Sacituzumab govitecan, a first-in-class, Trop-2–directed antibody–drug conjugate, showed in the ASCENT study a significant benefit among patients with relapsed or refractory metastatic triple negative breast cancer (TNBC) in terms of progression-free survival (PFS) and overall survival (OS) as compared with standard of care chemotherapy. Side effects, in particular myelosuppression and diarrhoea, were more frequent with sacituzumab govitecan than with chemotherapy. Dr. Aditya Bardia of the Massachusetts General Hospital Cancer Center in Boston, MA, US and the ASCENT investigators published the primary study results on 22 April 2021 in The New England Journal of Medicine.
The authors wrote in the background that patients with metastatic TNBC have poor survival outcomes. Although immunotherapy has shown promising first-line clinical activity, single-agent chemotherapy remains standard for previously treated (beyond first-line) patients with metastatic TNBC. However, chemotherapy is associated with low response rates and short PFS.
Sacituzumab govitecan is an antibody–drug conjugate composed of antibody targeting Trop-2, coupled to SN-38, the active metabolite of irinotecan and a topoisomerase I inhibitor, through a proprietary hydrolyzable linker. After administration, the anti–Trop-2 monoclonal antibody binds to Trop-2 expressed on the tumour-cell surface and allows for targeted delivery of SN-38 to tumour cells.
The IMMU-132-01, a phase I/II single group, basket study evaluated sacituzumab govitecan as monotherapy in metastatic, epithelial cancers. In the cohort of 108 patients with metastatic TNBC, an objective response rate of 33%, a median PFS of 5.5 months, and a median OS of 13.0 months was observed with sacituzumab govitecan. These results provided the basis for accelerated approval by the US Food and Drug Administration (FDA) in April 2020, with full approval contingent on the results of the confirmatory phase III study.
The confirmatory phase III ASCENT is a global, open-label, randomised study that evaluated the efficacy and safety of sacituzumab govitecan as compared with chemotherapy of the physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic TNBC. The primary endpoint was PFS as determined by blinded independent central review among patients without brain metastases.
In total, 468 patients without brain metastases were included and randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients were previously treated with taxanes.
The median PFS was 5.6 months (95% confidence interval [CI] 4.3 to 6.3) with sacituzumab govitecan and 1.7 months (95% CI 1.5 to 2.6) with chemotherapy (hazard ratio [HR] for disease progression or death 0.41; 95% CI 0.32 to 0.52; p < 0.001).
The median OS was 12.1 months (95% CI 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI 5.8 to 7.7) with chemotherapy (HR for death 0.48; 95% CI 0.38 to 0.59; p < 0.001).
The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy.
The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhoea (10% and <1%), anaemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.
Based on results from the ASCENT study, the FDA granted regular approval on 7 April 2021 to sacituzumab govitecan for 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.
Multiple studies of sacituzumab govitecan in patients with breast cancer are ongoing, including evaluation in neoadjuvant treatment of early TNBC (NeoSTAR), adjuvant treatment (GBG102-SASCIA), in the metastatic context in combination with immunotherapy-based regimens (Morpheus-TNBC and Saci-IO TNBC) or with a PARP inhibitor (NCT04039230) in advanced TNBC, and in hormone receptor positive and HER2-negative metastatic breast cancer (TROPiCS-02).
The ASCENT study was supported by Immunomedics, a subsidiary of Gilead Sciences.
Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med 2021; 384:1529-1541. DOI: 10.1056/NEJMoa2028485.