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Antibody-drug conjugate shows promise against metastatic triple-negative breast cancer

February 20, 2019

Treatment with the experimental drug sacituzumab govitecan produced a significant treatment response in patients with difficult-to-treat metastatic triple-negative breast cancer. Results from the clinical trial, published in the New England Journal of Medicine, reflect significantly better outcomes than expected from treatment with standard chemotherapy for triple-negative breast cancer.

"Patients with metastatic triple-negative breast cancer have an aggressive tumor biology, but effective treatment options are limited," says Aditya Bardia, MD, a physician at the Massachusetts General Hospital (MGH) Cancer Center and lead investigator of the trial conducted at multiple centers in the U.S. "Standard chemotherapy has been associated with low treatment response rates and considerable toxicity, highlighting the need for better therapies."

Triple-negative breast cancers lack the growth-stimulating target molecules - HER2, estrogen receptors or progesterone receptors - that drive other breast tumors. This means that hormonal treatment or drugs that target HER2 are not effective. Accounting for around 15 percent of invasive breast tumors and more common in younger patients and in African American women, triple-negative breast cancers are more aggressive and have a poor prognosis. Standard chemotherapy produces a treatment result - shrinking or slowing the growth of a tumor - in 10 to 15 percent of patients, and the response lasts only around two to three months. The average survival for metastatic triple-negative breast cancer is around 12 months and has not changed for around 20 years.

Being developed by the pharmaceutical company Immunomedics, Inc., which sponsored the current trial, sacituzumab govitecan is an antibody-drug conjugate that combines the antibody to the Trop-2 antigen, expressed on most breast cancer cells, with SN-38, the active metabolite of the chemotherapy drug irinotecan. After the antibody binds to Trop-2 molecules, the drug is taken into cancer cells, releasing SN-38 both within cells and into the tumor microenvironment. This allows delivery of the drug to nearby tumor cells that do not express Trop-2 and reduces the toxic effects that result from systemwide drug delivery. The drug was granted a "breakthrough therapy" designation by the U.S. Food and Drug Administration in 2016.

The MGH-led study - part of a larger, open-label clinical trial of sacituzumab govitecan against several types of advanced cancer - enrolled 108 patients with triple-negative breast cancers, all of whom had received several prior treatments, between June 2013 and February 2017. Treatment with sacituzumab govitecan produced a treatment response in 33 percent of patients, and responses lasted an average of 7.7 months.

Responses were seen in patients previously treated with chemotherapy or immunotherapy. Side-effects such as nausea, diarrhea and neutropenia - a drop in white blood cells - were manageable, and the more serious toxicities seen with standard chemotherapy were not observed. Patients continued to take the drug as long as they benefited from treatment, with eight still doing so as of December 2017. The average treatment duration of more than 5 months was longer than the average 2.5 months of patients' prior treatments.

"Our results suggest that sacituzumab govitecan is an active agent against metastatic triple-negative breast cancer that is not cross resistant with other treatments and has a manageable safety profile, thus representing a potential novel therapeutic paradigm," says Bardia, director of Precision Medicine at the MGH Cancer Center's Center for Breast Cancer and assistant professor of Medicine at Harvard Medical School. A randomized, phase 3 clinical trial (ASCENT) of sacituzumab govitecan for treatment-resistant metastatic triple-negative breast cancer, is currently recruiting in the U.S. and Europe.
The co-authors of the NEJM paper are Steven Isakoff, MD, PhD, MGH Cancer Center: Sara Tolaney, MD, M.P.H.; Dana-Farber Cancer Institute; Ingrid Mayer, MD, and Vandana Abramson, MD, Vanderbilt-Ingram Cancer Center, Nashville; Linda Vahdat, MD, MBA, Weill Cornell Medical College; Kevin Kalinsky, MD, Irving Medical Center, New York-Presbyterian-Columbia University; Jennifer Diamond, MD, University of Colorado Cancer Center; Joyce O'Shaughnessy, MD, Baylor University Medical Center; Rebecca Moroose, MD, and Nikita Shah, MD, Orlando Health University of Florida Health Cancer Center; Alessandro Santin, MD, Yale University School of Medicine; Hope Rugo, MD, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; David Goldenberg, ScD, MD, Robert Iannone, MD, Sarah Washkowitz, JD, Robert Sharkey, PhD, and William Wegener, MD, PhD, Immunomedics, Morris Plains, NJ; and Ala Sweidan, MBA, MS, AIS Consulting, Ann Arbor, Mich.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

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