Long-term follow-up data from the phase 3 KATHERINE trial demonstrate that adjuvant treatment with trastuzumab emtansine (T-DM1) provides a sustained overall survival (OS) and invasive disease-free survival (iDFS) benefit compared to trastuzumab alone in patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant therapy. The findings, published in the New England Journal of Medicine, reinforce T-DM1 as a standard of care for this high-risk population.
The KATHERINE trial enrolled 1,486 patients with HER2-positive early breast cancer who had residual invasive disease in the breast or axillary lymph nodes after neoadjuvant treatment with taxane-based chemotherapy and trastuzumab. Patients were randomized to receive either T-DM1 (3.6 mg/kg every 3 weeks) or trastuzumab (6 mg/kg every 3 weeks) for 14 cycles.
Sustained Improvements in Survival
After a median follow-up of approximately 8.4 years, the T-DM1 group showed a significant improvement in OS compared to the trastuzumab group (HR = 0.66, 95% CI = 0.51-0.87, P = 0.003). The estimated 7-year OS was 89.1% in the T-DM1 group and 84.4% in the trastuzumab group, representing an absolute difference of 4.7 percentage points.
The benefit in iDFS was also maintained, with a hazard ratio of 0.54 (95% CI = 0.44-0.66) favoring T-DM1. The 7-year iDFS rates were 80.8% and 67.1% for the T-DM1 and trastuzumab groups, respectively, an absolute difference of 13.7 percentage points.
Consistent Benefit Across Subgroups
An important finding from the KATHERINE trial was the consistent benefit of T-DM1 across various patient subgroups. According to Dr. Charles E. Geyer Jr., lead author and professor at UPMC Hillman Cancer Center, the analysis demonstrated an approximately 50% reduction in the risk of death and invasive disease, regardless of factors such as disease extent at presentation, hormone receptor status, neoadjuvant treatment regimen, and pathologic node status at surgery.
Safety Profile
While adverse events of grade 3 or higher were more frequent in the T-DM1 group (26.1%) compared to the trastuzumab group (15.7%), the overall safety profile of T-DM1 was considered acceptable. Serious adverse events occurred in 12.7% and 8.1% of patients in the T-DM1 and trastuzumab groups, respectively.
Implications for Clinical Practice
The KATHERINE trial has established neoadjuvant therapy as a standard of care for HER2-positive breast cancer, as it allows for the identification of patients who can benefit from adjuvant T-DM1. As Dr. Geyer noted, "KATHERINE is a landmark clinical trial that found 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."
Future Directions
Researchers are now exploring new antibody-drug conjugates, such as trastuzumab deruxtecan (T-DXd), for patients with lower HER2 expression levels who may not respond as well to T-DM1. These efforts aim to further improve outcomes for all patients with HER2-positive breast cancer.
