Despite recent advances, treatment of advanced or metastatic triple-negative breast cancer (mTNBC) remains limited.
Now, results from the international open-label phase 3 ASCENT-04/KEYNOTE-D19 study (NCT05382286), evaluating sacituzumab govitecan (Trodelvy®; Gilead Sciences) in combination with pembrolizumab (Keytruda®; Merck & CO/MSD), published in the January 21, 2026 edition of the New England Journal of Medicine (NEJM), demonstrate that the combination led to significantly longer progression-free survival (PFS) than chemotherapy + pembrolizumab among patients with previously untreated, PD-L1–positive (CPS ≥10), advanced triple-negative breast cancer.[1]
Sacituzumab govitecanis a first-in-class Trop-2-directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including more than 90% of breast and lung cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2-expressing cells and the tumor microenvironment through a bystander effect.
Most agressive type of Breast Cancer
TNBC is the most aggressive type of breast cancer and has historically been difficult to treat, accounting for approximately 15% of all breast cancers. TNBC disproportionally impacts younger, premenopausal, and Black and Hispanic women. TNBC cells lack estrogen and progesterone receptors and exhibit limited HER2 expression.
Due to the nature of TNBC, treatment options are extremely limited compared with other breast cancer types. TNBC has a higher chance of recurrence and metastases than other breast cancer types. The average time to metastatic recurrence for TNBC is approximately 2.6 years compared with 5 years for other breast cancers, and the relative five-year survival rate is much lower. Among women with metastatic TNBC, the five-year survival rate is 12%, compared with 28% for those with other types of mBC.
Despite progress in treatment, first-line metastatic TNBC has seen limited new approvals in recent years for tumors that express PD-L1+, and additional options are urgently needed. Despite recent advances, over 50% of patients do not receive treatment beyond first-line therapy, reinforcing the urgent need for new options to improve patient outcomes. Breast cancers expressing PD-L1 are overall more aggressive and associated with reduced survival time.
Study design
The ASCENT-04/KEYNOTE-D19 study, sponsored by Gilead Sciences, enrolled 443 patients across multiple study sites. Patients were randomized in a 1:1 ratio to receive either sacituzumab govitecan (10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle) plus pembrolizumab (200 mg intravenously on Day 1 of a 21-day cycle) or chemotherapy plus Keytruda.
The chemotherapy regimen included gemcitabine plus carboplatin, paclitaxel, or nab-paclitaxel. Treatment continued until blinded independent central review (BICR)-verified disease progression or unacceptable toxicity. Patients randomized to chemotherapy were allowed to cross over and receive Trodelvy upon disease progression as part of the study.
The primary endpoint of the study is progression-free survival (PFS) as determined by BICR using RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), time to onset of response (TTR), patient-reported outcomes (PROs), and safety.
The study successfully met its primary endpoint of PFS, with a 35% reduction in the risk of disease progression or death (HR: 0.65; p<0.001) for sacituzumab govitecan plus pembrolizumab (n=221) versus standard-of-care pembrolizumab plus chemotherapy (n=222). Median PFS with sacituzumab govitecan plus pembrolizumab was 11.2 months versus 7.8 months when pembrolizumab was given in combination with chemotherapy.
“Metastatic TNBC patients often show rapid progression and poor outcomes after current first-line therapies, illustrating the urgent need for new and more efficacious treatment options,” said Dietmar Berger, MD, PhD, Chief Medical Officer, Gilead Sciences.
“These results represent important progress toward our goal of delivering sacituzumab govitecan to patients in earlier lines of breast cancer treatment, with potential to become a backbone therapy for all frontline metastatic TNBC patients in need of innovative therapeutics,” Berger added.
Sara M. Tolaney, MD, MPH, is Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute.Limited treatment options
“Patients with PD-L1+ metastatic triple-negative breast cancer continue to face limited options in the first-line setting,” noted Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute and Principal Investigator of the ASCENT-04/KEYNOTE-D19 study.
“As such, these very promising data with the novel combination of sacituzumab govitecan and pembrolizumab in frontline metastatic TNBC represent a meaningful step forward in establishing a potential new standard of care for this challenging disease,” Tolaney further noted.
“[I believe that] there is a huge unmet need for new therapies for patients with triple-negative breast cancer,” Tolaney explained. “Hence, it is important that we work toward shifting these very effective novel drugs to the first line of therapy to move the needle and improve outcomes for these patients.”
The NEJM publication of the ASCENT-04/KEYNOTE-D19 study results follows a data presentation at the 2025 annual meeting of the American Society of Clinical Oncology (ASCO), as well as a simultaneous presentation at the 2025 European Society for Medical Oncology (ESMO) Congress and publication in NEJM of primary results from the ASCENT-03 trial (NCT05382299) of sacituzumab govitecan monotherapy in patients with first-line metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitors.
Based on these outcomes, Gilead Sciences has submitted supplemental applications for both indications to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).
The safety profile of sacituzumab govitecan plus pembrolizumab in ASCENT-04/KEYNOTE-D19 was consistent with the known safety profile of each agent. No new safety signals were identified with the combination, and the combination did not exacerbate the safety profile of either therapy.
“We hope these data will result in approval of sacituzumab govitecan plus pembrolizumab for first-line treatment in our patients with metastatic triple-negative breast cancer with tumors that are PD-L1-positive. Currently, we sometimes see patients experience deterioration in their health during first-line treatment, and they don’t always have an opportunity to benefit from these sacituzumab in later lines,” Tolaney noted.
“We need to move these agents up front so more patients can benefit,” she concluded.
Adverse events
The most frequent (≥10% of patients) grade ≥3 treatment-emergent adverse events with Trodelvy plus pembrolizumab were neutropenia (43%) and diarrhea (10%), and with pembrolizumab plus chemotherapy were neutropenia (45%), anemia (16%), and thrombocytopenia (14%). Fewer patients discontinued treatment due to adverse events on the Trodelvy plus Keytruda arm than on the pembrolizumab plus chemotherapy arm (12% vs. 31%).
Healthcare professionals have well-established experience with sacituzumab govitecan, with more than 60,000 breast cancer patients treated across 50+ countries over the past five years. It remains the only Trop-2-directed antibody-drug conjugate (ADC) to demonstrate meaningful survival benefits in both 2L+ metastatic TNBC and pre-treated HR+/HER2- metastatic breast cancer. With ASCENT (NCT02574455), TROPiCS-02 (NCT03901339), ASCENT-03, and ASCENT-04/KEYNOTE-D19, sacituzumab govitecan is also the only ADC with four positive Phase 3 trials in HER2-mBC (IHC 0, IHC 1+, or IHC 2+/ISH–).
The safety profile of sacituzumab govitecan in combination with pembrolizumab was consistent with the established profiles of each agent, and treatment discontinuation due to side effects was less frequent among patients taking the sacituzumab govitecan combination.
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Note: Sacituzumab govitecan is currently approved in more than 50 countries for second-line or later metastatic triple-negative breast cancer (TNBC) and in more than 40 countries for certain patients with pre-treated HR+/HER2- metastatic breast cancer (mBC). Sacituzumab govitecan is currently being evaluated in multiple ongoing Phase 3 trials across a range of tumor types with high Trop-2 expression. Studies with sacituzumab govitecan, both in monotherapy and in combination with pembrolizumab, involve earlier lines of treatment for TNBC and HR+/HER2- breast cancer—including in curative settings—as well as in lung and gynecologic cancers, where previous proof-of-concept studies have demonstrated clinical activity.
Note: The use of sacituzumab govitecan plus pembrolizumab in patients with first-line PD-L1+ metastatic TNBC and sacituzumab govitecan as monotherapy in patients with first-line metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitors are investigational, and the safety and efficacy of these uses have not been established.
Clinical trials
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 ID NCT05382286
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Patients With Previously Untreated Locally Advanced Inoperable or Metastatic Triple-Negative Breast Cancer (ASCENT-03) – ClinicalTrials.gov ID NCT05382299
Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Participants With HR+/HER2- Metastatic Breast Cancer (TROPiCS-02) – ClinicalTrials.gov ID NCT03901339
Trial of Sacituzumab Govitecan in Participants With Refractory/Relapsed Metastatic Triple-Negative Breast Cancer (TNBC) (ASCENT) – ClinicalTrials.gov ID NCT02574455
Highlights of prescribing information
Sacituzumab govitecan (Trodelvy®; Gilead Sciences)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & CO/MSD)[Prescribing Information]
Reference
Tolaney SM, de Azambuja E, Kalinsky K, Loi S, Kim SB, Yam C, Rapoport B, Im SA, Pistilli B, Mchayleh W, Cescon DW, Watanabe J, Bañuelas MAL, Freitas-Junior R, Salvador Bofill J, Afshari M, Gary D, Wang L, Lai C, Schmid P; ASCENT-04/KEYNOTE-D19 Clinical Trial Investigators. 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.
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