Sacituzumab Govitecan Plus Pembrolizumab Improves PFS in PD-L1–Positive mTNBC

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Sacituzumab govitecan-hziy (Trodelvy) in combination with pembrolizumab (Keytruda) improved progression-free survival (PFS) vs pembrolizumab plus chemotherapy in patients with previously untreated, PD-L1–positive (combined positive score [CPS] ≥ 10) metastatic triple-negative breast cancer (mTNBC), according to findings from the phase 3 ASCENT-04/KEYNOTE-D19 study (NCT05382286).1

An early trend toward improved overall survival (OS) was observed, though the OS data remained immature at the current analysis. Additionally, the safety profile of the combination was consistent with the known safety profiles of each agent, with no new safety signals identified. These findings build upon previous evidence supporting the use of sacituzumab govitecan in the relapsed/refractory TNBC setting and highlight the potential of combining targeted cytotoxic therapy with immunotherapy in the front-line setting for PD-L1–positive mTNBC, according to a news release.

“For patients with mTNBC, there is a critical need for more effective treatment options,” Sara Tolaney, MD, MPH, chief of the Division of Breast Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, as well as the principal investigator of the ASCENT-04 study, stated in a news release. “These data suggest that the combination of sacituzumab govitecan and pembrolizumab may offer a new treatment approach—bringing together a potent antibody-drug conjugate [ADC] with immunotherapy to improve outcomes for patients.”

Currently, sacituzumab govitecan remains the only FDA-approved TROP-2–directed ADC with demonstrated survival benefit in 2 distinct subtypes of metastatic breast cancer.

In 2020, the FDA approved sacituzumab govitecan for the treatment of patients with previously treated mTNBC. Additionally, in February 2023, the FDA approved sacituzumab govitecan for the treatment of patients with pretreated HR-positive, HER2-negative metastatic breast cancer.

ASCENT-04/KEYNOTE-D19 Study Design

The phase 3 ASCENT-04/KEYNOTE-D19 trial is a randomized, open-label study evaluating the efficacy of sacituzumab govitecan in combination with pembrolizumab vs pembrolizumab plus physician’s choice of chemotherapy in patients with previously untreated, locally advanced, inoperable or metastatic TNBC whose tumors express PD-L1 with a CPS of 10 or greater.2

Eligible patients are adults aged 18 years or older with histologically confirmed, unresectable, locally advanced or metastatic TNBC and no prior systemic therapy in the advanced setting. Patients must have measurable disease by RECIST 1.1 criteria and an ECOG performance status of 0 or 1. Key inclusion criteria require documented PD-L1 expression confirmed centrally and a duration of at least 6 months since completion of any curative-intent treatment, if applicable. Patients with de novo metastatic disease are also eligible.

The study excludes patients who are pregnant or lactating, have received prior immune checkpoint inhibitors or topoisomerase I inhibitors, or have a history of active autoimmune disease requiring systemic therapy in the past 2 years. Additional exclusion criteria include active secondary malignancies, serious infections, or viral hepatitis.

The trial’s primary objective is to assess PFS per RECIST 1.1 criteria. Secondary outcomes include OS, objective response rate (ORR), and safety.

“These findings are the first to show the transformative potential of an ADC combined with an immuno-oncology agent in early treatment lines of metastatic breast cancer,” Dietmar Berger, MD, PhD, chief medical officer of Gilead Sciences, added in the news release.1 “For patients with this difficult-to-treat type of breast cancer, these results potentially offer a new pathway that may redefine their treatment options.”

Future Steps

Comprehensive results from the ASCENT-04/KEYNOTE-D19 study are expected to be presented at an upcoming meeting and will be shared with regulatory authorities. At this time, the combination remains investigational in previously untreated patients with PD-L1–positive mTNBC, and its safety and efficacy in this setting have has not yet been established.

Investigators indicated that OS data will continue to be monitored, with ongoing patient follow-up and additional analyses planned.

Ongoing phase 3 trials evaluating sacituzumab govitecan across HER2-negative metastatic breast cancer subtypes include the ASCENT-03 study (EudraCT 2021-005743-79), which is assessing the agent in the first-line setting for patients with mTNBC who are not eligible for PD-L1–based therapy; the ASCENT-05 study (NCT05633654), which is investigating the ADC in patients with early-stage TNBC; and the ASCENT-07 study (NCT05840211), which is evaluating sacituzumab govitecan in patients with hormone receptor–positive, HER2-negative metastatic breast cancer following endocrine therapy.

Additionally, sacituzumab govitecan is under investigation in other phase 3 trials across tumor types, including lung and gynecologic malignancies.

References

1. Trodelvy plus Keytruda demonstrates a statistically significant and clinically meaningful improvement in progression-free survival in patients with previously untreated PD-L1+ metastatic triple-negative breast cancer. News Release. Gilead. April 21, 2025. Accessed, April 21, 2025. https://www.gilead.com/news/news-details/2025/trodelvy-plus-keytruda-demonstrates-a-statistically-significant-and-clinically-meaningful-improvement-in-progression-free-survival-in-patients-with-previously-untreated-pd-l1-metastatic-trip
2. 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. ClinicalTrials.gov. Updated December 24, 2024. Accessed April 21, 2025. https://clinicaltrials.gov/study/NCT05382286