The antibody-drug conjugate sacituzumab govitecan leads to clinically meaningful progression-free survival (PFS) benefit over single-agent chemotherapy in patients with heavily pretreated hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), endocrine-resistant metastatic breast cancer. Patients who received sacituzumab govitecan had a 34 percent reduction in the chance of death or worsening disease, with 3 times as many patients alive and without worsening disease at 12 months compared with patients who received chemotherapy.
Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the 5-year relative survival rate is 32 percent. International guidelines recommend endocrine therapy in combination with CDK4/6 inhibitors as the first treatment for metastatic HR+/HER2- breast cancer.
"Once endocrine resistance develops, sequential single-agent chemotherapy is recommended; however, it is associated with declining response rates, disease control, quality of life, and increased toxicity. Few chemotherapy options are available for patients with metastatic HR+/HER2- breast cancer that is progressing following multiple types of therapy, and there remains a high unmet clinical need," said lead author Hope S. Rugo, MD, FASCO, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center, during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.
Rugo presented the results of the Phase III TROPiCS-02 study evaluating sacituzumab govitecan as treatment for heavily pre-treated patients with HR+/HER2- metastatic disease who have received prior endocrine therapy, CDK4/6 inhibitor, and prior chemotherapy (Abstract LBA1001). Researchers randomly assigned 113 patients from international locations who had received 2-4 prior chemotherapy regimens for advanced disease to be given either sacituzumab govitecan or standard chemotherapy (capecitabine, eribulin, vinorelbine, or gemcitabine) until the disease progressed or the toxicity of the drugs became unacceptable. The primary endpoint was PFS with a secondary endpoint of overall survival (OS).
Key Findings
Results show that sacituzumab govitecan led to improved median PFS compared to standard chemotherapy (5.5 vs. 4 months); PFS rates at 6 and 12 months were 46 percent versus 30 percent and 21 percent versus 7 percent, respectively. Sacituzumab govitecan versus standard chemotherapy showed a nonsignificant trend for improvement in OS (13.9 vs. 12.3 months) in the first of three planned OS analyses.
The overall response rate (21% vs. 14%) and clinical benefit rate (34% vs. 22%) were higher with sacituzumab govitecan versus standard therapy and median duration of response was 7.4 versus 5.6 months, respectively. The safety profile of sacituzumab govitecan in patients with HR+/HER2- advanced breast cancer was manageable and consistent with previous studies, Rugo noted. No new safety signals were identified. The most commonly reported treatment-related safety events were neutropenia and diarrhea.
In patients who received sacituzumab govitecan, there were six events leading to death (2%). Only one event (less than 1%) was assessed as related to sacituzumab govitecan treatment. No other specific pattern was identified following detailed review of all safety events leading to death (COVID, other illness).
"It is very gratifying to see the benefit of sacituzumab govitecan for these patients who have had very limited treatment options," said Rugo. "Longer follow-up is needed to determine the impact on overall survival, and additional prespecified analyses will help us understand the potential role of sacituzumab govitecan in a setting where there are currently no other targeted treatment options available."
Sacituzumab govitecan is approved for metastatic triple-negative breast cancer previously treated with two or more prior therapies (at least one in the metastatic setting). If sacituzumab govitecan is approved by the FDA to treat HR+/HER2- advanced breast cancer, it would be the first antibody-drug conjugate approved for use in this setting.
Researchers are working to expand the patient benefit of sacituzumab govitecan beyond its current indications for second-line metastatic triple-negative breast cancer and accelerated approval in second-line metastatic bladder cancer. They are pursuing studies across multiple tumor types and earlier lines of therapy.
"In patients with heavily pre-treated HR+/HER2- advanced breast cancer with disease progression following endocrine-based therapy, including CDK4/6 inhibitor therapy, and at least two prior chemotherapy regimens in the metastatic setting, sacituzumab govitecan demonstrated a statistically significant and clinically meaningful benefit in PFS compared with standard chemotherapy," Hugo noted. "At the first planned interim analysis of OS, a numeric trend for improvement with sacituzumab govitecan compared with chemotherapy was observed; results are not yet mature, and further follow-up for OS is ongoing."
She stated that, due to the significant clinical benefit and manageable safety profile, sacituzumab govitecan should be considered a potential treatment option for these patients.
ASCO Expert Jane Lowe Meisel, MD, Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, commented: "This trial shows that sacituzumab govitecan may represent an important new option for patients with endocrine-resistant HR+/HER2- metastatic breast cancer. This would address a critical unmet medical need, given the limited number of effective treatment options currently available for these patients."
Mark L. Fuerst is a contributing writer.