Sacituzumab Govitecan/Pembrolizumab Offers Manageable, Predictable Safety Profile in TNBC

The combination of sacituzumab govitecan (Trodelvy) and pembrolizumab (Keytruda) offered a manageable and predictable safety profile in patients with previously untreated, PD-L1–positive metastatic triple-negative breast cancer (TNBC), according to a safety analysis of the phase 3 ASCENT-04 study (NCT05382286) presented as a poster at the 2025 San Antonio Breast Cancer Symposium.¹

Key findings indicated that, while the incidence of any treatment-emergent adverse events (TEAEs) was higher in the combination arm vs the control chemotherapy and pembrolizumab arm, the rate of TEAEs leading to dose reduction or discontinuation was lower compared with chemotherapy. Grade ≥3 TEAEs were reported in 71% of the experimental arm with an exposure-adjusted incidence rate (EAIR) of 2.19 (95% CI, 1.86–2.56) vs 70% in the chemotherapy arm with an EAIR of 2.13 (95% CI, 1.81–2.49). TEAEs that led to sacituzumab govitecan dose reduction occurred in 35% of patients (EAIR, 0.62; 95% CI, 0.49–0.78) vs 44% of patients who experienced a chemotherapy dose reduction (EAIR, 0.94; 95% CI, 0.76–1.15). Additionally, any treatment discontinuation was reported in 12% of the experimental arm (EAIR, 0.15; 95% CI, 0.10–0.21) compared with 31% in the chemotherapy arm (EAIR, 0.53; 95% CI, 0.41–0.67).

The TEAEs were consistent with the known safety profiles of sacituzumab govitecan and chemotherapy; the most common were neutropenia (65% in the experimental arm vs 60% in the chemotherapy arm), anemia (37% vs 51%), thrombocytopenia (5% vs 29%), diarrhea (70% vs 29%), colitis (6% vs 1%), nausea (68% vs 38%), pneumonitis (3% vs 8%), fatigue (58% vs 56%) and peripheral neuropathy (7% vs 21%).

TEAEs of Interest With Sacituzumab Govitecan and Pembrolizumab

Regarding neutropenia and diarrhea in the experimental arm, which were TEAEs of specific interest, the median times to onset were 19 (range, 6–624) days and 14 (range, 1–462) days, respectively. The respective median durations were 9 (range, 2–72) days and 7 (range, 1–709) days. Kalinsky et al, study authors, reported that the frequencies of neutropenia and diarrhea with sacituzumab govitecan and pembrolizumab were highest early in treatment. Most incidences of diarrhea were grade 1 (37%) and grade 2 (24%) in the experimental arm and managed primarily with loperamide. The use of primary prophylactic granulocyte colony-stimulating factor was associated with less frequent and less severe neutropenia in the experimental arm.

Pembrolizumab TEAEs of Special Interest

Immune-mediated AEs occurred in 30% of patients treated with sacituzumab govitecan and pembrolizumab and 40% of patients treated with chemotherapy and pembrolizumab. TEAEs of special interest associated with pembrolizumab included hypothyroidism (any-grade, 7% in the experimental arm vs 16% in the control arm), colitis (6% vs 1%), infusion reactions (5% vs 9%), hyperthyroidism (4% vs 6%), and pneumonitis (3% vs 8%).

About ASCENT-04

The ASCENT-04 study randomized patients with previously untreated, locally advanced, unresectable PD-L1–positive metastatic TNBC to receive sacituzumab govitecan (10 mg/kg intravenously on days 1 and 8 of a 21-day cycle) plus pembrolizumab (200 mg on day 1 of a 21-day cycle) or pembrolizumab and chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) until disease progression or unacceptable toxicity.^1,2 In this safety analysis, a total of 221 patients in the experimental arm and 220 in the control arm were evaluable.¹

The primary end point was progression-free survival (PFS); secondary end points included overall survival, overall response rate, duration of response, safety, and patient-reported outcomes.

Patient demographics were well-balanced between the treatment groups. In the chemotherapy arm, 51% of patients received taxane and 49% received gemcitabine/carboplatin. The median duration of treatment was 8.9 months for sacitizumab govitecan and 8.5 months for pembrolizumab in the experimental arm vs 6.2 months for chemotherapy and 6.4 months for pembrolizumab in the control arm.

Data presented at the 2025 ASCO Meeting showed that the frontline combination of sacituzumab govitecan and pembrolizumab led to a median PFS of 11.2 months (95% CI, 9.3–16.7) by blinded independent central review vs 7.8 months (95% CI, 7.3–9.3) with chemotherapy plus pembrolizumab, translating to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.51–0.84; P <.001).³

REFERENCES

1. Kalinsky K, Schmid P, de Azambuja E, et al. Safety analysis of phase 3 ASCENT-04 study of sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro for previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC). Presented at: 2025 San Antonio Breast Cancer Symposium; December 9–12, 2025; San Antonio, Texas. Abstract P5-02-28.

2. Study of sacituzumab govitecan-hziy and pembrolizumab versus treatment of physician's choice and pembrolizumab in patients with previously untreated, locally advanced inoperable or metastatic triple-negative breast cancer (ASCENT-04). ClinicalTrials.gov. Updated September 18, 2025. Accessed December 12, 2025. https://clinicaltrials.gov/study/NCT05382286

3. Tolaney SM, de Azambuja E, Kalinsky K, 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. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109