Sacituzumab Govitecan and Pembrolizumab: A New Frontline for mTNBC

The combination of sacituzumab govitecan-hziy (Trodelvy) and pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) compared with standard-of-care chemotherapy plus pembrolizumab in patients with previously untreated, PD-L1–positive metastatic triple-negative breast cancer (mTNBC).^1,2 Primary results from the phase 3 ASCENT-04/KEYNOTE-D19 trial (NCT05382286), published in The New England Journal of Medicine, demonstrated a 35% reduction in the risk of disease progression or death, positioning the antibody-drug conjugate (ADC) and immunotherapy combination as a potential new standard of care in the frontline setting.

Triple-negative breast cancer remains one of the most aggressive subtypes of breast cancer, often characterized by rapid progression and a lack of targeted therapeutic options beyond chemotherapy and immune checkpoint inhibitors. The ASCENT-04/KEYNOTE-D19 study evaluated whether replacing traditional chemotherapy with sacituzumab govitecan—a TROP-2 directed ADC—could enhance the efficacy of PD-1 inhibition in patients whose tumors express PD-L1 with a combined positive score of 10 or higher.

Efficacy Outcomes

Among 443 randomized patients, those receiving sacituzumab govitecan plus pembrolizumab (n = 221) achieved a median PFS of 11.2 months (95% CI, 9.3–16.7), compared with 7.8 months (95% CI, 7.3–9.3) for those receiving pembrolizumab plus physician’s choice of chemotherapy (n = 222). This difference was statistically significant (HR, 0.65; 95% CI, 0.51–0.84; P <.001). Landmark 12-month PFS rates further underscored the benefit, with 48% of patients in the sacituzumab govitecan arm remaining progression-free vs 33% in the chemotherapy arm.

Secondary end points also favored the ADC-immunotherapy combination. The objective response rate (ORR) was 60% in the sacituzumab govitecan group compared with 53% in the chemotherapy group, with complete response rates of 13% and 8%, respectively. Notably, the median duration of response (DOR) was nearly doubled with the sacituzumab govitecan combination at 16.5 months vs 9.2 months in the control arm. While overall survival (OS) data remain immature with only 26% of events occurring at the time of analysis, researchers observed an early favorable trend (HR, 0.89; 95% CI, 0.62–1.29).

Safety and Tolerability

The safety profile of sacituzumab govitecan plus pembrolizumab was consistent with the established profiles of the individual agents. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 71% of patients in the experimental arm and 70% in the control arm. The most frequent grade 3 or higher TEAEs for the sacituzumab govitecan combination were neutropenia (43%) and diarrhea (10%). In the chemotherapy-pembrolizumab arm, common high-grade toxicities included neutropenia (45%), anemia (16%), and thrombocytopenia (14%).

Importantly, the sacituzumab govitecan combination was associated with lower rates of treatment discontinuation due to TEAEs (35% vs 44%) and fewer dose reductions (12% vs 31%) compared with chemotherapy plus pembrolizumab. Patient-reported outcomes also indicated improvements in emotional functioning and pain management for those receiving the ADC combination.

Study Context and Clinical Implications

The ASCENT-04/KEYNOTE-D19 trial represents the first phase 3 evidence supporting the use of an ADC in the frontline metastatic setting for TNBC. Current standards for PD-L1–positive mTNBC typically involve pembrolizumab combined with taxanes or gemcitabine/carboplatin, based on the KEYNOTE-355 trial (NCT02819518).³ These new data suggest that the intracellular delivery of the cytotoxic payload SN-38 via the anti-TROP2 antibody may provide superior synergy with PD-1 blockade than conventional cytotoxic agents. As clinicians await mature OS data, these primary PFS results suggest a shift in the treatment paradigm for mTNBC toward ADC-based regimens in earlier lines of therapy.

REFERENCES

1. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026 Jan 22;394(4):354-366. doi: 10.1056/NEJMoa2508959. PMID: 41564397.

2. New England Journal of Medicine publishes phase 3 ASCENT-04/KEYNOTE-D19 results supporting Trodelvy® plus Keytruda® as a potential new standard of care in first-line PD-L1+ metastatic triple-negative breast cancer. News release. Gilead Sciences. January 22, 2026. Accessed January 22, 2026. https://tinyurl.com/2tukamah

3. Cortes J, Rugo HS, Cescon DW,et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022 Jul 21;387(3):217-226. doi: 10.1056/NEJMoa2202809. PMID: 35857659.