ASCENT-04 Safety Data Support Sacituzumab Govitecan Plus Pembrolizumab in PD-L1+ mTNBC

An in-depth safety analysis of the phase 3 ASCENT-04/KEYNOTE-D19 trial (NCT05382286) revealed a favorable benefit/risk profile for sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) vs chemotherapy plus pembrolizumab in patients with previously untreated metastatic triple-negative breast cancer (TNBC) and PD-L1 expression.¹

The data, which were shared during the 2025 San Antonio Breast Cancer Symposium, showed that treatment-emergent adverse effects (TEAEs) were aligned with the known toxicity profiles of the antibody-drug conjugate (ADC) and chemotherapy; they were observed in over 99% of patients in both arms. The most frequent TEAEs experienced with sacituzumab govitecan plus pembrolizumab included diarrhea, nausea, and neutropenia; with chemotherapy and pembrolizumab, the most common TEAEs were neutropenia, fatigue, and anemia.

The median duration of treatment in the ADC arm was 8.9 months with sacituzumab govitecan and 8.5 months with pembrolizumab; in the chemotherapy arm, the median duration of treatment with chemotherapy was 6.2 months vs 6.4 months with pembrolizumab.

After adjusting for longer treatment duration in the former arm, rates of TEAEs resulting in dose reduction (EAIR difference, –0.31; 95% CI, –0.56 to –0.08) or treatment discontinuation (–0.38; 95% CI, –0.53 to –0.25) favored the ADC/immunotherapy combination, as did rates of anemia (–0.59; 95% CI, –0.86 to –0.33), thrombocytopenia (–0.44; 95% CI, –0.58 to –0.31), pneumonitis (–0.08; 95% CI, –0.15 to –0.02), and peripheral neuropathy (–0.26; 95% CI –0.39 to –0.15. Rates of diarrhea (1.52; 95% CI, 1.18-1.89) and colitis (0.05; 95% CI, 0.00-0.11) favored the chemotherapy arm. These data aligned with prior reports.

Moreover, rates of TEAEs of special interest with pembrolizumab, such as hypothyroidism (7% vs 16%, respectively), pneumonitis (3% vs 8%), and infusion reactions (5% vs 9%), were lower in the ADC arm vs the chemotherapy arm. The median time to onset of diarrhea also proved shorter with the ADC regimen vs chemoimmunotherapy, at 14 days (range, 1-462) vs 64 days (range, 1-496), respectively. The median time to onset of neutropenia was comparable between the arms, at a median of 19 days (range, 6-624) vs 27 days (range, 7-366). The median duration of neutropenia (9 days [range, 2-72] vs 12 days [range, 2-61]) and diarrhea (7 days [range, 1-709] vs 6 days [range, 1-117]) were also comparable between the arms. Both AEs were determined to be manageable.

“Along with previously reported data, these results support sacituzumab govitecan plus pembrolizumab as an effective treatment with manageable adverse [effects] for people with metastatic triple-negative breast cancer that expresses PD-L1,” Kevin Kalinsky, MD, MS, FASCO, and colleagues, wrote in a poster of the data. Kalinsky is a professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, in Atlanta, GA. He is also the director of the Glenn Family Breast Center at Winship Cancer Institute.

What did the ASCENT-04 trial examine?

The phase 3 study included patients with treatment-naive, locally advanced unresectable or metastatic TNBC who were PD-L1 positive, which was defined as having a combined positive score (CPS) of 10 or higher per the 22C3 assay.² At least 6 months must have passed since curative treatment, where previous anti–PD-(L)1 inhibition was allowed.

Patients (n = 443) were randomly assigned 1:1 to receive 10 mg/kg of sacituzumab govitecan on days 1 and 8 and 200 mg of pembrolizumab on day 1 of 21-day treatment cycles (n = 221) vs pembrolizumab at the same dose and schedule paired with of 90 mg/m² of paclitaxel or 100 mg/m² of nab-paclitaxel (Abraxane) on days 1, 8, and 15 of 28-day cycles or 1000 mg/m² of gemcitabine plus area under the curve 2 of carboplatin on days 1 and 8 of 21-day cycles (n = 222). Treatment continued until progressive disease and intolerable toxicity. All patients who experienced disease progression by blinded independent central review (BICR) were able to cross over to receive sacituzumab govitecan monotherapy as second-line treatment.

The primary end point of the study was progression-free survival (PFS) by BICR, and secondary end points included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by BICR, safety, and quality of life.

What findings were previously shared from ASCENT-04 with sacituzumab govitecan?

Previous data from ASCENT-04 shared during the 2025 ASCO Annual Meeting showed that the combination of sacituzumab govitecan and pembrolizumab significantly improved PFS vs chemotherapy plus pembrolizumab, at a median of 11.2 months (95% CI, 9.3-16.7) vs 7.8 months (95% CI, 7.3-9.3), respectively (HR, 0.65; 95% CI, 0.51-0.84; P < .001). The 6-month PFS rate with the ADC was 72% (95% CI, 65%-77%); the 12-month PFS rate was 48% (95% CI, 41%-56%). These respective rates were 63% (95% CI, 56%-69%) and 33% (95% CI, 26%-40%) in the chemotherapy arm. OS data were immature at the time of the report.

What was examined in the current safety analysis?

At this year’s SABCS, investigators provided a detailed safety analysis to determine which combination was more effective as frontline treatment in patients with metastatic TNBC and PD-L1 positivity.¹ To do so, they performed an exploratory analysis for EAIRs, which was defined as the number of patients with 1 or more specified TEAE per patient-year of exposure. They examined incidence, severity, time to onset and duration, as well as the impact of toxicity management.

Demographics and baseline characteristics were well balanced between the arms, as has been shared in prior reports. All patients were female, and in the chemotherapy arm, 51% of patients had received a taxane and 49% received gemcitabine plus carboplatin.

What additional findings were reported?

The EAIRs for grade 3 or higher TEAEs in the sacituzumab arm were 2.19 (95% CI, 1.86-2.56) vs 2.13 (95% CI, 1.81-2.49) in the chemotherapy arm (difference, 0.06; 95% CI, –0.43 to 0.55). For serious TEAEs, the EAIRs in the respective arms were 0.59 (95% CI, 0.47-0.73) and 0.52 (95% CI, 0.410.66; difference, 0.06; 95% CI, –0.12 to 0.25). The EAIR differences between the sacituzumab and chemotherapy arms for treatment-related grade 3 or higher toxicities and treatment-related serious toxicities were 0.20 (95% CI, –0.24 to 0.64) and 0.11 (95% CI, –0.03 to 0.25).

Regarding management, primary prophylaxis with granulocyte colony-stimulating factor was linked with less frequent and severe neutropenia in the ADC arm. Of those who received it in the ADC (n = 43) arm, 47% experienced any-grade neutropenia and 35% experienced grade 3 or higher neutropenia; of those who received it in the chemotherapy arm (n = 20), these rates were 65% and 54%, respectively.

Nineteen percent of patients in the sacituzumab govitecan arm experienced neutropenia that required dose reduction vs 18% of those in the chemotherapy arm; this toxicity led to discontinuation for 1% and 2% of patients, respectively. Moreover, diarrhea led to dose reductions in 5% of those in the ADC arm and 1% of those in the chemotherapy arm; this toxicity led to discontinuation in less than 1% of patients. Loperamide was the most common antidiarrheal leveraged to manage this effect, with 90% of patients in the ADC arm having received it and 77% of those in the chemotherapy arm. More patients in the sacituzumab govitecan arm received atropine vs those in the chemotherapy arm, at 12% vs 3%.

Lastly, 9 of the 13 cases of colitis reported on the study were not determined to be severe; only 1 case resulted in treatment discontinuation in the ADC arm.

References

1. Kalinsky K, Schmid P, de Azambuja E, et al. Safety analysis of phase 3 ASCENT-04 study of sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab for previously untreated PD-L1+ metastatic triple-negative breast cancer. Presented at: 2025 San Antonio Breast Cancer Conference; December 9-12, 2025; San Antonio, TX. Abstract PS5-02-28.
2. 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