FDA Clears Trodelvy for First-Line Metastatic Triple-Negative Breast Cancer

The FDA has approved Gilead’s Trodelvy (sacituzumab govitecan-hziy) for the first-line treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC), representing the first expansion of the drug's label into the initial treatment setting.¹

The approval covers two distinct patient populations: those ineligible for checkpoint inhibitor-based therapy, who may receive the drug as a single agent, and those with PD-L1-positive tumors (combined positive score ≥10), who may receive it in combination with Keytruda (pembrolizumab) or the subcutaneous formulation Keytruda and berahyaluronidase alfa-mph.¹

The regulatory action carries significant commercial weight for Gilead. More than 75,000 patients across 60 countries have received Trodelvy in previously approved indications, and the shift into first-line therapy opens the drug to a substantially broader patient population. Global regulatory submissions based on the supporting trials are underway.

"For people living with mTNBC, the first treatment choice can be pivotal, as many patients may not have the opportunity to receive subsequent therapies," said Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute and a principal investigator of the supporting trials, in a press release. "This approval is heartening news for patients and the clinical community, and I believe offers a practice-changing first-line treatment option for all patients across PD-L1 status."¹

What Did the ASCENT-03 and ASCENT-04 Trials Show About Sacituzumab Govitecan in First-Line mTNBC?

The FDA based its decision on data from two Phase 3 studies. ASCENT-03 (NCT05382299) enrolled 558 patients with previously untreated, unresectable locally advanced or mTNBC who were ineligible for checkpoint inhibitor therapy. Participants were randomly assigned in a 1:1 ratio to receive Trodelvy or physician's choice of chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin).

The primary endpoint of progression-free survival (PFS) by blinded independent central review was 9.7 months with Trodelvy versus 6.9 months in the control cohort, reflecting a 38% reduction in the risk of disease progression or death (hazard ratio 0.62; 95% confidence interval, 0.50–0.77; P<0.0001).² Median duration of response was 12.2 months in the sacituzumab govitecan arm compared with 7.2 months in the chemotherapy arm.

ASCENT-04/KEYNOTE-D19 (NCT05382286) enrolled 443 patients with previously untreated, PD-L1-positive locally advanced or mTNBC.³ Patients were randomly assigned to receive Trodelvy plus Keytruda or chemotherapy plus Keytruda.

The combination produced a median PFS of 11.2 months versus 7.8 months with the chemotherapy-based regimen, a 35% reduction in the risk of progression or death (hazard ratio 0.65; 95% confidence interval, 0.51–0.84; P<0.001).³ Duration of response extended to 16.5 months with Trodelvy plus Keytruda compared with 9.2 months in the comparator arm. Overall survival (OS) data were not mature at primary analysis in either trial.

The National Comprehensive Cancer Network has incorporated both regimens as category 1 preferred first-line options for mTNBC across PD-L1 status in its breast cancer guidelines, based on these results.

What is the Significance of First-Line Approval in mTNBC for the Treatment Landscape?

Triple-negative breast cancer, defined by the absence of estrogen and progesterone receptor expression and limited HER2 expression, accounts for roughly 10% to 15% of all breast cancer diagnoses and carries a notably worse prognosis than hormone receptor-positive subtypes.⁴ The disease disproportionately affects younger, premenopausal women and Black and Hispanic patients.

Among those who develop metastatic disease, the five-year survival rate is approximately 12%, compared with 28% for other metastatic breast cancer types. The treatment landscape in first-line mTNBC has seen limited regulatory movement in recent years.

The introduction of pembrolizumab plus chemotherapy for PD-L1-positive disease earlier this decade represented the last major shift in the standard of care. Critically, over half of patients with mTNBC do not proceed to a second line of therapy, which places heightened pressure on initial treatment selection.

"TNBC disproportionately affects younger women—many in the prime of their lives—and often leads to poorer outcomes," said Ricki Fairley, co-founder and CEO of TOUCH, The Black Breast Cancer Alliance, in the press release. "Because so many patients may never receive subsequent lines of therapy, the ability to start with a promising option like Trodelvy with or without Keytruda is critical. We have sought additional alternatives to chemotherapy-containing regimens in the first-line metastatic setting since TNBC was classified as a disease more than 20 years ago."

How Does Trodelvy’s Mechanism and Safety Profile Affect Clinical Use?

Trodelvy is a Trop-2-directed antibody-drug conjugate that delivers SN-38, a topoisomerase I inhibitor payload, via a proprietary hydrolyzable linker. Trop-2 is a cell-surface antigen expressed in more than 90% of breast cancers.

The linker design allows payload delivery both to Trop-2-expressing tumor cells and, through a bystander effect, to adjacent cells in the tumor microenvironment. The drug carries a boxed warning for severe neutropenia and diarrhea, both of which require proactive management.

In ASCENT-03, Grade 3–4 neutropenia occurred in a substantial proportion of patients, with serious adverse reactions in 26% of participants; fatal adverse reactions occurred in 2.5%. In ASCENT-04, serious adverse reactions were reported in 38% of patients, and fatal adverse reactions in 3.2%. Febrile neutropenia, diarrhea, and pneumonia were among the most frequently cited serious events across both studies.

What Are the Open Questions Following This Approval?

OS data from both trials remain immature, and whether the PFS gains translate into meaningful overall survival improvement will be critical to assessing the drug's full clinical value. The absence of head-to-head comparison with Keytruda plus chemotherapy in PD-L1-positive patients receiving Trodelvy as monotherapy also leaves gaps in the benefit-risk picture for that population.

Trodelvy is currently under evaluation in ongoing Phase 3 trials across additional tumor types with high Trop-2 expression, including earlier-line settings for hormone receptor-positive and HER2-negative breast cancer, as well as lung and gynecologic cancers.

Sources

1. Gilead Sciences, Inc. U.S. FDA approves Trodelvy for first-line treatment of metastatic triple-negative breast cancer. News release. June 24, 2026. https://www.gilead.com/news/news-details/2026/u-s--fda-approves-trodelvy-for-first-line-treatment-of-metastatic-triple-negative-breast-cancer

2. Cortés J, Punie K, Barrios C, et al. Sacituzumab govitecan in untreated, advanced triple-negative breast cancer. N Engl J Med. 2025. doi:10.1056/NEJMoa2511734

3. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959

4. U.S. Food and Drug Administration. FDA approves sacituzumab govitecan-hziy as monotherapy and in combination with pembrolizumab for first-line treatment of triple-negative breast cancer. June 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sacituzumab-govitecan-hziy-monotherapy-and-combination-pembrolizumab-first-line