The phase 3 ASCENT-04/KEYNOTE-D19 trial, published in The New England Journal of Medicine in January 2026, provides compelling evidence that combining the Trop-2–directed antibody–drug conjugate sacituzumab govitecan with the PD-1 inhibitor pembrolizumab significantly improves clinical outcomes in patients with previously untreated, PD-L1–positive, locally advanced unresectable or metastatic triple-negative breast cancer (TNBC). This study represents a pivotal step forward in first-line treatment for one of the most aggressive and therapeutically challenging breast cancer subtypes.
ASCENT-04
Triple-Negative Breast Cancer: Symptoms ,Causes, Types, Diagnosis and Treatment
Clinical Context: The Unmet Need in First-Line TNBC
Triple-negative breast cancer is characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression and is associated with early relapse, visceral metastases, and poor long-term survival. Although immune checkpoint inhibition combined with chemotherapy has become the standard first-line approach for PD-L1–positive metastatic TNBC, outcomes remain suboptimal, and nearly half of patients do not proceed beyond first-line therapy. Improving the depth and durability of response early in the disease course remains a major clinical priority.
Trial Design and Treatment Strategy
ASCENT-04/KEYNOTE-D19 was a randomized, open-label, international phase 3 trial conducted across 186 sites in 28 countries. A total of 443 patients with previously untreated advanced TNBC and PD-L1–positive tumors (combined positive score ≥10) were randomly assigned to receive either sacituzumab govitecan plus pembrolizumab or investigator’s choice chemotherapy plus pembrolizumab.
Sacituzumab govitecan was administered at 10 mg/kg on days 1 and 8 of a 21-day cycle, combined with pembrolizumab 200 mg every 3 weeks. The control arm consisted of standard chemotherapy regimens (taxane-based or gemcitabine–carboplatin) plus pembrolizumab. The primary end point was progression-free survival assessed by blinded independent central review.
Efficacy: Meaningful Improvement in Progression-Free Survival
The trial met its primary end point, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival with sacituzumab govitecan plus pembrolizumab. Median progression-free survival was 11.2 months in the experimental arm compared with 7.8 months in the chemotherapy plus pembrolizumab arm, corresponding to a 35% reduction in the risk of disease progression or death.
This near-one-year median progression-free survival compares favorably with outcomes from prior pivotal trials of chemotherapy–immunotherapy combinations in this setting, where median progression-free survival has generally ranged between 7 and 10 months. Importantly, the progression-free survival benefit was consistent across predefined subgroups, including patients with aggressive disease features such as liver metastases and early relapse after curative-intent therapy.
Response Depth and Durability
Objective response rates were numerically higher with sacituzumab govitecan plus pembrolizumab (60%) than with chemotherapy plus pembrolizumab (53%). More notably, responses were substantially more durable. Among patients achieving a confirmed response, the median duration of response was 16.5 months in the sacituzumab-based arm, compared with 9.2 months in the chemotherapy arm.
These findings suggest that antibody–drug conjugate–based strategies may provide more sustained tumor control than conventional chemotherapy, even when initial response rates are similar. The durability of response is particularly relevant in metastatic TNBC, where early loss of disease control often limits long-term benefit.
Overall Survival
At the time of the primary analysis, overall survival data were immature, with approximately one quarter of patients having died. Median overall survival had not yet been reached in either treatment arm. Interpretation of future overall survival outcomes will need to account for the high rate of crossover to sacituzumab govitecan among patients initially assigned to chemotherapy plus pembrolizumab.
Safety and Treatment Tolerability
The safety profile of sacituzumab govitecan plus pembrolizumab was consistent with the known toxicities of each agent. Grade 3 or higher adverse events occurred at similar frequencies in both arms. However, treatment discontinuation due to adverse events was substantially lower in the sacituzumab-based arm (12%) compared with the chemotherapy arm (31%).
The most common adverse events with sacituzumab govitecan plus pembrolizumab included diarrhea, nausea, and neutropenia, while chemotherapy plus pembrolizumab was more frequently associated with anemia and thrombocytopenia. Importantly, immune-mediated adverse events were less frequent in the sacituzumab-based combination. These findings suggest that improved tolerability and lower discontinuation rates may allow patients to remain on effective therapy longer, potentially contributing to improved clinical benefit.
Biological and Therapeutic Implications
Sacituzumab govitecan delivers the topoisomerase I inhibitor SN-38 directly to Trop-2–expressing tumor cells through a hydrolyzable linker, enabling high intratumoral drug exposure. While sacituzumab govitecan is not considered intrinsically immunomodulatory, emerging evidence suggests that antibody–drug conjugates may enhance antitumor immune responses when combined with checkpoint inhibition, providing a biologic rationale for this combination.
The results of ASCENT-04/KEYNOTE-D19 support the concept of moving effective antibody–drug conjugates earlier in the treatment paradigm, not merely as salvage therapy but as foundational components of first-line treatment.
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