Sacituzumab govitecan plus pembrolizumab outperforms chemotherapy in PD-L1+ metastatic TNBC

Results from the phase 3 ASCENT-04/KEYNOTE-D19 trial show that sacituzumab govitecan, an antibody-drug conjugate (ADC) targeting Trop-2, in combination with pembrolizumab, significantly outperforms chemotherapy plus pembrolizumab in terms of disease control and tolerability.

ASCENT-04/KEYNOTE-D19 (NCT05382286) enrolled 443 patients with unresectable, locally advanced or metastatic PD-L1-positive triple-negative breast cancer (TNBC). Dr Sara M. Tolaney (Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA) noted [1]: “A significant portion of patients with metastatic TNBC do not receive treatment beyond the first line due to clinical deterioration or death. This emphasises the urgent need for more effective and tolerable first-line options.”

Participants were randomised to receive either sacituzumab govitecan and pembrolizumab (n=221) or standard chemotherapy with pembrolizumab (n=222). After a median follow-up of 14 months, the combination of sacituzumab govitecan and pembrolizumab achieved a median progression-free survival (PFS) of 11.2 months, compared with 7.8 months in the control arm. This represents a 35% reduction in the risk of progression.

In addition, the median duration of response was also notably longer with ADC combination (16.5 months vs 9.2 months with chemotherapy plus pembrolizumab). The safety profile of the ADC combination was manageable, with grade 3/4 adverse events including neutropenia (43%) and diarrhoea (10%), compared with neutropenia (45%), anaemia (16%), and thrombocytopenia (14%) in the chemotherapy arm.

Ongoing follow-up will determine whether the combination confers an overall survival benefit. Additionally, sacituzumab govitecan is being evaluated in broader breast cancer subtypes, including HER2-negative metastatic disease, early-stage TNBC, and HR-positive/HER2-negative cancers post-endocrine therapy. Sacituzumab govitecan is already approved for use in later treatment lines. This trial marks the first time a Trop-2-directed ADC has demonstrated superiority over chemotherapy when used with checkpoint inhibition in the first-line setting.

The official ASCO comment on the study, by Prof. Jane Lowe Meisel (Emory University School of Medicine, GA, USA), placed the findings in perspective: “This study shows that sacituzumab govitecan, when combined with pembrolizumab as an initial treatment for patients with metastatic triple-negative breast cancer, delivers superior disease control and fewer side effects compared with chemotherapy plus pembrolizumab. These findings build on the proven efficacy of sacituzumab govitecan alone later in treatment, and sacituzumab govitecan plus pembrolizumab will likely become a new front-line standard-of-care in this setting.”

1. Tolaney S, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. Abstract LBA109, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.

Medical writing support was provided by Dr Rachel Giles.
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Posted on 2 June 20252 June 2025