Long-Term KATHERINE Trial Analysis Shows Kadcyla Significantly Improves Survival in HER2-Positive Early Breast Cancer

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An updated prespecified final analysis of the Phase III KATHERINE trial (NCT01772472) found that adjuvant treatment with Kadcyla (trastuzumab emtansine; T-DM1) produced improved overall survival (OS) along with a sustained improvement in long-term invasive disease–free survival (IDFS) compared to trastuzumab monotherapy in patients with HER2-positive early breast cancer with residual invasive disease.^1,2 The trial data, published by The New England Journal of Medicine, show that T-DM1 achieved sustained benefits across most patient subgroups with an acceptable safety profile.

“Patients with human epidermal growth factor receptor 2 (HER2)–positive early breast cancer treated with neoadjuvant chemotherapy plus HER2-targeted therapy have residual invasive disease at surgery in 45 to 66% of cases depending on estrogen-receptor status, with an increased risk of recurrence and death,” the study authors wrote.¹

T-DM1 is an antibody–drug conjugate that is comprised of a stable linker that connects a cytotoxic drug to trastuzumab, an anti-HER2 antibody. Prior trials of the drug showed its promise in the front-line treatment of metastatic breast cancer with improved safety compared to standard chemotherapy with trastuzumab.³

“T-DM1 represents a major shift in the treatment of patients with breast cancer as it replaces traditional nontargeted chemotherapy with a ‘smart’ medication that directs the cytotoxic therapy to cancer cells by using a known biomarker,” wrote the authors of a study published by Future Oncology.³

Trial Design

The randomized, multicenter, open-label KATHERINE trial compared the efficacy and safety of T-DM1 to trastuzumab monotherapy in the adjuvant treatment of patients with HER2-positive breast cancer with the presence of residual tumor in the breast or axillary lymph nodes after preoperative therapy. Eligibility requirements included presentation of HER2-positive early breast cancer treated with a minimum of six cycles of neoadjuvant chemotherapy with at least nine weeks of taxane-based therapy plus at least nine weeks of trastuzumab, and residual invasive cancer in the breast or resected axillary nodes at surgery.

Patients were randomly assigned in a 1:1 ratio using a permuted-block randomization scheme to either T-DM1 administered at a dose of 3.6 mg per kilogram of body weight intravenously (IV) every three weeks or IV trastuzumab monotherapy at a dose 6 mg per kilogram every three weeks for 14 cycles. Randomization was arranged as per clinical stage at presentation, specifically inoperable (tumor stage T4 or nodal stage N2 or N3) vs. operable (tumor stage T1 to T3 and nodal stage N0 or N1); hormone-receptor status based on either estrogen receptor–positive or progesterone receptor–positive vs. both receptors negative or unknown; preoperative HER2-directed therapy based on trastuzumab monotherapy vs. trastuzumab combined with another HER2-directed agent; and pathological nodal status following neoadjuvant therapy based on node-positive vs. node-negative or not evaluated.

Trial Results

Across a median follow-up of 8.4 years, T-DM1 demonstrated a sustained improvement in invasive IDFS (unstratified hazard ratio for invasive disease or death, 0.54; 95% confidence interval [CI], 0.44 to 0.66), showing a seven-year IDFS of 80.8% compared to 67.1% with trastuzumab monotherapy. Additionally, T-DM1 had a seven-year OS rate of 89.1% compared to 84.4% with trastuzumab monotherapy (unstratified hazard ratio, 0.66; 95% CI, 0.51 to 0.87; P=0.003). In terms of safety, grade 3 or higher adverse events were reported by 26.1% of the patients administered T-DM1 compared to 15.7% of patients administered trastuzumab monotherapy.

“The primary analysis of the KATHERINE trial showed that T-DM1, as compared with trastuzumab, improved invasive disease–free survival after neoadjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease,” the study authors concluded. “This prespecified long-term follow-up analysis provides additional support for the neoadjuvant therapy paradigm by showing that adjuvant T-DM1 also provided a significant improvement in overall survival and no evidence of long-term safety issues.”¹

References

1. Geyer, Jr., C., et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med 2025;392:249-257. Vol. 392 No. 3.

2. A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE). ClinicalTrials.gov. Updated January 7, 2025. https://clinicaltrials.gov/study/NCT01772472

3. Peddi PF, Hurvitz SA. Trastuzumab emtansine: the first targeted chemotherapy for treatment of breast cancer. Future Oncol. 2013 Mar;9(3):319-26. doi: 10.2217/fon.13.7. PMID: 23469968; PMCID: PMC3860880.