Sacituzumab govitecan plus pembrolizumab improves survival in advanced triple-negative breast cancer

1. Among patients with previously untreated programmed death-ligand 1 positive, triple-negative breast cancer, first-line sacituzumab govitecan plus pembrolizumab significantly prolonged progression-free survival compared to chemotherapy plus pembrolizumab.

2. The sacituzumab combination was also associated with longer response duration and fewer treatment discontinuations due to adverse events, despite similar rates of high-grade toxicities.

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer associated with poor survival. Over one-third of these tumors express programmed death-ligand 1 (PD-L1), for which immune checkpoint inhibition has become a first-line treatment strategy. While pembrolizumab plus chemotherapy has extended survival in this population, the overall prognosis remains guarded and further improvement is needed, especially since many patients do not proceed to second-line therapy. Sacituzumab govitecan (Trodelvy) is a trophoblast cell-surface antigen 2 (Trop-2)–directed antibody–drug conjugate which has been shown to produce significant survival benefit as a third-line treatment in metastatic triple-negative breast cancer. This randomized controlled trial evaluated whether combining sacituzumab govitecan with pembrolizumab in advanced PD-L1–positive TNBC offers superior outcomes to the current standard of chemotherapy plus pembrolizumab. It was found that patients who received the sacituzumab combination had significantly longer progression-free survival, which was consistent across predefined subgroups based on age, disease status, and region. The percentage of patients with an objective response was also numerically higher in the experimental arm, although this difference did not meet the threshold for statistical significance. The frequency and severity of adverse events were similar between the two groups, but the sacituzumab group had a notably lower likelihood of treatment discontinuation. Limitations of this study included the open-label design, immature overall survival data, and the impact of treatment crossover. Additionally, few patients had prior exposure to checkpoint inhibitors in earlier-stage disease, potentially limiting generalizability as neoadjuvant immunotherapy use continues to grow. Nonetheless, these results suggested that sacituzumab govitecan may have utility as a backbone treatment option in advanced PD-L1–positive, triple-negative breast cancer.

Click to read the study in NEJM

Relevant Reading: Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer

In-Depth [randomized controlled trial]: This phase 3, open-label, randomized controlled trial (ASCENT-04/KEYNOTE-D19) compared sacituzumab govitecan plus pembrolizumab versus physician’s choice chemotherapy plus pembrolizumab in patients with previously untreated, PD-L1–positive, locally advanced, unresectable, or metastatic triple-negative breast cancer (TNBC). A total of 443 patients were enrolled across 28 countries. All participants had tumors with a PD-L1 combined positive score (CPS) ≥10 and no prior treatment for advanced disease. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. The sacituzumab group had a median PFS of 11.2 months (95% confidence interval [CI], 9.3 to 16.7 months), versus a PFS of 7.8 months in the chemotherapy group (95% CI, 7.3 to 9.3 months). This corresponded to a hazard ratio for progression or death of 0.65 (95% CI, 0.51 to 0.84; p<0.001). Objective response rate was slightly higher in the sacituzumab group (60% vs. 53%), but this difference was not statistically significant with a stratified odds ratio of 1.3 (95% CI, 0.9 to 1.9). Further, treatment responses were more durable in the sacituzumab group versus chemotherapy (median 16.5 vs. 9.2 months). Although both arms experienced high rates of grade ≥3 adverse events (71% vs. 70%), the sacituzumab group had fewer treatment discontinuations due to toxicity (12% vs. 31%). Diarrhea and neutropenia were common with sacituzumab govitecan, while chemotherapy was associated with higher rates of anemia and neuropathy. Overall, this trial demonstrated improved progression-free survival and better treatment tolerability with sacituzumab govitecan over chemotherapy.

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