A long-term follow-up analysis of the phase 3 KATHERINE trial has demonstrated that trastuzumab emtansine (T-DM1) significantly improves overall survival compared to trastuzumab in patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant therapy. The study, published in the January 16, 2025 issue of the New England Journal of Medicine, was funded by F. Hoffmann–La Roche/Genentech.
The KATHERINE trial was an open-label, randomized study conducted at 273 sites across 28 countries. It enrolled 1,486 patients with HER2-positive early breast cancer who had residual invasive disease in the breast or axilla after completing neoadjuvant therapy with taxane-based chemotherapy and trastuzumab. Patients were randomly assigned 1:1 to receive either T-DM1 or trastuzumab for 14 cycles as adjuvant therapy.
The primary endpoint was invasive disease-free survival, with overall survival as a key secondary endpoint. This prespecified final analysis was conducted after a median follow-up of 101 months, with 385 invasive disease events or deaths recorded.
Results showed that T-DM1 maintained its superiority over trastuzumab in terms of invasive disease-free survival, with a hazard ratio of 0.54 (95% CI, 0.44-0.66). The 7-year invasive disease-free survival rate was 80.8% in the T-DM1 group compared to 67.1% in the trastuzumab group, representing an absolute difference of 13.7 percentage points.
Importantly, the study also demonstrated a significant improvement in overall survival with T-DM1. The hazard ratio for death was 0.66 (95% CI, 0.51-0.87; P=0.003), crossing the prespecified O'Brien-Fleming stopping boundary for statistical significance. The 7-year overall survival rate was 89.1% with T-DM1 versus 84.4% with trastuzumab, an absolute difference of 4.7 percentage points.
The safety profile of T-DM1 remained consistent with previous reports. Adverse events of grade 3 or higher were observed in 26.1% of patients in the T-DM1 group compared to 15.7% in the trastuzumab group. No new safety signals were identified during the extended follow-up period.
Subgroup analyses showed that the benefits of T-DM1 were generally consistent across various patient populations. However, patients with both immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)-amplified disease appeared to derive less benefit from T-DM1 compared to those with IHC 3+ disease. This finding suggests that tumors with higher HER2 expression may be more responsive to T-DM1 therapy.
The study had some limitations, including the open-label design and the underrepresentation of Black patients. Additionally, the analysis of certain subgroups, such as those with minimal residual disease, was exploratory in nature and should be interpreted with caution.
The authors concluded that adjuvant T-DM1 provides a significant and sustained improvement in both invasive disease-free survival and overall survival compared to trastuzumab in patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant therapy. These results further support the use of the neoadjuvant-adjuvant approach in this patient population.
The clinical implications of this study are substantial. The findings reinforce the role of T-DM1 as a standard of care in the adjuvant setting for patients with residual invasive HER2-positive breast cancer after neoadjuvant therapy. The demonstrated overall survival benefit provides strong evidence for the long-term efficacy of this treatment strategy.
However, the study also highlights areas for future research. The identification of patient subgroups who may benefit less from T-DM1, such as those with IHC 2+ disease, suggests a need for alternative or additional therapies in these populations. Ongoing trials are exploring combinations of T-DM1 with other agents, including tucatinib and immune checkpoint inhibitors, which may further improve outcomes in high-risk patients.
In conclusion, this long-term follow-up of the KATHERINE trial provides compelling evidence for the use of adjuvant T-DM1 in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy. The significant improvements in both invasive disease-free survival and overall survival, coupled with a manageable safety profile, solidify the position of T-DM1 as a key component in the treatment arsenal for this patient population.
References
Geyer CE Jr, Untch M, Huang CS, et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med. 2025;392(3):249-257. doi:10.1056/NEJMoa2406070
