Insights on Sacituzumab Govitecan for Triple-Negative Breast Cancer

Breast Cancer: Breast CancerTriple-negative breast cancer (TNBC) accounts for approximately 10-20 percent of all breast cancers. Patients with metastatic TNBC have a poor prognosis, with a 5-year relative survival rate of 12 percent. Although TNBC has fewer treatment options than other types of invasive breast cancer, significant research efforts are underway for these patients. In April 2021, the FDA granted full approval to sacituzumab govitecan for the treatment of patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease. Sacituzumab govitecan is an antibody-drug conjugate, which binds to cancer cells and kills them. Previously, in April 2020, the treatment had been granted accelerated approval for metastatic TNBC based on data from a Phase I/II trial of the agent (N Engl J Med 2019; doi: 10.1056/NEJMoa1814213). The multicenter, open-label, randomized Phase III ASCENT trial was the confirmatory trial of sacituzumab govitecan in pretreated TNBC compared with physician's choice chemotherapy. The study evaluated the efficacy and safety of sacituzumab govitecan in 529 patients from sites in seven countries with unresectable locally advanced or TNBC who had relapsed after at least two prior chemotherapies, one of which could be in the neoadjuvant or adjuvant setting if disease progression occurred within 12 months. Patients were randomly assigned 1:1 to receive either sacituzumab govitecan 10 mg/kg as an intravenous infusion on days 1 and 8 of a 21-day cycle (n=267) or investigator's choice of single-agent chemotherapy determined prior to random assignment (n=262; chemotherapy options consisted of eribulin [n=139], capecitabine [n=33], gemcitabine [n=38], or vinorelbine [n=52]). Treatment continued until disease progression or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) in a total of 468 patients without brain metastases who were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients) as determined by a blinded independent centralized review and RECIST v1.1 criteria. The median age was 54 years. Additional efficacy endpoints included PFS for the full population (with and without brain metastases) and overall survival (OS). As reported in The New England Journal of Medicine by Aditya Bardia, MD, and colleagues, the findings demonstrated that among all randomly assigned patients (with and without brain metastases), the median PFS was 4.8 months (95% CI, 4.1-5.8) in the sacituzumab govitecan arm versus 1.7 months (95% CI, 1.5-2.5) in the chemotherapy arm (HR=0.43; 95% CI, 0.35-0.54; P <.0001); this translated to a 57 percent reduction in the risk of disease worsening or death (2021; doi: 10.1056/NEJMoa2028485). Median OS was 11.8 months (95% CI=10.5-13.8 months) and 6.9 months (95% CI=5.9-7.6 months), respectively (HR=0.51, 95% CI=0.41-0.62, P <.0001); this translated to a 49 percent reduction in the risk of death. The safety analysis revealed that sacituzumab govitecan was found to have a toxicity profile that proved to be consistent with what was indicated on the prior approved FDA label. The incidences of key treatment-related adverse events of Grade 3 or higher were observed in 52 percent of the sacituzumab govitecan group versus 34 percent of the chemotherapy group. The most commonly reported adverse reactions (incidence >25%) in patients receiving sacituzumab govitecan were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain. Oncology Times checked in with Aditya Bardia, MD, MPH, Director of the Breast Cancer Research Program at Massachusetts General Cancer Center, Assistant Professor of Medicine at Harvard Medical School, and global principal investigator of the ASCENT study, for his clinical perspectives on sacituzumab govitecan and ongoing research efforts in TNBC. Oncology Times: What is the significance of sacituzumab govitecan for women with metastatic TNBC? Bardia: “TNBC represents an aggressive subtype of breast cancer associated with poor prognosis. For patients with pre-treated metastatic TNBC, standard chemotherapy is associated with low response rate (5-10%) and poor PFS (2-3 months). “Sacituzumab govitecan is a first-in-class, trop-directed, antibody-drug conjugate (ADC) which combines SN-38, an active metabolite of irinotecan, with an antibody against Trop-2, an antigen overexpressed in majority of TNBC. The ADC delivers SN-38 selectively to tumor cells and the tumor microenvironment at concentrations higher than with standard chemotherapy, thus optimizing the efficacy/toxicity ratio.” Oncology Times: Based on the ASCENT study results, is sacituzumab govitecan potentially a candidate to be used earlier in TNBC therapy or a good partner candidate for combination with other therapies? Bardia: “The ASCENT trial demonstrated that efficacy of sacituzumab govitecan is superior to standard chemotherapy in pretreated metastatic TNBC. Moving forward, the drug needs to be evaluated in earlier lines, including first-line therapy for metastatic TNBC. In the ASCENT trial, patients who had received prior immunotherapy also had benefit with sacituzumab govitecan, suggesting there is no cross-resistance between sacituzumab govitecan and immunotherapy, and potentially combining sacituzumab govitecan with immunotherapy would be an attractive therapeutic option for patients with PD-L1-positive metastatic TNBC.” Oncology Times: Does sacituzumab govitecan have the potential to fulfill other existing unmet needs? Are there studies being conducted to evaluate the utility of it in other types of breast cancers? Bardia: “Besides TNBC, Trop-2 is overexpressed in hormone receptor-positive (HR+) breast cancer, which could potentially be targeted with sacituzumab govitecan. In the Phase I/II basket clinical trial, clinical activity with sacituzumab govitecan was observed in patients with metastatic HR+ breast cancer (Ann Oncol 2020; https://doi.org/10.1016/j.annonc.2020.09.004). The Phase III clinical trial, TROPiCS-02, is evaluating the efficacy of sacituzumab govitecan compared to standard chemotherapy in HR+ metastatic breast cancer (Future Oncol 2020; doi: 10.2217/fon-2020-0163).” Oncology Times: What are your hopes for the next decade in the field of TNBC research? Bardia: “Given the initial success, we are likely going to see an increasing interest in developing antibody-drug conjugates targeting different antigens in breast cancer, which could lead to further improvement in clinical outcomes for patients with TNBC.” Dibash Kumar Das is a contributing writer.