Just 1 month after the DESTINY-Breast04 data were presented at the 2022 ASCO Annual Meeting Plenary Session,1 an ASCO expert panel released updated guidance that endorses the adoption of the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) into clinical practice for patients with “HER2-low” disease.1 The panel now recommends offering T-DXd to patients with HER2-low metastatic breast cancer who have received at least one prior chemotherapy for metastatic disease and, if they have hormone receptor–positive disease, that is refractory to endocrine therapy.
HER2-low expression is defined as immunohistochemistry (IHC) and/or in situ hybridization findings of IHC 1+ or IHC 2+/in situ hybridization–negative.
This rapid recommendation update augments a 2014 ASCO guideline, which underwent a full overhaul in July 2021 to reflect the most up-to-date research in this disease setting.2-4
Beverly Moy, MD, MPH
“ASCO issues rapid guideline recommendation updates when important advances in the treatment and management of cancer are presented,” said Beverly Moy, MD, MPH, of Massachusetts General Hospital, who coauthored the T-DXd update. “The fact that a rapid update had to be issued just 1 year after the full updated guideline was published is a testament to the great advances made in cancer research and clinical trials.”
Data Supporting the Rapid Recommendation Update
Results from the randomized phase III DESTINY-Breast04 trial showed that T-DXd successfully prolonged both progression-free survival and overall survival among patients categorized with HER2-low unresectable and/or metastatic breast cancer, as compared with physician’s choice of standard single-agent chemotherapy.5 Of the 557 patients in the trial followed for a median of 18.4 months, T-DXd conferred a 50% reduction in the risk of disease progression (median progression-free survival = 9.9 months vs 5.1 months; hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.40–0.63; P < .0001), along with a 36% reduction in the risk of death (median overall survival: 23.4 vs 16.8 months; HR = 0.64, 95% CI = 0.49–0.84; P = .0010).
Of note, the progression-free survival and overall survival benefits of T-DXd were observed in patients with either hormone receptor–positive disease or hormone receptor–negative disease. For example, T-DXd prolonged median overall survival by 6.4 months in the hormone receptor–positive subgroup and by 9.9 months in the hormone receptor–negative subgroup when compared with single-agent chemotherapy.
Lisa A. Carey, MD, ScM, FASCO
Lisa A. Carey, MD, ScM, FASCO, of the University of North Carolina Lineberger Comprehensive Cancer Center, who also coauthored the T-DXd guidelines update, noted that the hormone receptor–negative subgroup included in DESTINY-Breast04 was small (63 patients), representing just 11% of the total study population. Although more data are needed for this subset to confirm the benefit of T-DXd in previously treated patients, the panel opted to take the DESTINY-Breast04 data at face value and included individuals with hormone receptor–negative disease within the updated guidance, given the strong signal of improved survival.
Dr. Carey emphasized that the DESTINY-Breast04 data as a whole are practice-changing, not only for the clinically meaningful improvements in patient survival among individuals harboring disease with low HER2 expression levels, but also with regard to how clinicians should approach this large but unique subset of patients, who have typically been regarded as having HER2-negative disease. “People need to start thinking through the implications of the HER2-low classification, which is not how we have categorized breast cancer up until now,” she said.
1. Modi S, Jacot W, Yamashita T, et al: Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Results of DESTINY-Breast04, a randomized, phase 3 study. 2022 ASCO Annual Meeting. Abstract LBA3.
2. Moy B, Rumble RB, Carey LA: Chemotherapy and targeted therapy for HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor–negative: ASCO Guideline rapid recommendation update. J Clin Oncol 40:3088-3090, 2022.
3. Partridge AH, Rumble RB, Carey LA, et al: Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2–negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 32:3307-3329, 2014.
4. Moy B, Rumble RB, Come SE, et al: Chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor–negative: ASCO Guideline Update. J Clin Oncol 39:3938-3958, 2021.
5. Modi S, Jacot W, Yamashita T, et al, DESTINY-Breast04 Trial Investigators: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 387:9-20, 2022.
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