Follow-up analysis of the phase III ASCENT study, which included patients with pretreated metastatic triple-negative breast cancer (TNBC) with and without baseline brain metastases, validates the clinical benefit of sacituzumab govitecan over single-agent chemotherapy of physician’s choice in progression-free survival (PFS) and overall survival (OS).
Sacituzumab govitecan efficacy was established across Trop-2 expression subgroups, confirming that Trop-2 immunohistochemistry testing is unnecessary for treatment with sacituzumab govitecan. Final results from the ASCENT study are published by Dr. Aditya Bardia of the Massachusetts General Hospital Cancer Center, Harvard Medical School in Boston, MA, US and colleagues on 29 February 2024 in the JCO.
An epithelial antigen Trop-2 is overexpressed in 80-90% of all TNBCs and associated with poor prognosis, increased tumour growth, decreased survival, representing a potential treatment target. Sacituzumab govitecan, an antibody-drug conjugate with Trop-2 antibodies coupled to a cytotoxic SN-38 payload via a proprietary hydrolysable linker, was the first antibody-drug conjugate approved in multiple countries for patients with metastatic TNBC based on the results from the international, multicentre, phase III ASCENT study.
In the latest article published in the JCO, the study team presents the results from the final preplanned efficacy and safety secondary outcomes of sacituzumab govitecan versus treatment of physician's choice in the intention-to-treat population and post hoc biomarker analyses.
Patients were randomly assigned 1:1 to receive sacituzumab govitecan or treatment of physician's choice until unacceptable toxicity/ progression. Final efficacy secondary endpoint analyses and post hoc analyses of outcomes stratified by Trop-2 expression and HER2 status are reported. Updated safety analyses are also provided.
In this final analysis, sacituzumab govitecan, given to 267 patients, improved median PFS, 4.8 versus 1.7 months (hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.33 to 0.52) and median OS, 11.8 versus 6.9 months (HR 0.51, 95% CI 0.42 to 0.63) over treatment of physician's choice given to 262 patients.
There was a significant benefit with sacituzumab govitecan for patients in the two highest Trop-2–expressing quartiles in PFS, OS, and objective response rate. In the lowest two quartiles of Trop-2 expression, there were favourable HR point estimates for sacituzumab govitecan. These post hoc analyses were exploratory in nature and not powered to evaluate the impact of Trop-2 expression on the benefit of sacituzumab govitecan versus treatment of physician's choice.
The authors wrote that efficacy of sacituzumab govitecan in low–Trop-2-level tumours may be due to sacituzumab govitecan bystander effect, high binding affinity, and high drug-antibody ratio, leading to effective antitumour activity even with low antigen expression. Thus, Trop-2 testing is not required for treatment with sacituzumab govitecan.
Overall, sacituzumab govitecan had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.
The authors commented that limitations include the exploratory nature of the subgroup analyses, the relatively small number of patients in each subgroup, the use of archival tissue, and the lack of a prespecified analysis.
They concluded that their data reinforce sacituzumab govitecan as a standard-of-care treatment option in patients with pretreated metastatic TNBC.
The findings were previously presented at the ASCO 2022 Annual Meeting.
The study was sponsored by Gilead Sciences, Inc.
Reference
Bardia A, Rugo HS, Tolaney SM, et al. Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression. JCO; Published online 29 February 2024. DOI: https://doi.org/10.1200/JCO.23.01409