Single-agent chemotherapy remains the standard of care for patients with previously treated metastatic triple-negative breast cancer (TNBC). However, this approach has been associated with low response rates and short progression-free survival (PFS). Sacituzumab govitecan (Trodelvy), a Trop-2 antibody and topoisomerase inhibitor, showed promising results in a small clinical trial of patients with metastatic TNBC. These findings provided the basis for accelerated FDA approval of this agent in April 2020 for the treatment of patients with metastatic TNBC who have received ≥2 previous therapies in the metastatic setting, with full approval contingent on the results of the confirmatory phase 3 ASCENT study (Bardia A, et al. N Engl J Med. 2021;384:1529-1541). In April 2021, the FDA granted sacituzumab govitecan regular approval based on findings from this much larger study, which showed a statistically significant survival benefit with the drug compared with standard chemotherapy.
ASCENT was a global, open-label, randomized, phase 3 study of 468 patients with unresectable locally advanced or metastatic TNBC without brain metastases who had relapsed after at least 2 prior chemotherapies, one of which could be in the neoadjuvant or adjuvant setting if progression occurred within 12 months. Patients were randomized in a 1:1 ratio to sacituzumab govitecan (N = 235) 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle or single-agent chemotherapy (N = 233) of the physician’s choice (eribulin [Halaven], vinorelbine [Navelbine], gemcitabine [Gemzar], or capecitabine [Xeloda]).
The primary efficacy end point was PFS in patients without brain metastases at baseline as measured by a blinded, independent, centralized review assessed using RECIST version 1.1 criteria. Additional efficacy end points included PFS for the full population (with and without brain metastases) and overall survival.
At the time of data cutoff, the median follow-up time was 17.7 months. The median PFS was 5.6 months with sacituzumab govitecan and 1.7 months with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% confidence interval, 0.32-0.52; P <.001). Sacituzumab govitecan also prolonged median overall survival versus chemotherapy at 12.1 months versus 6.7 months, respectively (hazard ratio, 0.48; 95% confidence interval, 0.38-0.59; P <.001).
In addition, the objective response rate was higher with sacituzumab govitecan versus chemotherapy (35% vs 5%, respectively). The median duration of response was 6.3 months with sacituzumab govitecan and 3.6 months with chemotherapy.
The most common treatment-related adverse events (TRAEs) of any grade with sacituzumab govitecan and chemotherapy were neutropenia (63% and 43%, respectively), diarrhea (59% and 12%, respectively), nausea (57% and 26%, respectively), alopecia (46% and 16%, respectively), fatigue (45% and 30%, respectively), and anemia (34% and 24%, respectively). The incidences of key grade ≥3 TRAEs observed with sacituzumab govitecan and chemotherapy were neutropenia (51% and 33%, respectively), leukopenia (10% and 5%, respectively), diarrhea (10% and <1%, respectively), anemia (8% and 5%, respectively), and febrile neutropenia (6% and 2%, respectively). Three deaths attributed to adverse events were reported in each arm; no treatment-related deaths occurred with sacituzumab govitecan.
The researchers noted that multiple clinical trials of sacituzumab govitecan involving patients with breast cancer are underway, including evaluation of the agent as neoadjuvant therapy in early-stage TNBC, as adjuvant therapy in the metastatic setting in combination with immunotherapy-based regimens, or with a PARP inhibitor in advanced TNBC, and in hormone receptor–positive and HER2-negative metastatic disease.