In a phase III randomised DESTINY-Breast06 study, trastuzumab deruxtecan showed a significant benefit with respect to progression-free survival (PFS) as compared with chemotherapy among patients with hormone receptor (HR)-positive, HER2-low or HER2-ultralow metastatic breast cancer, after one or more lines of endocrine therapy-based regimens.
No new safety signals were identified. Interstitial lung disease remains an important safety risk of treatment with trastuzumab deruxtecan. The findings are published by Drs. Aditya Bardia of the Jonsson Comprehensive Cancer Center, University of California in Los Angeles, CA, US, Giuseppe Curigliano of the European Institute of Oncology, IRCCS and Department of Oncology and Hematology–Oncology, University of Milan in Milan, Italy and colleagues on 14 September 2024 in The New England Journal of Medicine.
The authors explained in the background that a spectrum of HER2 expression exists among breast cancers that are categorised as HER2-negative, defined as a score on immunohistochemical (IHC) analysis of 0, 1+, or 2+ and negative results on in situ hybridisation (ISH). Cancers with an IHC score of 1+ or 2+ with negative results on ISH are currently defined as HER2-low. The subdivision of IHC 0 into two categories, defined according to membrane staining that is faint and is seen in 10% of tumour cells or fewer (HER2-ultralow) or no observable staining, has recently been proposed.
The authors also explained that currently, the standard treatment for patients with HR-positive, HER2-negative metastatic breast cancer is an endocrine therapy-based regimen, usually with a CDK4/6 inhibitor as first-line treatment, with suggested consideration of additional targeted therapies in the second-line of treatment. Despite good outcomes with first-line endocrine therapy plus CDK4/6 inhibitors, the most appropriate sequence of therapies after disease progression remains unclear.
In the DESTINY-Breast04 study, trastuzumab deruxtecan showed statistically significant and clinically meaningful benefits with respect to PFS and overall survival (OS) as compared with standard chemotherapy among patients with HER2-low metastatic breast cancer with HR-positive or HR-negative disease.
Given that additional patients may benefit from HER2-directed treatment in earlier lines, the DESTINY-Breast06 study sought to evaluate the efficacy and safety of trastuzumab deruxtecan as compared with the physician’s choice of chemotherapy (single-agent capecitabine, nab-paclitaxel, or paclitaxel) in patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more endocrine-based therapies but no previous chemotherapy for metastatic disease.
This phase III, multicentre, open-label study involved patients with HR-positive metastatic breast cancer with low HER2 expression (defined as a score of 1+ or 2+ on IHC analysis and negative results on ISH) or ultralow HER2 expression (defined as IHC 0 with membrane staining). Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of chemotherapy. The primary endpoint was PFS according to blinded independent central review among the patients with HER2-low disease. Secondary endpoints included PFS among all the patients who had undergone randomisation, OS and safety.
Of the 866 patients who underwent randomisation, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median PFS was 13.2 months (95% confidence interval [CI] 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death 0.62, 95% CI 0.51 to 0.74; p < 0.001). The results were consistent in the exploratory HER2-ultralow population. Data for OS survival were immature.
Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%) with three events of grade 5 in severity and in one patient (0.2%) with grade 2.
Effects of trastuzumab deruxtecan on patient-reported outcomes were presented during the ESMO Congress 2024. Trastuzumab deruxtecan preserved quality-of-life (QoL) while delaying deterioration in physical/role functioning and pain versus physician’s choice of chemotherapy, albeit with more gastrointestinal symptoms.
During the ESMO Congress 2024, the study team presented also the data from HER2-low and HER2-ultralow status determination. Patients with HR-positive metastatic breast cancer determined as HER2-low or HER2-ultralow using the VENTANA HER2 (4B5) assay and ISH when applicable derived clinical benefit from trastuzumab deruxtecan, irrespective of sample type used to determine HER2 status. Of note, 64% of patients with a local HER2 IHC 0 score were classed as HER2-low or HER2-ultralow by central test.
The results of the DESTINY-Breast06 study indicate that a subgroup of patients currently categorised as having tumours with an IHC score of 0 with membrane staining can also benefit from trastuzumab deruxtecan. The current data suggest that there is no need to discriminate between HER2-low and HER2-ultralow disease because of the consistent benefit in both populations, albeit with limited patient numbers in the HER2-ultralow population.
The study was not powered to show statistical significance in the HER2-ultralow population, and it should also be acknowledged that patients with HR-negative disease were not included, so it remains unclear whether trastuzumab deruxtecan could replace first-line chemotherapy in this population.
The study was supported by AstraZeneca, in collaboration with Daiichi Sankyo.
References
- Bardia A, Hu X, Dent R, et al. for the DESTINY-Breast06 Trial Investigators. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. NEJM; Published online 14 September 2024. DOI: 10.1056/NEJMoa2407086
- LBA22 – Hu X, Curigliano G, Yonemori K, et al. Effects of trastuzumab deruxtecan (T-DXd) vs choice of chemotherapy (TPC) on patient-reported outcomes (PROs) in hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer (mBC): Results from DESTINY-Breast06. Annals of Oncology 2024;35(Suppl 2):S1214-S1215.
- LBA21 – Salgado RF, Bardia A, Curigliano G, et al. Human epidermal growth factor receptor 2 (HER2)-low and HER2-ultralow status determination in tumors of patients (pts) with hormone receptor–positive (HR+) metastatic breast cancer (mBC) in DESTINY-Breast06 (DB-06). Annals of Oncology 2024;35(Suppl 2):S1213-S1214.