T-DM1 reduced the 3-year rate of invasive disease by 11% compared with trastuzumab. The rate of 3-year survival without invasive disease events was 88% in patients who received T-DM1 versus 77% in patients who received trastuzumab. The benefit of T-DM1 over trastuzumab was consistent among all patient subgroups, and although there were more frequently reported adverse events with T-DM1, drug safety was manageable.
“Additional follow-up will be necessary to evaluate the effect of T-DM1 on survival. KATHERINE will likely form the foundation of a new standard of care for this population and increase the use of neoadjuvant therapy in HER2-positive early breast cancer,” stated lead investigator Charles E. Geyer, Jr, MD, FACP, Associate Director of Clinical Research, Massey Cancer Center, Virginia Commonwealth University, Richmond. The results of the study were published simultaneously online in the New England Journal of Medicine.1
The KATHERINE Trial
HER2-directed monoclonal antibody therapy improves outcomes in patients with HER2-positive early breast cancer when added to chemotherapy. If the surgical margins are clear and the nodes are negative, the prognosis is favorable; however, if residual invasive disease is present in the breast or axillary nodes, the prognosis is less favorable and the risk for death or recurrence is increased.
T-DM1 is FDA approved for the treatment of HER2-positive metastatic disease as second-line therapy after chemotherapy and HER2-targeted therapy.
KATHERINE investigated the effect of substituting T-DM1 for trastuzumab in the adjuvant setting in 1486 patients with residual disease in tumor or axillary nodes after having surgery and receiving neoadjuvant chemotherapy plus trastuzumab. The patients were randomized to 14 cycles of T-DM1 or trastuzumab.
“HER2-positive breast cancers have a lot of variability, so we had 4 stratification factors: inoperable versus operable presentation, hormone receptor–positive or –negative, single or dual preoperative therapy, and positive versus negative nodal status,” Dr Geyer said.
The study’s primary end point 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.”1
Invasive disease and death were reduced by 50% with T-DM1; 165 (22.2%) events were reported in the trastuzumab arm versus 91 (12.2%) in the T-DM1 arm (P <.0001). The rates of 3-year invasive disease events were 77% with trastuzumab versus 88.3% with T-DM1.
In a subgroup analysis of patients with invasive disease events, a consistent benefit for T-DM1 was observed across all 4 prespecified subgroups, as well as for age and race.
“There was a striking homogeneity in consistency for all prespecified factors, plus no difference in efficacy by age and race,” Dr Geyer stated.
Compliance to the treatment regimen was slightly higher in the trastuzumab arm than in the T-DM1 arm. A total of 80% of patients received 14 cycles of trastuzumab compared with 71% of patients who received 14 cycles of T-DM1.
“We had stringent stopping rules in this potentially curative population, and some of the discontinuations are related to our precautions,” Dr Geyer noted.
Regarding adverse events, Dr Geyer said, “Safety data were consistent with the known toxicities of T-DM1, with expected increases in manageable adverse events associated with T-DM1 compared to trastuzumab.”
The rates of adverse events of any grade and serious adverse events were higher in patients who received T-DM1. The rates of adverse events of any grade or type were 98.8% in the T-DM1 arm versus 93.3% in the trastuzumab arm. Serious adverse event rates were 12.2% with T-DM1 and 8.1% with trastuzumab.
The rates of grade ≥3 adverse events were 25.7% with T-DM1 versus 15.4% with trastuzumab. Grade ≥3 adverse events reported with T-DM1 and trastuzumab, respectively, included thrombocytopenia (5.7% vs 0.3%), hypertension (2.0% vs 1.2%), and peripheral sensory neuropathy (1.4% vs 0), decreased neutrophil count (1.2% vs 0.7%), hypokalemia (1.2% vs 0.1%), fatigue (1.1% vs 0.1%), and anemia (1.1% vs 0.1%).
Peripheral sensory neuropathy of any grade was 18.6% with T-DM1 versus 6.9% with trastuzumab; this adverse event resolved in approximately 74% of patients.
Dr Geyer and colleagues plan to study baseline and posttreatment tumor samples, and they will also analyze patient-reported outcomes.
- von Minckwitz G, Huang CS, Mano MS, et al; for the KATHERINE investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380:617-628.