In the phase III ASCENT-04/KEYNOTE-D19 trial, the combination of the TROP2-directed antibody-drug conjugate sacituzumab govitecan-hziy plus the PD-1 inhibitor pembrolizumab in previously untreated patients with PD-L1–positive advanced triple-negative breast cancer significantly reduced the risk of disease progression by 35% (P < .001) and showed a trend toward improved overall survival. Sara M. Tolaney, MD, MPH, FASCO, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, Boston, reported these study findings on behalf of her colleagues as a late-breaking abstract at the 2025 ASCO Annual Meeting.¹

“We will be looking retrospectively at TROP2 levels in ASCENT-04 and hopefully will share those data in a future presentation.”

— SARA M. TOLANEY, MD, MPH, FASCO

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“The results of this study support the use of sacituzumab govitecan plus pembrolizumab as a potential new first-line standard of care, for patients with PD-L1–positive, metastatic, triple-negative breast cancer,” Dr. Tolaney said. Median progression-free survival was 11.2 months with the novel combination compared with 7.8 months with pembrolizumab and chemotherapy (hazard ratio [HR] = 0.65; P < .001).

ASCENT-04/KEYNOTE-D19 is the first randomized phase III study to evaluate the efficacy of an antibody-drug conjugate in combination with a checkpoint inhibitor for the first-line treatment of patients with PD-L1–positive metastatic breast cancer, Dr. Tolaney noted.

“This really does change the game for PD-L1–positive metastatic triple-negative breast cancer,” ASCO expert Jane Lowe Meisel, MD, FASCO, a breast medical oncologist at Emory University, Atlanta, commented during a press briefing. “The nice thing is that many of us have used both these agents, sacituzumab govitecan and pembrolizumab, quite a bit and will feel comfortable with [the combination]…. I look forward to seeing patients benefit as this regimen makes its way into clinical practice.”

Combination Therapy Meets a Need

As Dr. Tolaney pointed out, the study addresses an unmet need. For patients who have PD-L1–positive metastatic triple-negative breast cancer, the current first-line standard of care is chemotherapy plus a checkpoint inhibitor. Such treatment offers the average patient around 8 to 10 months of disease control, but most patients experience disease progression, and about half do not go on to second-line therapy, either because of deterioration in health or death.

“This really does change the game for PD-L1–positive metastatic triple-negative breast cancer.”

— Jane Lowe Meisel, MD, FASCO

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Sacituzumab govitecan has demonstrated an overall survival benefit in multiple phase III studies—the only TROP2-directed antibody-drug conjugate to do so. It is approved for the second- and later-line treatment of triple-negative metastatic breast cancer and previously treated hormone receptor–positive, HER2-negative metastatic breast cancer. Findings from previous studies have suggested that antitumor effects may be enhanced when immunotherapy is combined with antibody-drug conjugates. “There’s been much interest in trying to combine these drugs,” Dr. Tolaney commented.

About the Study

ASCENT-04/KEYNOTE-D19 evaluated sacituzumab govitecan plus pembrolizumab in 443 patients diagnosed with metastatic triple-negative breast cancer who were PD-L1–positive (combined positive score [CPS] ≥ 10). Almost half had recurred more than 12 months after completion of systemic therapy for their initial breast cancer diagnosis, and one-third had de novo metastatic disease. Patients were randomly assigned to receive sacituzumab govitecan plus pembrolizumab or chemotherapy (choice of paclitaxel or nab-paclitaxel, or gemcitabine and carboplatin) plus pembrolizumab until disease progression. The primary endpoint was progression-free survival by blinded independent central review.

Improvement in All Endpoints

For the landmark 12-month progression-free survival analysis, the curves separated early and widened over time. They demonstrated that 48% of patients were free of disease progression or death in the arm given sacituzumab govitecan plus pembrolizumab vs 33% in the chemotherapy-plus-pembrolizumab arm. Overall survival demonstrated a favorable trend as well.

“Although the overall survival data remain very immature—with just 26% of survival events having occurred at the time of this analysis—there is a trend in improvement,” Dr. Tolaney said, based on 53 events in the experimental arm and 61 events in the control arm (HR = 0.89; 95% confidence interval = 0.62–1.29). This was observed despite the fact that 81% of patients who went on to receive further systemic therapy after discontinuing chemotherapy plus pembrolizumab crossed over to receive sacituzumab govitecan.

Other outcomes were improved, as observed for sacituzumab govitecan plus pembrolizumab vs chemotherapy plus pembrolizumab, respectively:

• Objective response rate: 60% vs 53%
• Complete response rate: 13% vs 8%
• Median duration of response: 16.5 months vs 9.2 months.

Future Directions

Since sacituzumab govitecan is a TROP2-directed antibody-drug conjugate, would patients with higher levels of TROP2 necessarily have better responses to the drug? Dr. Tolaney addressed this question during a press briefing, noting that prior research, most notably the original ASCENT trial,² found a correlation between TROP2 expression and greater benefit. The key point, however, is that sacituzumab govitecan outperforms chemotherapy at all TROP2 expression levels, she said.

“We saw [previously] that progression-free survival outcomes did numerically increase as TROP2 expression increased, but sacituzumab govitecan always did better than chemotherapy, irrespective of TROP2 levels. This suggested you did not need to preselect patients for the use of sacituzumab govitecan by TROP2 expression,” Dr. Tolaney explained. “We will be looking retrospectively at TROP2 levels in ASCENT-04 and hopefully will share those data in a future presentation.”

Safety and Tolerability

The overall safety profile of the combination of sacituzumab govitecan plus pembrolizumab was consistent with the known safety profiles of each drug. The rate of serious adverse events was higher in the group given sacituzumab govitecan plus pembrolizumab; however, the rate of treatment-emergent adverse events leading to dose reductions or treatment discontinuation was lower in this group.

The most frequent grade 3 or 4 adverse events with sacituzumab govitecan plus pembrolizumab were neutropenia (43%) and diarrhea (10%); for chemotherapy plus pembrolizumab, they were neutropenia (45%), anemia (16%), and thrombocytopenia (14%). The rate of treatment-emergent serious adverse events was 38% and 31%, respectively; those leading to treatment discontinuation were reported in 12% and 31%, respectively. Dr. Tolaney noted that although the treatment duration was longer with sacituzumab govitecan—about 9 months vs 6 months with chemotherapy—when adjustments were made for treatment exposure, the rates of serious adverse events were comparable.

DISCLOSURE: Dr. Tolaney reported personal financial relationships with Aadi Bioscience, Ambrx, Artios Biopharmaceuticals, Arvinas, AstraZeneca, Bayer, BeiGene, Bicycle Therapeutics, BioNTech, Blueprint Medicines, Bristol Myers Squibb, Circle Pharma, Cullinan Oncology, Daiichi Sankyo, eFFECTOR Therapeutics, Eisai, Genentech, Hengrui Pharmaceutical (USA), Immunomedics/Gilead, Incyte, Jazz Pharmaceuticals, Johnson & Johnson, Launch Therapeutics, Lilly, Menarini Group, Merck, Mersana, Natera, Novartis, Pfizer, Reveal Genomics, Sanofi, Seagen, Sumitovant Biopharma, Summit Therapeutics, SystImmune, Tango Therapeutics, Zentalis Pharmaceuticals, Zuellig Pharma, and Zymeworks. Dr.Meisel has served as an advisor or consultant to Pfizer, AstraZeneca, Olema Pharmaceuticals, Sermonix Pharmaceuticals, Novartis, and Puma Biotechnology; and has received institutional research funding from AstraZeneca, Olema Pharmaceuticals, Sermonix Pharmaceuticals, and Pfizer.

REFERENCES

1. Tolaney SM, de Azambuja E, Kalinsky K, et al: Sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab in previously untreated PD-L1–positive advanced triple-negative breast cancer: Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. 2025 ASCO Annual Meeting. Abstract LBA109. Presented May 27, 2025.

2. Bardia A, Tolaney SM, Punie K, et al: Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol 32:1148-1156, 2021.