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Adjuvant T-DM1 in HER2-positive Early Breast Cancer With Residual Invasive Disease After Completion of Neoadjuvant Therapy

The results from the KATHERINE study
06 Dec 2018
Breast cancer;  Anticancer agents & Biologic therapy

The KATHERINE investigators reported at San Antonio Breast Cancer Symposium and published on 5 December 2018 in The New England Journal of Medicine that adjuvant trastuzumab emtansine (T-DM1) is superior to trastuzumab with respect to invasive disease-free survival in the setting of residual disease after induction treatment for HER2-positive early breast cancer. 

The study team wrote in the background that patients with residual invasive breast cancer after receiving neoadjuvant chemotherapy in addition to HER2–targeted therapy have a worse prognosis than those who have no residual cancer. 

In two phase III trials that involved patients with HER2-positive advanced breast cancer who previously received HER2-targeted therapy including trastuzumab and chemotherapy, T-DM1 showed superior efficacy and a favourable risk–benefit profile as compared with capecitabine plus lapatinib or treatment of the physician’s choice. T-DM1 is approved for use in patients with HER2-positive metastatic breast cancer who previously received treatment with trastuzumab and a taxane. 

Given the activity of T-DM1, breast cancer researchers thought that it may provide a benefit for patients in whom residual invasive cancer is detected in the resected breast specimen or axillary nodes at surgery after completion of trastuzumab-based neoadjuvant treatment. A phase II trial showed that administration of 17 cycles of T-DM1 after an anthracycline regimen was feasible and was not associated with unacceptable toxic effects in patients with HER2-positive early breast cancer. 

It prompted the KATHERINE investigators to conduct a phase III (NCT01772472), open-label study among patients with HER2-positive early breast cancer with residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy. The neoadjuvant treatment consisted a taxane with or without anthracycline and trastuzumab. The patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. 

The primary endpoint was invasive disease–free survival defined as freedom from ipsilateral invasive breast tumour recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause.

The study randomly assigned 1486 patients; 743 in the T-DM1 group and 743 in the trastuzumab group. 

At the interim 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%). 

The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. 

Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; p < 0.001). 

Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. 

The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone. 

KATHERINE is the third global, phase III trial to show greater improvement in outcomes with additional HER2-targeted therapy than with 1 year of trastuzumab alone in patients with HER2-positive, early breast cancer. The ExteNET trial evaluated 1 year of extended adjuvant therapy with neratinib monotherapy as compared with placebo after completion of 1 year of trastuzumab. In the APHINITY trial, patients were randomly assigned to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab for resected, operable, HER2-positive breast cancer. 

The KATHERINE trial focused on higher-risk patients with residual invasive breast cancer after completion of neoadjuvant chemotherapy administered with trastuzumab-containing therapy. Differences in trial designs and patient populations limit the usefulness of comparisons among these studies. The patients in the KATHERINE trial had a substantially worse baseline prognosis than those enrolled in the ExteNET and APHINITY trials. 

The KATHERINE investigators concluded that 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. 

The study was funded by F. Hoffmann–La Roche/Genentech. 


von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. NEJM; Published online 5 December, 2018. DOI: 10.1056/NEJMoa1814017.

Last update: 06 Dec 2018

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