The combination of sacituzumab govitecan (Trodelvy®; Gilead Sciences; See ADC Drugmap)* + pembrolizumab (Keytruda®; Merck & Co/MSD) reduced the risk of disease progression or death by 35% (HR: 0.65) versus standard of care (SoC) pembrolizumab plus chemotherapy in first-line treatment for patients with PD-L1+ (CPS ≥10) metastatic triple-negative breast cancer (TNBC).[1]
Sacituzumab govitecan given in combination with pembrolizumab resulted in a median progression-free survival (PFS) of 11.2 months vs 7.8 months when pembrolizumab was given in combination with chemotherapy. These data from the pivotal Phase 3 ASCENT-04/KEYNOTE-D19 study (NCT05382286) were presented were presented at the annual meeting of the American Society of Clinical Oncology (ASCO; #LBA109) , held May 30-June 3, 2025 in Chicago, Illinois.[1]
Sacituzumab govitecan is an antibody-drug conjugate (ADC) This type of targeted therapy pairs an antibody with an anticancer drug. The antibody carries the drug to a specific protein found on cancer cells. Sacitizumab govitecan targets a protein called Trop-2, which is found on tumor cells.
The ASCENT-04/KEYNOTE-D19 study was funded by Gilead Sciences.
Triple-negative breast cancer
Triple-negative breast cancer or TNBC, is the most aggressive type of breast cancer and has historically been difficult to treat. The disease accounts for approximately 15% of all breast cancers and is diagnosed more frequently in younger and premenopausal women. The disease is also more prevalent in Black and Hispanic women.[2][3][4]
Because TNBC cells do not have estrogen and progesterone receptors and have limited HER2, treatment options are extremely limited compared with other breast cancer types. Furthermore, TNBC has a higher chance of recurrence and metastases than other breast cancer types.[2][3][4]
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 mTNBC, the five-year survival rate is 12%, compared with 28% for those with other types of mBC.[2][3][4]
Despite progress in treatment, first-line mTNBC 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, reinforcing the urgent need for new options to help improve patient outcomes. Breast cancers expressing PD-L1 are overall more aggressive and associated with reduced survival time.[4]
Why important
Although the combination of PD-1/PD-L1 inhibitors and chemotherapy have expanded treatment options for patients with previously untreated PD-L1–positive advanced or metastatic triple-negative breast cancer (TNBC), there remains a critical unmet need to improve treatment outcomes.
“A significant portion of patients with metastatic triple-negative breast cancer do not receive treatment beyond the first-line setting for various reasons, including a decline in their health or death, demonstrating an unmet need for first-line treatment options,” noted lead study author Sara M. Tolaney, MD, MPH, Dana-Farber Cancer Institute in Boston, Massachusetts.
“These results are an important advancement for patients with PD-L1–positive metastatic triple-negative breast cancer, a population for whom first-line options remain limited,” Tolaney added.
“By combining sacituzumab govitecan with pembrolizumab, we’re seeing meaningful gains in progression-free survival and a promising trend in overall survival—findings that could support a new frontline standard of care for this aggressive disease,” Tolaney said.
“The ASCENT-04 results build on Gilead’s aspiration of transforming the treatment of breast cancer with sacituzumab govitecan in earlier lines of therapy,” said Dietmar Berger, MD, PhD.
“Together with the recently reported clinically meaningful topline results from our first-line monotherapy study, these data reinforce our confidence in sacituzumab govitecan’s utility both as a single agent and in combination with immunotherapy in the frontline metastatic TNBC setting. We are actively engaging with the FDA to explore a potential regulatory path forward for this combination for the benefit of patients,” Berger further noted.
Study design
The ASCENT-04/KEYNOTE-D19 clinical trial, a randomized, open-label, Phase 3 Study, was designed to study the use of the antibody-drug conjugate sacituzumab govitecan in combination with pembrolizumab as a first-line treatment for patients with unresectable locally advanced or metastatic PD-L1-positive TNBC.
The trial enrolled 443 patients from 26 countries. The demographics of the participants were balanced between the two treatment arms and consistent with the characteristics of people diagnosed with metastatic TNBC. Patients were randomly assigned (1:1) to receive either sacituzumab govitecan (10 mg/kg IV, day 1 & 8) and pembrolizumab (200 mg, day 1, max 35 cycles) in 21-day cycles (n = 221) or chemotherapy (gemcitabine + carboplatin, paclitaxel, nab-paclitaxel) and pembrolizumab (222 patients). Both treatments were given until cancer progression or until the treatment needed to be stopped due to side effects.
The randomization was stratified by curative treatment-free interval, geography, and prior exposure to anti–PD-(L)1 therapy in the curative setting. Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Key secondary endpoints include overall survival (OS); objective response rate (ORR) and duration of response (DOR) by BICR; and safety.
Study Findings
- After a median follow-up of 14 months, patients treated with sacituzumab govitecan and pembrolizumab had a progression-free survival (PFS) of 11.2 months vs. 7.8 months in the chemotherapy and pembrolizumab arm. [(hazard ratio [HR], 0.65; 95% CI, 0.51-0.84; P = .0009]
- Patients treated with sacituzumab govitecan and pembrolizumab had a 35% lower risk of cancer progression compared to patients treated with chemotherapy and pembrolizumab.
- Median duration of response was 16.5 months for the sacituzumab govitecan and pembrolizumab arm vs. 9.2 months for the chemotherapy and pembrolizumab arm.
The most frequent grade 3 and 4 adverse events in the sacituzumab govitecan and pembrolizumab arm were neutropenia (43%) and diarrhea (10%). In the chemotherapy and pembrolizumab arm, the most frequent grade 3 and 4 adverse events were neutropenia (45%), anemia (16%), and thrombocytopenia (14%).
Next Steps
Researchers are expected to continue to follow these patients to better understand if there is an overall survival benefit for patients treated with sacituzumab govitecan and pembrolizumab compared to the control group. This drug combination is also being studied in patients with human epidermal growth factor receptor (HER2)-negative metastatic breast cancer, early-stage TNBC, and hormone receptor-positive/HER2-negative metastatic breast cancer after hormone therapy.
__
Note:* Sacituzumab govitecan is a first-in-class Trop-2-directed antibody-drug conjugate ADC). Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and lung cancers. Sacituzumab govitecan 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.
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
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
[1] Tolaney S, De Azambuja E, Kalinsky K, Loi S, Kim SB, Yam C, Rapoport B, Im SA, Pistilli B, McHayleh W, Cescon D, Watanabe J, Lara A, Freitas-Junior R, Bofill J, Afshari M, Gary D, Wang L, Lai C, Schmid P. 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 43, 2025 (suppl 17; abstr LBA109) [Article]
[2] Derakhshan F, Reis-Filho JS. Pathogenesis of Triple-Negative Breast Cancer. Annu Rev Pathol. 2022 Jan 24;17:181-204. doi: 10.1146/annurev-pathol-042420-093238. PMID: 35073169; PMCID: PMC9231507.
[3] Howard FM, Olopade OI. Epidemiology of Triple-Negative Breast Cancer: A Review. Cancer J. 2021 Jan-Feb 01;27(1):8-16. doi: 10.1097/PPO.0000000000000500. PMID: 33475288; PMCID: PMC12050094.
[4] Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O’Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. doi: 10.1056/NEJMoa2028485. PMID: 33882206.
This article was first published in ADC Review | J. Antibody-drug Conjugates.
Featured image courtesy © 2019 – 2025 ASCO/Max Gersh . Used with permission.
DOI
* + pembrolizumab (Keytruda®; Merck & Co/MSD) reduced the risk of disease progression or death by 35% (HR: 0.65) versus standard of care (SoC) pembrolizumab plus chemotherapy in first-line treatment for patients with PD-L1+ (CPS ≥10) metastatic triple-negative breast cancer (TNBC)){kind=link}