SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.
The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive early stage, as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.
KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival (OS), when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.
It is well established that patients with HER2-positive early breast cancer, following HERCEPTIN® based neoadjuvant therapies, have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy.
KATHERINE trial was conducted to evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.
The KATHERINE trial is an open-label, Phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Patients also received standard-of-care radiation and endocrine therapy as per institutional guidelines. Both treatment groups were well balanced and Hormone Receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival-iDFS (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). The Primary analysis showed that 3-year invasive DFS was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (88.3% vs. 77.0%; HR=0.50; P<0.001), suggesting that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%.
The researchers in this publication reported the prespecified final analysis of invasive DFS, and the second interim analysis of Overall Survival. With a median follow-up of 8.4 years, KADCYLA® sustained its superiority over HERCEPTIN® in improving invasive DFS and OS. The 7-year invasive DFS rate was 80.8% with KADCYLA® vs. 67.1% with HERCEPTIN® (unstratified HR=0.54, confirming a 46% reduction in risk. The 7-year OS was 89.1% with KADCYLA® vs. 84.4% with HERCEPTIN® (unstratified HR=0.66; P=0.003), demonstrating a 34% reduction in mortality risk.
Further analyses revealed consistent benefits across key subgroups which included patients with low tumor burden minimal residual disease (1 cm or less, node-negative), HER2-negative residual disease on retesting, both ER-positive and ER-negative patients, as well as HER2 expression level, with patients with IHC 3+ HER2 expression experiencing the most significant benefit (HR=0.47), whereas those with IHC 2+ ISH-amplified tumors had a smaller, though still positive, effect (HR=0.84).
The incidence of adverse events of Grade 3 or higher was noted in 26.1% of patients receiving KADCYLA® compared to 15.7% in the HERCEPTIN® group. The frequency of CNS metastases was comparable between the two cohorts, suggesting that while KADCYLA® enhances control of extracranial disease, it does not necessarily reduce CNS metastases.
In conclusion, the KATHERINE trial has established KADCYLA® as the new standard of care for patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy. Long-term follow-up confirms sustained benefits in invasive DFS and OS, with an acceptable safety profile. While KADCYLA® significantly reduces recurrence and improves survival, certain high-risk subgroups may require additional therapeutic strategies, prompting the need for ongoing research. Future advancements in HER2-targeted therapies, including Tyrosine Kinase Inhibitors, Antibody Drug Conjugates, and immunotherapy combinations, will further refine treatment strategies and improve outcomes for this high-risk patient population.
Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. Geyer CE, Untch M, Huang C-S, et al. for the KATHERINE Study Group. N Engl J Med 2025;392:249-257
