Sacituzumab Govitecan Plus Pembrolizumab Improves PFS in Metastatic TNBC
Key Clinical Summary
- In the phase 3 ASCENT-04/KEYNOTE-D19 trial, sacituzumab govitecan plus pembrolizumab significantly improved median progression-free survival (PFS) vs chemotherapy plus pembrolizumab (11.2 vs 7.8 months; HR 0.65; P <.001) for triple-negative breast cancer (TNBC).
- Objective response rates were 60% vs 53%, with longer median duration of response (16.5 vs 9.2 months).
- Grade ≥ 3 adverse events were similar between arms (71% vs 70%), with lower treatment discontinuation in the sacituzumab arm (12% vs 31%).
TNBC remains an aggressive subtype with limited first-line treatment durability in programmed death-ligand 1 (PD-L1)–positive, locally advanced unresectable or metastatic disease. In the phase 3 ASCENT-04/KEYNOTE-D19 trial, sacituzumab govitecan combined with pembrolizumab significantly improved PFS compared with chemotherapy plus pembrolizumab, positioning antibody–drug conjugate-based therapy as a potential new backbone option in this setting.
Study Findings
ASCENT-04/KEYNOTE-D19 was an international, open-label, phase 3 trial enrolling 443 patients with previously untreated, PD-L1–positive (combined positive score ≥ 10), locally advanced unresectable or metastatic TNBC. Patients were randomly assigned 1:1 to receive sacituzumab govitecan plus pembrolizumab (n = 221) or chemotherapy plus pembrolizumab (n=222).
The primary endpoint was PFS by blinded independent central review. Median PFS was 11.2 months (95% CI, 9.3-16.7) in the sacituzumab arm versus 7.8 months (95% CI, 7.3-9.3) in the chemotherapy arm, corresponding to a hazard ratio (HR) for disease progression or death of 0.65 (95% CI, 0.51-0.84; P < .001).
Overall survival data were immature at the time of primary analysis. Objective response occurred in 60% (95% CI, 53-66) of patients receiving sacituzumab govitecan plus pembrolizumab versus 53% (95% CI, 46-60) with chemotherapy plus pembrolizumab. Among responders, median duration of response was 16.5 months (95% CI, 12.7-19.5) and 9.2 months (95% CI, 7.6-11.3), respectively.
Grade 3 or higher adverse events occurred in 71% of patients in the sacituzumab arm and 70% in the chemotherapy arm. Treatment discontinuation due to adverse events was less frequent with sacituzumab govitecan plus pembrolizumab (12% vs 31%). Adverse events leading to death occurred in 3% of patients in each group.
Clinical Implications
The 3.4-month improvement in median PFS observed with sacituzumab govitecan plus pembrolizumab compares favorably with prior phase 3 trials of chemotherapy–immunotherapy combinations in first-line PD-L1–positive metastatic TNBC, where median PFS has ranged from approximately 5.9 to 9.7 months.
Notably, responses appeared more durable with the antibody–drug conjugate combination, despite similar initial response rates. The median duration of response of 16.5 months suggests more sustained tumor control, which is particularly relevant given that nearly half of patients with metastatic TNBC do not receive treatment beyond first-line therapy.
For oncology clinical pathways and payer considerations, the lower rate of treatment discontinuation (12% vs 31%) may be clinically meaningful. The safety profile was consistent with known toxicities of each agent, with no new safety signals. Toxicities associated with sacituzumab govitecan plus pembrolizumab may be more manageable with supportive care compared with less reversible adverse effects such as neuropathy associated with chemotherapy.
According to the investigators, “The trial showed a significant difference of 3.4 months in median progression-free survival…with sacituzumab govitecan plus pembrolizumab as compared with chemotherapy plus pembrolizumab.” They further noted that the improved PFS, longer duration of response, and lower likelihood of treatment discontinuation “highlight sacituzumab govitecan plus pembrolizumab as an advancement in improving treatment outcomes for this difficult-to-treat patient population…”
Conclusion
Sacituzumab govitecan plus pembrolizumab significantly prolonged PFS compared with chemotherapy plus pembrolizumab in previously untreated, PD-L1–positive advanced TNBC. Ongoing phase 3 trials will further clarify its role in earlier-stage and high-risk disease settings.
Reference
Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959
