Adjuvant Trastuzumab Emtansine vs Trastuzumab in Patients With HER2-Positive Breast Cancer With Residual Disease After Neoadjuvant Therapy
As reported at the recent San Antonio Breast Cancer Symposium and in The New England Journal of Medicine by von Minckwitz et al, an interim analysis of the phase III KATHERINE trial has shown that adjuvant trastuzumab emtansine (T-DM1; Kadcyla) improved invasive disease–free survival vs trastuzumab (Herceptin) in patients with HER2-positive breast cancer with residual disease after neoadjuvant therapy.
Study Details
In the open-label trial, 1,486 patients from 273 sites in 28 countries were randomly assigned between April 2013 and December 2015 to receive adjuvant T-DM1 3.6 mg/kg intravenously (IV) every 3 weeks (n = 743) or trastuzumab 6 mg/kg IV every 3 weeks (n = 743) for 14 cycles. Patients had to have residual invasive disease in the breast or axilla at surgery after neoadjuvant therapy containing a taxane (with or without an anthracycline) and trastuzumab. Randomization was stratified by clinical stage, hormone receptor status, preoperative HER2-directed therapy, and pathologic nodal status after neoadjuvant therapy.
The primary endpoint was invasive disease–free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause) in the intention-to-treat population.
Invasive Disease–Free Survival
The early reporting efficacy boundary was crossed at the prespecified interim analysis, triggering full trial analysis. Median duration of follow-up was 41 months. At the time of analysis, invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). Estimated 3-year invasive disease–free survival was 88.3% in the T-DM1 group vs 77.0% in the trastuzumab group (hazard ratio [HR] = 0.50, P < .001). Distant recurrence as the first invasive disease event occurred in 10.5% of patients in the T-DM1 group vs 15.9% of the trastuzumab group (HR = 0.60, 95% confidence interval [CI] = 0.45–0.79). Subgroup analysis showed consistent benefit of T-DM1 across stratification groups and other subgroups, including in both hormone receptor–positive and hormone receptor–negative disease, both positive and negative pathologic nodal status after neoadjuvant therapy, and both no residual invasive primary disease and residual primary disease of ≥ 1 cm in the breast. There were a total of 98 deaths at time of analysis, including 42 in the T-DM1 group and 56 in the trastuzumab group; overall survival analysis did not cross the early reporting efficacy boundary (HR = 0.70, P = .08).
Adverse Events
Safety data were consistent with the known safety profile of T-DM1, with more adverse events being associated with T-DM1 vs trastuzumab. Treatment-related grade ≥ 3 adverse events occurred in 25.7% of the T-DM1 group vs 15.4% of the trastuzumab group; the most common in the T-DM1 group were decreased platelet count (5.7%) and hypertension (2.0%) and the most common in the trastuzumab group were hypertension (1.2%) and radiation-related skin injury (1.0%). Serious adverse events occurred in 12.7% of the T-DM1 group vs 8.1% of the trastuzumab group. Adverse events led to discontinuation of study drug in 18.0% vs 2.1% of patients. Peripheral sensory neuropathy of any grade occurred in 18.6% vs 6.9%.
The investigators concluded, “Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone.”
Disclosure: The study was funded by F. Hoffmann–La Roche/Genentech. The study authors’ full disclosures can be found at nejm.org.
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