T-DM1 reduces the long-term risk of death in patients with HER2-positive breast cancer

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

The findings, published today in (), provide long-term evidence that T-DM1 is an effective adjuvant treatment in this breast cancer population, confirming preliminary results from a 3-year follow-up published in 2019 that found TDM1 reduced risk of death or invasive disease by 50%.

KATHERINE is a landmark clinical trial that found T-DM1 to have such superior activity compared to trastuzumab that the results were announced earlier than anticipated at the initial design stage of the trial. The results changed the standard of care for HER2-positive patients around the world early breast cancer. We continued to follow patients to understand the full extent 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.”

Charles E. Geyer Jr., MD, lead author, professor in the Division of Malignant Hematology and Medical Oncology at Pitt School of Medicine, UPMC Hillman and UPMC Magee-Womens Hospital

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

The KATHERINE study enrolled 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 preoperative or neoadjuvant treatment, taxane-based chemotherapy and HER2-targeted trastuzumab, and after surgical removal of the tumor. These patients are at high risk of cancer recurrence and death.

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

After 7 years of 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 there were more adverse events in the T-DM1 group (26.1%) compared to patients receiving trastuzumab (15.7%), the overall safety of the drug was considered acceptable.

According to Geyer, an important finding was the consistent benefits of T-DM1 across all patient subgroups. The analysis showed an approximately 50% reduction in the risk of death and invasive diseases, regardless of the extent of the disease at the time of presentation, hormone receptor status, neoadjuvant treatment regimen, pathological nodal status at the time of 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,” Geyer said. “From the excitement of identifying gene amplification and the resulting protein overexpression as a target oncogene, through the development of amplification-targeted drugs and their evaluation in groundbreaking clinical trials, I have been privileged to be part of the HER2 story, and it is extremely rewarding to be part of the research efforts that have led to to a new standard of care for patients with this disease.”

And this story is still being written. Currently, 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 levels of HER2 protein expression, who did not respond well to T-DM1 as patients with high HER2 expression.

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

Other authors are mentioned in the article.

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