As reported in The New England Journal of Medicine by Aditya Bardia, MD, of the Division of Medical Oncology, Massachusetts General Hospital Cancer Center, and colleagues, the phase III ASCENT trial has shown prolonged progression-free and overall survival with the Trop-2–directed antibody-drug conjugate sacituzumab govitecan-hziy vs single-agent chemotherapy in patients with relapsed or refractory metastatic triple-negative breast cancer without brain metastases (primary trial population).1 Sacituzumab govitecan also significantly improved progression-free and overall survival in the population of all randomly assigned patients (full population), including those with baseline brain metastases.
Aditya Bardia, MD
The trial supported the April 2021 regular approval of sacituzumab govitecan for treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one of them for metastatic disease. Efficacy results in product labeling are from the full population of all randomly assigned patients.
In the open-label trial, 529 patients from sites in seven countries who had received two or more previous standard chemotherapy regimens for unresectable locally advanced or metastatic disease and a taxane for any indication were randomly assigned to receive sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle (n = 267) or the investigator’s choice of single-agent chemotherapy determined prior to randomization (n = 262). Enrollment had a 15% cap on patients with baseline brain metastases.
Chemotherapy options consisted of eribulin, vinorelbine, capecitabine, and gemcitabine: eribulin was given at 1.4 mg/m2 (North America) or 1.23 mg/m2 (Europe) on days 1 and 8 of a 21-day cycle; vinorelbine at 25 mg/m2 on day 1 weekly; capecitabine at 1,000 to 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day cycle; and gemcitabine at 800 to 1,200 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Treatment continued until disease progression or unacceptable toxicity.
A total of 61 patients had brain metastases at baseline (32 in the sacituzumab govitecan group and 29 in the chemotherapy group). The primary trial population consisted of the remaining 468 patients with no evidence of brain metastases, including 235 in the sacituzumab govitecan group vs 233 in the chemotherapy group. In the chemotherapy group, 54% received eribulin, 20% received vinorelbine, 13% received capecitabine, and 12% received gemcitabine. The primary endpoint was progression-free survival on blinded independent central review among patients without brain metastases.
A total of 32 patients assigned to receive chemotherapy in the primary trial population received no trial drug (26 patients) or withdrew consent (6 patients) before treatment; these patients are included in the efficacy analysis but not in the safety analyses.
Progression-Free and Overall Survival
Median follow-up was 17.7 months (range = 5.8–28.1 months). In the primary trial population, median progression-free survival was 5.6 months (95% confidence interval [CI] = 4.3–6.3 months) in the sacituzumab govitecan group vs 1.7 months (95% CI = 1.5–2.6 months) in the chemotherapy group (hazard ratio [HR] = 0.41, 95% CI = 0.32–0.52, P < .001). Median overall survival was 12.1 months (95% CI = 10.7–14.0 months) in the sacituzumab govitecan group vs 6.7 months (95% CI = 5.8–7.7 months) in the chemotherapy group (HR = 0.48, 95% CI = 0.38–0.59, P < .001).
An objective response was observed in 35% vs 5% of patients, with a complete response in 4% vs 1%. Median duration of response was 6.3 months vs 3.6 months (HR = 0.39, 95% CI = 0.14–1.07). An additional 10% vs 4% of patients had stable disease for at least 6 months, yielding clinical benefit rates of 45% vs 9%.
In the total randomly assigned population of 529 patients (including the 61 patients with baseline brain metastases), median progression-free survival was 4.8 months (95% CI = 4.1–5.8 months) in the sacituzumab govitecan group vs 1.7 months (95% CI = 1.5–2.5 months) in the chemotherapy group (HR = 0.43, 95% CI = 0.35–0.54, P < .001). Median overall survival was 11.8 months (95% CI = 10.5–13.8 months) in the sacituzumab govitecan group vs 6.9 months (95% CI = 5.9–7.7 months) in the chemotherapy group (HR = 0.51, 95% CI = 0.41–0.62).
An objective response was observed in 31% vs 4% of patients, with a complete response in 4% vs 1%. Median time to response was 1.5 vs 1.5 months. Median duration of response was 6.3 months vs 3.6 months. An additional 19% vs 4% of patients had stable disease for at least 6 months, yielding clinical benefit rates of 40% vs 8%.
The safety population consisted of 258 patients in the sacituzumab govitecan group and 224 in the chemotherapy group who received at least one dose of the study drug. Treatment-related grade 3 to 4 adverse events were observed in 64% of the sacituzumab govitecan group vs 47% of the chemotherapy group, with the most common in the sacituzumab group being neutropenia (51% vs 33% with chemotherapy), leukopenia (10% vs 5%), diarrhea (10% vs < 1%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). Concomitant growth factor support was received by 49% vs 23% of patients.
In the sacituzumab govitecan group, treatment-related rash of any grade occurred in 9% of patients (grade 3 in one patient), and ocular adverse events occurred in 5% (none grade > 1). No neuropathy of grade > 2 was observed. No grade 1 or 2 interstitial lung disease was reported, with grade 3 pneumonitis being observed in one patient.Serious treatment-related adverse events occurred in 15% vs 8% of patients. Adverse events led to permanent treatment discontinuation in 5% of both treatment groups.
The investigators concluded: “Both progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan.”
DISCLOSURE: The study was funded by Immunomedics (Gilead). Dr. Bardia has served as a consultant or advisor to bioTheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech, Immunomedics, Merck, Novartis, Pfizer, Philips, Puma Biotechnology, Radius Pharma, Sanofi, and Spectrum Pharmaceuticals; has served as an institutional consultant or advisor to Genentech/Roche, Immunomedics, Innocrin Pharma, Novartis, Pfizer, and Radius Health; and has received institutional research funding from AstraZeneca, Daiichi Sankyo, Genentech, Immunomedics, Merck, Novartis, Pfizer, Radius, and Sanofi.
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