Trastuzumab emtansine improves long-term survival in HER2 breast cancer

(Press-News.org) In patients with high-risk HER2-positive breast cancer, post-surgery, or adjuvant, treatment with trastuzumab emtansine (T-DM1) reduced the long-term risk of death or invasive disease by 46% and improved survival compared to trastuzumab alone, according to the final results of the phase 3 KATHERINE clinical trial led by researchers from the University of Pittsburgh and UPMC Hillman Cancer Center. 

The findings, published today in the New England Journal of Medicine (NEJM), provide long-term evidence that T-DM1 is an effective adjuvant treatment for this population of breast cancer patients, supporting initial results with 3-year follow-up published in the NEJM in 2019, which found that TDM1 reduced the risk of death or invasive disease by 50%. 

“KATHERINE is a landmark clinical trial that found T-DM1 had such improved activity relative to trastuzumab that the results were reported earlier than had been anticipated when the study was originally designed. The results changed the standard of care globally for patients with HER2-positive early breast cancer,” said lead author Charles E. Geyer Jr., M.D., professor in the Division of Malignant Hematology and Medical Oncology at the Pitt School of Medicine, UPMC Hillman and UPMC Magee-Womens Hospital. “We continued to follow patients to understand the full magnitude of the benefit, and we now show that T-DM1 leads to stable long-term improvements in invasive disease-free survival and improves overall survival.” 

T-DM1 is an antibody-drug conjugate that combines trastuzumab and a chemotherapy drug called emtansine. When trastuzumab attaches to the HER2 receptor on cancer cells, it acts like a trojan horse, allowing emtansine to more effectively enter the cancer cells and kill them from within.  

The KATHERINE trial included 1,486 patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer who had residual invasive disease in the breast or axillary lymph node after pre-surgery, or neoadjuvant, treatment with taxane-based chemotherapy and the HER2-targeted agent trastuzumab and surgical removal of the tumor. These patients are at high risk of cancer recurrence and death.  

After surgery, patients were randomly assigned to receive adjuvant standard trastuzumab or T-DM1. 

At 7-years follow up, invasive disease-free survival was 80.8% with adjuvant T-DM1 and 67.1% with adjuvant trastuzumab alone. Overall survival was 89.1% with T-DM1 and 84.4% with trastuzumab alone. 

Although adverse events were higher in the T-DM1 group (26.1%) compared to patients who received trastuzumab (15.7%), the overall safety of the drug was considered acceptable.  

According to Geyer, an important finding was the consistent benefit of T-DM1 across patient subgroups. The analysis showed an approximately 50% reduction in risk of death and invasive disease regardless of the extent of disease at presentation, hormone receptor status, neoadjuvant treatment regimen, pathological node status at surgery, age and race. 

“When I started my career in oncology, we knew that some breast cancers were more aggressive, but we didn’t know why,” said Geyer. “From the excitement of identifying HER2 gene amplification and resultant protein overexpression as a targetable oncogene, through the development of drugs targeting HER2 amplification and evaluating them in landmark clinical trials, I’ve had the privilege of being part of the HER2 story, and it’s incredibly satisfying to have been part of research effort that has led to a new standard of care for patients with this disease.”   

And that story is still being written. Now, Geyer and his colleagues are investigating a promising new antibody-drug candidate called trastuzumab deruxtecan, or T-DXd, for certain groups of patients such as those with lower expression levels of the HER2 protein who didn’t respond as well to T-DM1 as patients with high HER2 expression. 

“As oncologists, we are greedy,” said Geyer. “We will never be satisfied until we reach 100% cancer-free survival outcomes for our breast cancer patients.” 

Other authors are listed in the NEJM paper. 

The KATHERINE clinical trial was funded by Hoffmann–La Roche/Genentech.

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