Abstract
Results from a phase I/II trial suggest that an antibody–drug conjugate, sacituzumab govitecan, is active against refractory, metastatic triple-negative breast cancer. A phase III trial is under way to compare its safety and efficacy with that of standard chemotherapy.
Historically, patients with refractory, metastatic triple-negative breast cancer have lacked effective treatments: Only 10% to 15% respond to standard chemotherapy, with median progression-free survival (PFS) of 2 to 3 months. Recently, however, a phase I/II trial showed that the antibody–drug conjugate (ADC) sacituzumab govitecan (IMMU-132; Immunomedics) is active in this group of patients (N Engl J Med 2019;380:741–51).
“The need for better treatment options for patients with metastatic breast cancer and the unique structure of sacituzumab govitecan, which is quite different from that of traditional ADCs, is what prompted us to participate in this clinical trial,” says Aditya Bardia, MD, MPH, of Massachusetts General Hospital in Boston, lead author of the paper outlining the results.
Sacituzumab govitecan consists of a monoclonal antibody against human trophoblast cell-surface antigen 2, highly expressed by most triple-negative breast cancer cells, conjugated to SN-38, a topoisomerase I inhibitor. Because SN-38 is only moderately toxic, it can be delivered to cells in greater concentrations than the more toxic drugs carried by existing ADCs. Thus, sacituzumab govitecan has been designed with a relatively high drug-to-antibody ratio of roughly 8 to 1; most ADCs have ratios of less than 4 to 1. Investigators hoped that each sacituzumab govitecan molecule's ability to deliver large amounts of SN-38 would kill tumor cells efficiently without causing considerable side effects.
Researchers tested the agent in 108 patients with metastatic triple-negative breast cancer who had received at least two prior therapies. Patients received the ADC until their disease progressed or they experienced unacceptable side effects. The observed response rate was 33%, with a median PFS of 5.5 months and median overall survival of 13 months. Although patient subgroups were too small to draw firm conclusions, response rates appeared similar regardless of patient age, number of previous therapies, presence or absence of visceral metastases, or prior treatment with checkpoint inhibitors. The latter finding “suggests a lack of cross-resistance with immunotherapy,” says Bardia. “Thus, in the future, combination therapy with sacituzumab govitecan and checkpoint inhibitors could be considered.”
Although 32% of patients experienced serious adverse events, “only 3% of patients came off therapy for toxicity reasons, which is a good sign,” says Lisa Carey, MD, of the University of North Carolina at Chapel Hill, who was not involved in the trial.
Bardia also notes that no serious cases of peripheral neuropathy emerged. This side effect often occurs in patients receiving taxane chemotherapy, so sacituzumab govitecan may someday offer an alternative treatment option.
One limitation of the trial, Carey points out, was its lack of randomization. However, she notes that prior to receiving sacituzumab govitecan, participants received only 2.5 months of standard chemotherapy, which is typical. This suggests that the trial results are unlikely to reflect the selection of participants with unusual characteristics.
Investigators have launched the phase III ASCENT trial to directly compare sacituzumab govitecan with physician's choice of four types of single-agent chemotherapy in patients with refractory, metastatic triple-negative breast cancer. Additional trials are assessing the safety and efficacy of the ADC in several other cancers, including lung and urothelial cancers. –Kristin Harper
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