Event-driven prespecified final analysis of invasive disease-free survival (iDFS) and the second interim analysis of overall survival (OS) of a phase III, open-label KATHERINE study showed sustained improvement in iDFS with adjuvant trastuzumab emtansine compared to trastuzumab in patients with HER2-positive early breast cancer (EBC) with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment.
This prespecified long-term follow-up analysis provides additional support for the neoadjuvant treatment paradigm by showing that adjuvant trastuzumab emtansine also provided a significant improvement in OS and no evidence of long-term safety issues. The findings were reported by Dr. Charles E. Geyer Jr. of the UPMC Hillman Cancer Center in Pittsburgh, PA, US and colleagues on 15 January 2025 in The New England Journal of Medicine.
The authors wrote in the background that patients with HER2-positive EBC treated with neoadjuvant chemotherapy plus HER2-targeted therapy have residual invasive disease at surgery in 45-66% of cases depending on oestrogen receptor status, with an increased risk of recurrence and death.
The phase III KATHERINE study assessed trastuzumab emtansine as compared with trastuzumab as adjuvant treatment in patients with HER2-positive EBC with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment with taxane-based chemotherapy and trastuzumab. The primary analysis showed that 3-year iDFS was significantly higher in the trastuzumab emtansine group than in the trastuzumab group; however, the OS did not cross the early reporting boundary.
In the latest manuscript, the study team reported the findings from the event-driven, prespecified final analysis of iDFS and the second interim analysis of OS. The study investigators randomly assigned patients with HER2-positive EBC with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment with taxane-based chemotherapy and trastuzumab to receive trastuzumab emtansine or trastuzumab for 14 cycles.
With a median follow-up of 8.4 years, trastuzumab emtansine sustained the improvement in iDFS over trastuzumab (unstratified hazard ratio [HR] for invasive disease or death 0.54, 95% confidence interval [CI] 0.44 to 0.66). Seven-year iDFS was 80.8% with trastuzumab emtansine and 67.1% with trastuzumab.
Trastuzumab emtansine also led to a significantly lower risk of death than trastuzumab (unstratified HR 0.66, 95% CI 0.51 to 0.87; p = 0.003). Seven-year OS was 89.1% with trastuzumab emtansine and 84.4% with trastuzumab. On the basis of reported subsequent treatments, differences in treatments for metastatic disease were unlikely to account for OS improvement.
Adverse events of grade 3 or higher were noted in 26.1% of the patients in the trastuzumab emtansine group and 15.7% of those in the trastuzumab group. Because patients had already completed treatment at the time of the primary analysis, safety data at this update were as expected, and delayed side effects were rarely observed with adjuvant trastuzumab emtansine.
Although demonstration of the long-term efficacy and safety of adjuvant trastuzumab emtansine represents a major advance, review of 7-year iDFS and OS across key subgroups identifies cohorts for whom elevated absolute risk of recurrence remains despite trastuzumab emtansine therapy. These findings warrant evaluation of additional or alternative therapies to improve outcomes for these patients, including those who had initially presented with inoperable disease, those with positive axillary nodes after neoadjuvant treatment, and those with both IHC 2+ and ISH-amplified disease.
The CompassHER2 RD study is currently assigning high-risk patients to receive adjuvant trastuzumab emtansine plus HER2-specific tyrosine kinase inhibitor tucatinib or trastuzumab emtansine plus placebo. In the DESTINY-Breast05 study, the antibody drug conjugate trastuzumab deruxtecan is being compared with adjuvant trastuzumab emtansine in patients with the high-risk features identified in the KATHERINE study. In addition, atezolizumab in combination with trastuzumab emtansine is being evaluated in a similar high-risk population in the ASTEFANIA study.
The KATHERINE study was supported by F. Hoffmann–La Roche/Genentech.
Reference
Geyer Jr. CE, Untch M, Huang C-S, et al. for the KATHERINE Study Group. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med 2025;392:249-257.