Triplet for Advanced HER2-Negative Breast Cancer

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A novel three-drug combination achieved notable responses in patients with advanced HER2-negative breast cancer, according to new research published by Roussos Torres et al in Nature Cancer. The regimen included a histone deacetylase (HDAC) inhibitor combined with two types of checkpoint inhibitors.

The multicenter phase Ib study, which aimed to improve response to checkpoint inhibitors by sensitizing the tumor microenvironment, found that the combination therapy—comprising entinostat, nivolumab, and ipilimumab—resulted in a 25% overall response rate in patients with advanced HER2-negative breast cancer. Patients with triple-negative breast cancer, who have fewer treatment options than patients with other types of breast cancer, had an overall response rate of 40% with the triplet combination.

“Our findings show that pretreatment with the HDAC inhibitor entinostat and the use of dual immune checkpoint inhibitors is a safe and promising strategy for metastatic breast cancer, warranting further clinical evaluation in a phase II study,” said lead study author Evanthia Roussos Torres, MD, PhD, Assistant Professor at the University of Southern California Keck School of Medicine, who was at the Johns Hopkins University School of Medicine and Kimmel Cancer Center when the work was conducted. “These results certainly met our hypothesis that we could improve response to checkpoint inhibition in metastatic breast cancer.” 

More Study Details

This study, sponsored by the National Cancer Institute, was conducted across four clinical sites and included 24 women with HER2-negative metastatic breast cancer. Of these women, 12 had hormone receptor–positive disease and 12 had triple-negative disease. All patients received entinostat plus two types of immunotherapy: the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab. 

The study met its primary endpoint of safety by demonstrating that there were expected and tolerable toxicities among patients, with none requiring discontinuation of therapy. The average progression-free survival was 50% at 6 months. Future studies will address the treatment’s efficacy. 

“To our knowledge, this is the first published study that investigates treatment with an HDAC inhibitor in combination with dual immune checkpoint inhibitor therapy in patients with advanced breast cancer,” said study coauthor Elizabeth Jaffee, MD, the Dana and Albert “Cubby” Broccoli Professor of Oncology and Deputy Director of the Johns Hopkins Kimmel Cancer Center. “Heavily pretreated advanced breast cancer remains an area of unmet need, and a combination strategy that results in the overall response rate and progression-free survival described is of interest.” 

“Although we did see very good responses, the question is whether we did it by changing the tumor microenvironment, but the study was not powered to answer this question,” Dr. Roussos Torres explained. “Our study highlights the need for a deeper investigation of the breast cancer tumor microenvironment with a focus on changes in myeloid (immune) cell populations to determine their role in sensitization of the tumor microenvironment to treatment with immune checkpoint inhibitors.” 

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