Adjuvant treatment with the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) may improve survival in patients with high-risk HER2-positive breast cancer and residual invasive disease, according to long-term findings from the phase III KATHERINE trial published by Geyer et al in The New England Journal of Medicine.
Background
T-DM1 is an antibody-drug conjugate combining trastuzumab and the chemotherapy drug emtansine. When trastuzumab attaches to the HER2 receptor on cancer cells, it allows emtansine to more effectively enter the cancer cells and kill them from within.
Three-year data from KATHERINE, published in 2019 by von Minckwitz et al in The New England Journal of Medicine, found that adjuvant T-DM1 reduced the risk of mortality or invasive disease by 50% among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy.
Study Methods
Researchers recruited 1,486 patients with HER2-positive early breast cancer who had residual invasive disease in the breast or axillary lymph node following neoadjuvant treatment with taxane-based chemotherapy and the HER2-targeted agent trastuzumab as well as surgical removal of the tumor. These patients were determined to be at high risk of cancer recurrence and mortality. Postsurgery, the patients were randomly assigned to receive either adjuvant standard trastuzumab or adjuvant T-DM1.
Compared with treatment with trastuzumab alone, adjuvant T-DM1 decreased the risk of mortality or invasive disease by 46%. After a follow-up of 7 years, invasive disease–free survival was 80.8% among the patients who received adjuvant T-DM1 and 67.1% among those who received adjuvant trastuzumab alone. Overall survival was 89.1% in the adjuvant T-DM1 group and 84.4% in the trastuzumab alone group.
Although adverse events were higher in the adjuvant T-DM1 group (26.1%) compared with the trastuzumab alone group (15.7%), the overall safety of the drug was considered acceptable. The researchers noted the consistent benefit of adjuvant T-DM1 across patient subgroups. The analysis showed an approximately 50% reduction in risk of mortality and invasive disease regardless of the extent of disease at presentation, hormone receptor status, neoadjuvant treatment regimen, pathologic node status at surgery, age, and race.
“When I started my career in oncology, we knew that some breast cancers were more aggressive, but we didn’t know why,” detailed lead study author Charles E. Geyer, Jr, MD, Professor in the Division of Malignant Hematology and Medical Oncology at the University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, and UPMC Magee-Womens Hospital. “From the excitement of identifying HER2 gene amplification and resultant protein overexpression as a targetable oncogene, through the development of drugs targeting HER2 amplification and evaluating them in landmark clinical trials, I’ve had the privilege of being part of the HER2 story, and it’s incredibly satisfying to have been part of research effort that has led to a new standard of care for patients with this disease,” he emphasized.
Conclusions
“KATHERINE is a landmark clinical trial that found [adjuvant T-DM1] had such improved activity relative to trastuzumab that the results were reported earlier than had been anticipated when the study was originally designed. The results changed the standard of care globally for patients with HER2-positive early breast cancer,” highlighted Dr. Geyer. “We continued to follow patients to understand the full magnitude of the benefit, and we now show that [adjuvant T-DM1] leads to stable long-term improvements in invasive disease–free survival and improves overall survival,” he indicated.
The researchers are currently investigating the effectiveness of the antibody-drug candidate fam-trastuzumab deruxtecan-nxki in certain groups of patients, including those with lower expression levels of the HER2 protein who didn’t respond as well to adjuvant T-DM1 as patients with high HER2 expression.
Disclosure: The research in this study was funded by Hoffmann–La Roche/Genentech. For full disclosures of the study authors, visit nejm.org.
