for antitumour activity with trastuzumab deruxtecan, especially concordance between local and central IHC assessment in the DESTINY-Breast04 study has not been reported.
The study was funded by Daiichi Sankyo and AstraZeneca.
- Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 2022;387:9-20.
- Hurvitz SA. DESTINY-Changing Results for Advanced Breast Cancer. N Engl J Med 2022;387:75-76.