A shift in the way advanced triple-negative breast cancer is treated may be on the horizon with mounting evidence that moving sacituzumab govitecan, an antibody-drug conjugate (ADC), to the first line of treatment confers long-term benefit compared to standard therapy, including continued benefit even after subsequent therapy. The evidence comes from two clinical trials, ASCENT-04, led by Sara Tolaney, MD, MPH, chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, as well as the ASCENT-03 study where Tolaney served as the senior author, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago on June 2 in Chicago.
These findings strengthen the case for approval of sacituzumab govitecan as first-line treatment of patients with advanced triple-negative breast cancer who are not eligible for immunotherapy, which was evaluated in ASCENT-03, and of sacituzumab govitecan plus pembrolizumab as first-line treatment of patients whose tumors are positive for the immune checkpoint PD-L1, evaluated in ASCENT-04.
"We're very excited about these results because this is a challenging disease to treat," says Tolaney. "Changing a patient's first line treatment to something much more effective is very meaningful. A change in this setting, if approved, would hopefully shift the needle for patients with advanced triple negative breast cancer and help them to live longer and better."
Triple-negative breast cancer is an aggressive and difficult to treat form of breast cancer that accounts for about 15 percent of all breast cancer cases. The five-year survival rate for patients with metastatic triple-negative breast cancer is just 12 percent.
Sacituzumab govitecan is an antibody-drug conjugate designed to direct a potent chemotherapy drug into cancer cells by targeting a protein called TROP-2 that is found on triple-negative breast cancer cells. It is currently approved as second line or later therapy for advanced triple-negative breast cancer, though approximately half of the patients who receive the current standard first-line treatment for disease do not go on to receive a second line of therapy.
The global, open-label ASCENT-03 study enrolled 558 patients who were randomized to receive either sacituzumab govitecan or chemotherapy as a first-line treatment. Eligible patients had locally advanced or unresectable triple-negative breast cancer and were not candidates for immune checkpoint inhibitors. Earlier this year, Tolaney published results from the study showing that first-line sacituzumab govitecan led to prolonged progression free survival.
The global, open-label ASCENT-04 study enrolled 443 patients who were randomized to receive either sacituzumab govitecan plus pembrolizumab, an immune checkpoint inhibitor, or chemotherapy plus pembrolizumab. Eligible patients had locally advanced or unresectable triple-negative breast cancer that tested positive for the immune checkpoint PD-L1. Earlier this year, Tolaney published results from the study showing that first-line sacituzumab govitecan plus pembrolizumab led prolonged progression free survival.
In the abstracts presented at ASCO today, overall survival was immature. To assess long term clinical benefit of the study therapies, the team evaluated progression free survival after a subsequent line of treatment, a measure called PFS2.
PFS2 helps investigators learn more about whether getting the ADC in the first line is better than getting it later, as second line therapy. This question is particularly relevant in these two studies where most patients crossed over to receive the study therapy after progression on the control therapy. In ASCENT-03, 79 percent of patients who received first line chemotherapy crossed over to receive sacituzumab govetecan, and in ASCENT-04, 77 percent crossed over.
"Getting sacituzumab govitecan in the first line setting was associated with much longer PFS2, despite the very high crossover rate in both studies," says Tolaney. "This data is informative and suggests that first-line sacituzumab govitecan may have impact on longer term outcomes for patients."
In the ASCENT-03 study, at the time of data cut off, 27 percent of patients remained on sacituzumab govitecan, and 14 percent on chemotherapy. Among patients who received the ADC as first-line treatment and progressed, the median time to the first subsequent therapy was 18.2 months, compared to 14 months for those who received chemotherapy first. Treatment with first-line sacituzumab govitecan reduced the risk of a second progression by 30 percent.
In the ASCENT-04 study, at a median of 14 months of follow up, 43 percent of patients remained on sacituzumab govitecan plus pembrolizumab, and 23 percent remained on chemotherapy. Among patients who received the ADC combination as first-line treatment and progressed, the median time to the first subsequent therapy was 17.3 months, compared to 9.8 months for those who received chemotherapy first. Treatment with first-line sacituzumab govitecan plus pembrolizumab reduced the risk of a second progression by 33 percent.
Tolaney also presented results of a subgroup analysis of the ASCENT-04 study based on biomarkers including Trop-2 expression, tumor BRCA mutation status, and HER2 expression. Patients were grouped into categories including four Trop-2 expression level categories, BRCA wild-type or mutant, and HER2 zero or low. Across all subgroups, patients who received sacituzumab govitecan plus pembrolizumab as first-line therapy had longer progression free-survival compared to chemotherapy plus pembrolizumab. Similar findings were presented by a study collaborator for ASCENT-03.
"These data are reassuring and suggest that there isn't a biomarker that you need to look at to choose which patient should get sacituzumab govitecan," says Tolaney. "The ADC always did better than chemotherapy."
Funding: Gilead Sciences, Inc.
