How Antibody-Drug Conjugates Have Impacted HER2-Positive Breast Cancer Treatment

Antibody-drug conjugates, or ADCs, have had a tremendous impact on the treatment of some types of breast cancer, according to Dr. Charles E. Geyer.

Geyer is a professor of medicine at the University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center and UPMC Magee-Womens Hospital, in Pittsburgh, as well as the chief scientific officer at the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation. He is among the authors of a study published in The New England Journal of Medicine detailing the latest findings from the phase 3 KATHERINE trial.

Geyer and his colleagues found that among patients with HER2-positive early breast cancer, at a median follow-up of 8.4 years Kadcyla (ado-trastuzumab emtansine) showed sustained improvement in invasive disease-free survival compared with Herceptin, with seven-year invasive disease-free survival rates of 80.8% and 67.1%, respectively. Additionally, seven-year overall survival rates were 89.1% and 84.4% between the two approaches.

Antibody-drug conjugates, as defined by the National Cancer Institute, are comprised of a monoclonal antibody chemically linked to a drug. The antibody binds to a specific protein on a cancer cell, and the linked drug enters the cell and kills it without harming other cells.

CURE sat down with Geyer to discuss the path that led to Kadcyla making history as the first antibody-drug conjugate approved for the treatment of a solid tumor in 2013, when it received approval from the U.S. Food and Drug Administration (FDA) for patients with metastatic, HER2-positive breast cancer who had previously been treated with Herceptin or taxanes.

Transcript:

One of the early recognitions, when HER2 gene amplification was identified as an underlying driver of this subset of aggressive, fast-growing, and relatively chemo-resistant cancers, was that this amplification places a significant load of HER2-positive proteins on the surface of cancer cells. That protein is what drives the cancer's aggressive behavior. So, it was ideal that we could develop HER2-directed antibodies to bind to those proteins, interfere with their function, internalize them, activate the immune system, and ultimately improve therapy. And we did. 

In the early studies, back when we performed surgery first in nearly all patients and then administered adjuvant therapy, we saw striking results when [Herceptin] was added to chemotherapy. Patients did significantly better with [Herceptin]. At one of the ASCO annual research meetings, there was a spontaneous standing ovation when the results were presented—everyone was excited about the dramatic improvement. The introduction of a monoclonal antibody into treatment was a game-changer. Theoretically, an antibody that binds very specifically to a target protein can act as a Trojan horse when loaded with chemotherapy. When these antibodies bind to receptors, they get internalized. 

The first antibody-drug conjugate in this space was [Kadcyla], which quickly became the standard of care in third-line and second-line metastatic HER2-positive breast cancer. However, it did not outperform standard chemotherapy combined with antibodies delivered separately in the first-line setting. Still, when we applied it in the KATHERINE trial, the results were dramatic. 

Transcript has been edited for clarity and conciseness.

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