Sacituzumab Govitecan Plus Pembrolizumab: A New First-Line Treatment Option for Advanced Triple-Negative Breast Cancer

Table of Contents

• Key Points
• Understanding Triple-Negative Breast Cancer
• Why This Research Matters
• How the Study Was Designed
• Who Participated in the Study
• Key Finding: Longer Time Before Cancer Progression
• Key Finding: Tumor Shrinkage and Duration of Response
• Safety and Side Effects
• What This Means for Patients
• Study Limitations
• Questions to Ask Your Doctor
• Frequently Asked Questions
• Source Information

Key Points

• In a phase 3 trial of 443 patients, sacituzumab govitecan plus pembrolizumab delayed cancer progression by a median of 11.2 months vs 7.8 months with chemotherapy plus pembrolizumab.
• The combination reduced the risk of disease progression or death by 35% compared to standard treatment in PD-L1-positive advanced triple-negative breast cancer.
• Tumor responses lasted nearly twice as long with the new combination: median 16.5 months vs 9.2 months.
• Fewer patients stopped treatment due to side effects with sacituzumab govitecan plus pembrolizumab (12%) than with chemotherapy plus pembrolizumab (31%).
• Overall survival data are not yet mature; longer follow-up is needed to determine if the new combination improves how long patients live.

Understanding Triple-Negative Breast Cancer

Breast cancer is the leading cause of cancer-related death in women worldwide. Among all breast cancer types, triple-negative breast cancer is the most aggressive subtype. The name comes from the fact that these tumors lack three key features: they do not express estrogen receptors (ER), they do not express progesterone receptors (PR), and they have low or no expression of human epidermal growth factor receptor 2 (HER2).

Because these tumors lack those three targets, many standard hormone-based or HER2-directed therapies do not work for them. This makes treatment more challenging.

For people with metastatic triple-negative breast cancer (cancer that has spread beyond the breast), the outlook has historically been poor. The 5-year relative survival rate is approximately 15%, meaning only about 15 out of every 100 patients live at least 5 years after diagnosis.

About 40% of triple-negative breast cancer cases are PD-L1–positive. PD-L1 (programmed death ligand 1) is a protein found on the surface of some cancer cells. It acts like a "brake" on the immune system, preventing immune cells from attacking the tumor. The combined positive score (CPS) measures how much PD-L1 is present by counting PD-L1-staining tumor cells, lymphocytes, and macrophages, dividing by the total number of viable tumor cells, and multiplying by 100. A CPS of 10 or higher is considered PD-L1–positive in this setting.

Why This Research Matters

The current preferred first-line treatment for patients with previously untreated, PD-L1–positive metastatic triple-negative breast cancer is pembrolizumab (Keytruda), a type of immunotherapy called a PD-1 immune checkpoint inhibitor, combined with chemotherapy. This recommendation is based on a previous phase 3 trial called KEYNOTE-355.

In that earlier trial, pembrolizumab plus chemotherapy (taxanes or gemcitabine–carboplatin) resulted in significantly longer progression-free survival than chemotherapy alone — a median of 9.7 months versus 5.6 months. Overall survival was also longer: 23.0 months versus 16.1 months among patients whose tumors expressed PD-L1 with a CPS of 10 or higher.

Despite this progress, there is still room for improvement. Approximately half of all patients with metastatic triple-negative breast cancer never receive treatment beyond their first line of therapy. This means the first treatment patients receive is especially important — it may be their only opportunity for effective disease control.

Sacituzumab govitecan (marketed as Trodelvy) is a different type of drug called an antibody–drug conjugate. It is built from a humanized antibody that targets a protein called Trop-2 (trophoblast cell-surface antigen 2), which is found on the surface of many cancer cells. The antibody is attached to a chemotherapy drug called SN-38, a topoisomerase I inhibitor, through a special hydrolyzable linker. This design allows the drug to deliver chemotherapy directly to cancer cells.

Sacituzumab govitecan is already approved in multiple countries for patients with metastatic triple-negative breast cancer after at least two prior systemic therapies (at least one given for metastatic disease). That approval was based on the phase 3 ASCENT trial, which showed significant improvements in both progression-free and overall survival with sacituzumab govitecan compared with chemotherapy in that later-line setting.

The ASCENT-04/KEYNOTE-D19 trial asked a new question: Could sacituzumab govitecan be used earlier — as part of the first treatment patients receive for advanced disease — when combined with pembrolizumab?

How the Study Was Designed

This was a phase 3, open-label (meaning both patients and doctors knew which treatment was given), randomized international trial conducted at 186 sites in 28 countries. The study enrolled adults with locally advanced unresectable (cancer that cannot be removed with surgery) or metastatic triple-negative breast cancer whose tumors were PD-L1–positive with a CPS of 10 or higher. Patients must not have received any prior therapy for advanced disease.

Triple-negative status was confirmed centrally on tumor samples. To qualify, tumors had to have less than 1% of cells positive for estrogen receptor or progesterone receptor, and a HER2 immunohistochemistry (IHC) result of 0, 1+, or 2+ with negative in situ hybridization. PD-L1 expression was measured using the PD-L1 IHC 22C3 pharmDx assay (Dako, Agilent Technologies).

Eligible patients were randomly assigned in a 1:1 ratio — like a coin flip — to receive one of two treatments:

• Sacituzumab govitecan plus pembrolizumab: Sacituzumab govitecan was given intravenously at a dose of 10 mg per kilogram of body weight on days 1 and 8 of each 21-day cycle. Pembrolizumab was given intravenously at a fixed dose of 200 mg on day 1 of each 21-day cycle.
• Chemotherapy plus pembrolizumab (the control group): Patients received one of three chemotherapy options chosen by their doctor — paclitaxel at 90 mg per square meter of body-surface area, or nanoparticle albumin-bound paclitaxel (nab-paclitaxel) at 100 mg per square meter, both given on days 1, 8, and 15 of 28-day cycles; or gemcitabine at 1000 mg per square meter plus carboplatin (dosed to target an area under the concentration–time curve of 2 mg per milliliter per minute) given on days 1 and 8 of 21-day cycles. Pembrolizumab was given at 200 mg on day 1 of each 21-day cycle.

Patients were divided into groups (stratified) at randomization based on three factors:

1. Disease status: metastatic disease at initial diagnosis, disease that recurred within 6 to 12 months after completing curative-intent treatment, or disease that recurred more than 12 months after completing curative-intent treatment
2. Geographic region: Canada, the United States, or western Europe versus the rest of the world
3. Previous exposure to an anti–PD-1 or anti–PD-L1 agent given as adjuvant or neoadjuvant (before or after surgery) therapy: yes versus no

Treatment continued until disease progression was confirmed by blinded independent central review (an independent panel of radiologists who did not know which treatment patients received), the development of unacceptable side effects, withdrawal of consent, or death. Pembrolizumab was given for a maximum of 35 cycles.

Importantly, the trial included a crossover phase. Patients who had received chemotherapy plus pembrolizumab could receive sacituzumab govitecan as a single agent after their disease was confirmed to have progressed, if they met eligibility criteria.

The primary end point (the main question the trial was designed to answer) was progression-free survival — the length of time from randomization until the cancer grew or the patient died, whichever came first, as judged by blinded independent central review.

Key secondary end points included:

• Overall survival (how long patients lived)
• Objective response — whether tumors shrank partially or disappeared completely
• Duration of response — how long tumor shrinkage lasted
• Time to response — how quickly tumors responded
• Safety

Tumor assessments were performed with computed tomography (CT) or magnetic resonance imaging (MRI) every 8 weeks during the first 18 months, then every 12 weeks until disease progression was confirmed. Tumor response was measured using standard criteria called RECIST version 1.1 (Response Evaluation Criteria in Solid Tumors).

The trial was designed to enroll approximately 440 patients. For the primary analysis, 227 events of disease progression or death would provide 90% power to detect a hazard ratio of 0.65 at a two-sided significance level of 5%. The trial used a hierarchical testing approach to control the overall error rate.

Who Participated in the Study

A total of 443 patients were enrolled between October 17, 2022, and August 21, 2024. Of these, 221 were assigned to receive sacituzumab govitecan plus pembrolizumab, and 222 were assigned to receive chemotherapy plus pembrolizumab. The two groups were well balanced in their characteristics.

Key baseline characteristics included:

• Median age: 54 years (range, 23 to 88) in the sacituzumab govitecan group versus 55 years (range, 27 to 82) in the chemotherapy group
• Age 65 or older: 58 patients (26%) in each group
• Female sex: 100% of patients in both groups (221 and 222 patients, respectively)
• Race: White — 139 (63%) versus 118 (53%); Asian — 43 (19%) versus 63 (28%); American Indian or Alaska Native — 14 (6%) versus 13 (6%); Black — 13 (6%) versus 11 (5%); other or not specified — 12 (5%) versus 17 (8%)
• Geographic region: Canada, United States, or western Europe — 85 patients (38%) in each group; rest of the world — 136 (62%) versus 137 (62%)
• ECOG performance status: A score of 0 (fully active) was seen in 156 patients (71%) versus 154 (69%); a score of 1 (restricted in strenuous activity but able to walk and do light work) in 65 (29%) versus 67 (30%)
• PD-L1–positive status: 100% of patients in both groups, as required by the enrollment criteria

Patients' disease status at enrollment was also similar:

• Metastatic at initial diagnosis: 75 patients (34%) in each group
• Recurrent within 6–12 months after completing curative-intent treatment: 40 patients (18%) in each group
• Recurrent more than 12 months after completing curative-intent treatment: 106 (48%) versus 107 (48%)

Metastatic sites at baseline included lymph nodes (159 [72%] versus 154 [69%]), lung (111 [50%] versus 95 [43%]), liver (55 [25%] versus 57 [26%]), bone (61 [28%] versus 45 [20%]), brain (8 [4%] versus 6 [3%]), and other sites such as pleura, skin, soft tissue, chest wall, and muscle (81 [37%] versus 71 [32%]).

Only a small number of patients had previously received anti–PD-1 or anti–PD-L1 therapy in the adjuvant or neoadjuvant setting: 9 patients (4%) in the sacituzumab govitecan group and 11 patients (5%) in the chemotherapy group, based on the clinical database.

Among the 220 patients who actually received chemotherapy plus pembrolizumab, 113 (51%) received a taxane (paclitaxel or nab-paclitaxel), and 107 (49%) received gemcitabine plus carboplatin.

At the data cutoff date of March 3, 2025, the median follow-up was 14.0 months (range, 0.1 to 28.6 months).

Key Finding: Longer Time Before Cancer Progression

The main result of the trial was clear: patients receiving sacituzumab govitecan plus pembrolizumab experienced significantly longer progression-free survival than those receiving chemotherapy plus pembrolizumab.

• Median progression-free survival: 11.2 months (95% confidence interval [CI], 9.3 to 16.7) with sacituzumab govitecan plus pembrolizumab versus 7.8 months (95% CI, 7.3 to 9.3) with chemotherapy plus pembrolizumab
• Hazard ratio for disease progression or death: 0.65 (95% CI, 0.51 to 0.84; two-sided P<0.001)

A hazard ratio of 0.65 means that patients in the sacituzumab govitecan group had a 35% lower risk of their cancer progressing or dying at any given time compared with the chemotherapy group. The P value of less than 0.001 means there is less than a 0.1% chance this result was due to random chance — a result that is considered highly statistically significant.

Put in absolute terms: at 6 months, approximately 72 out of 100 patients (72%, 95% CI 65–77) in the sacituzumab govitecan group were alive without disease progression, compared with 63 out of 100 (63%, 95% CI 56–69) in the chemotherapy group. At 12 months, the difference was larger: approximately 48 out of 100 (48%, 95% CI 41–56) versus 33 out of 100 (33%, 95% CI 26–40). At 18 months, the corresponding figures were about 33 out of 100 versus about 20 out of 100 patients.

The results were consistent when doctors (rather than the blinded central reviewers) assessed progression. Investigator-assessed median progression-free survival was 11.3 months (95% CI, 9.2 to 14.6) with sacituzumab govitecan plus pembrolizumab versus 8.3 months (95% CI, 7.3 to 9.3) with chemotherapy plus pembrolizumab (hazard ratio, 0.67; 95% CI, 0.52 to 0.87).

The progression-free survival benefit was consistent across all predefined patient subgroups, including those defined according to age, disease status, and geographic region.

A total of 109 events of disease progression or death occurred in the sacituzumab govitecan group, compared with 140 in the chemotherapy group.

At the time of the primary analysis, overall survival data were not yet mature. Only 26% of the total number of patients had died, and the median overall survival had not been reached in either group. This means the trial is still ongoing, and longer follow-up will be needed to determine whether the new combination extends life overall.

Of note, 119 patients who stopped chemotherapy plus pembrolizumab went on to receive subsequent treatment. Of these, 96 patients (81%) received sacituzumab govitecan as their next anticancer therapy through the crossover phase. This crossover may affect the final overall survival comparison, because many patients in the chemotherapy group eventually received the investigational drug.

More patients in the sacituzumab govitecan group were still receiving treatment at the data cutoff: 95 patients (43%) versus 52 patients (23%). The most common reasons for stopping the sacituzumab govitecan or chemotherapy were disease progression (in 37% versus 55% of patients) and adverse events (in 8% versus 18%). For pembrolizumab specifically, the most common reasons for discontinuation were disease progression (37% versus 58%) and adverse events (10% versus 14%).

Key Finding: Tumor Shrinkage and Duration of Response

The objective response rate — the percentage of patients whose tumors shrank partially or disappeared completely — was higher with the sacituzumab govitecan combination:

• Objective response rate: 60% (95% CI, 53 to 66) with sacituzumab govitecan plus pembrolizumab versus 53% (95% CI, 46 to 60) with chemotherapy plus pembrolizumab

In absolute terms, this means about 60 out of 100 patients in the sacituzumab govitecan group had their tumors shrink, versus about 53 out of 100 in the chemotherapy group.

Perhaps even more importantly, among patients whose tumors responded, the response lasted substantially longer:

• Median duration of response: 16.5 months (95% CI, 12.7 to 19.5) with sacituzumab govitecan plus pembrolizumab versus 9.2 months (95% CI, 7.6 to 11.3) with chemotherapy plus pembrolizumab

This means that when the cancer did respond to the new combination, the response lasted a median of more than 16 months — nearly twice as long as responses in the chemotherapy group.

Safety and Side Effects

Both treatment combinations caused side effects, and the overall rates of serious side effects were similar between the two groups. The safety profile observed in this trial was consistent with what is already known about these drugs from earlier studies.

• Grade 3 or higher adverse events (severe side effects requiring medical intervention): occurred in 71% of patients receiving sacituzumab govitecan plus pembrolizumab versus 70% of those receiving chemotherapy plus pembrolizumab
• Treatment discontinuation due to adverse events: 12% in the sacituzumab govitecan group versus 31% in the chemotherapy group
• Adverse events leading to death: 3% in each group

One notable finding is that patients receiving chemotherapy plus pembrolizumab were more than twice as likely to stop treatment because of side effects (31% versus 12%). This suggests the sacituzumab govitecan combination may be better tolerated overall, despite similar rates of severe side effects.

Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 27.1 and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The relationship of each event to the trial drugs was assessed by the investigator.

Patients should discuss the specific side effect profiles — including common side effects such as diarrhea, low white blood cell counts (neutropenia), nausea, and fatigue — with their oncology team. The trial publication focuses on overall safety rates; detailed side-effect lists are included in the Supplementary Appendix.

What This Means for Patients

This trial provides strong evidence that sacituzumab govitecan plus pembrolizumab is a more effective first-line treatment than the current standard of chemotherapy plus pembrolizumab for patients with PD-L1–positive advanced triple-negative breast cancer. The benefit was seen in an international, diverse patient population treated at 186 sites across 28 countries.

The key takeaways for patients are:

• Better progression-free survival: The new combination delayed cancer growth by an average of about 3.4 additional months compared with standard treatment (11.2 months versus 7.8 months). Longer follow-up will determine whether this translates into longer overall survival.
• More durable responses: When tumors responded, they stayed under control nearly twice as long with sacituzumab govitecan (16.5 months versus 9.2 months). This durability can matter more than the initial response rate.
• Fewer treatment discontinuations: Only 12% of patients stopped the sacituzumab govitecan combination due to side effects, versus 31% in the chemotherapy group — a potentially important quality-of-life consideration.
• A meaningful treatment option: Sacituzumab govitecan is already approved and available for later-line treatment of metastatic TNBC. Its use earlier in the disease course, in combination with pembrolizumab, may become a new standard of care.

For patients newly diagnosed with PD-L1–positive advanced triple-negative breast cancer, this study supports discussing sacituzumab govitecan plus pembrolizumab with their oncologist as a potential first-line treatment option.

Study Limitations

Every clinical trial has limitations, and it is important for patients to understand what this study could and could not show.

• Overall survival data are immature. Only 26% of patients had died at the time of data cutoff, and median overall survival was not reached in either group. It remains unknown whether the new combination improves how long patients live, not just how long they live without cancer progression.
• Crossover may dilute survival differences. Because 81% of patients in the chemotherapy group who received subsequent therapy went on to receive sacituzumab govitecan, any eventual difference in overall survival between the two groups may be smaller than the true benefit of the drug.
• The trial was open-label. Both patients and doctors knew which treatment was being given. Although the primary end point was assessed by blinded independent central review (which reduces bias), open-label designs can still influence patient-reported outcomes and management decisions.
• The population was limited to PD-L1–positive patients. These results apply only to patients whose tumors have a CPS of 10 or higher. They do not apply to the roughly 60% of triple-negative breast cancer patients whose tumors are PD-L1–negative.
• Only female patients were enrolled. Although triple-negative breast cancer occurs overwhelmingly in women, the results may not fully apply to the rare male patients with this disease.
• No health-related quality-of-life data were reported in this publication. Patient-reported outcomes were collected but not included in this report, so we cannot yet assess whether the longer progression-free survival translates into better quality of life.
• The 95% confidence intervals for secondary end points (such as response rate and duration of response) were not adjusted for multiple comparisons, meaning those results should be interpreted with some caution.

Questions to Ask Your Doctor

If you or a loved one has been diagnosed with PD-L1–positive advanced triple-negative breast cancer, this research may be relevant to your treatment discussions. Consider asking your oncology team the following questions:

1. Is my tumor PD-L1 positive? — Ask about your combined positive score (CPS) and whether it is 10 or higher, since this trial only included patients with CPS of 10 or above.
2. Would sacituzumab govitecan plus pembrolizumab be an appropriate first-line treatment for me? — This combination is not yet universally approved, so availability and insurance coverage may vary by region.
3. What are the expected side effects? — Ask specifically about diarrhea, low blood counts, nausea, fatigue, and immune-related side effects from pembrolizumab, and how these would be managed.
4. What chemotherapy options would I otherwise receive? — The trial compared the new combination with taxane-based or gemcitabine–carboplatin regimens, so ask how those compare in your situation.
5. Is there a clinical trial I might qualify for? — If the combination is not yet approved where you live, a clinical trial may be an avenue to access it.
6. What are my options if the first treatment stops working? — In this trial, patients could receive sacituzumab govitecan after progression, so ask about sequencing of treatments.

The results of this trial are encouraging, but treatment decisions are always personal. Your medical team can help you weigh the potential benefits against the risks based on your specific situation.

Frequently Asked Questions

What is triple-negative breast cancer and why is it hard to treat?

Triple-negative breast cancer (TNBC) is an aggressive subtype that lacks estrogen, progesterone, and HER2 receptors, so hormone or HER2-targeted therapies don't work. About 40% of TNBC cases are PD-L1 positive, meaning they have a protein that can be targeted by immunotherapy. This makes treatment challenging, but new combinations are being studied.

Who was eligible for this clinical trial?

The trial enrolled adults with advanced triple-negative breast cancer that was PD-L1 positive (CPS of 10 or higher), had not received prior therapy for advanced disease, and was either metastatic or locally advanced unresectable. Patients had to have confirmed triple-negative status and no prior treatment for advanced disease. Both women and men were eligible, but only women enrolled.

What were the main results of the trial?

In the trial of 443 patients, those receiving sacituzumab govitecan plus pembrolizumab lived without cancer progression for a median of 11.2 months, compared to 7.8 months for those on chemotherapy plus pembrolizumab. This was a 35% reduction in risk of progression or death, and the difference was highly statistically significant.

What side effects were seen with the new combination?

Severe side effects (grade 3 or higher) occurred in 71% of patients on sacituzumab govitecan plus pembrolizumab versus 70% on chemotherapy plus pembrolizumab. However, fewer patients stopped treatment due to side effects with the new combination (12% versus 31%). Common side effects included diarrhea, low white blood cell counts, nausea, and fatigue.

Is this new treatment available now?

Sacituzumab govitecan is already approved for later-line treatment of metastatic triple-negative breast cancer, but its use in combination with pembrolizumab as first-line therapy is not yet universally approved. Availability and insurance coverage may vary by region, so patients should discuss with their oncologist and consider clinical trials if not approved.

What are the limitations of this study?

Overall survival data are not yet mature, so it's unknown if the new combination improves how long patients live. The trial was open-label, and many patients in the chemotherapy group later received sacituzumab govitecan, which may dilute survival differences. Results apply only to PD-L1-positive patients with CPS of 10 or higher.

I have PD-L1-positive advanced triple-negative breast cancer and my doctor recommends sacituzumab govitecan plus pembrolizumab as first-line treatment. Should I get a second opinion before starting?

A second opinion can help confirm that sacituzumab govitecan plus pembrolizumab is the right first-line choice for your PD-L1-positive advanced triple-negative breast cancer. This trial showed it delays cancer growth longer than chemotherapy plus pembrolizumab (median 11.2 vs 7.8 months) and responses last nearly twice as long. However, overall survival data are not yet mature, and the combination may not be universally approved or covered. A second opinion can also clarify side effects and alternative options. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article: "Sacituzumab Govitecan plus Pembrolizumab for Advanced Triple-Negative Breast Cancer" by S.M. Tolaney, E. de Azambuja, K. Kalinsky, S. Loi, S.-B. Kim, C. Yam, B. Rapoport, S.-A. Im, B. Pistilli, W. Mchayleh, D.W. Cescon, J. Watanabe, M.A.L. Bañuelas, R. Freitas-Junior, J. Salvador Bofill, M. Afshari, D. Gary, L. Wang, C. Lai, and P. Schmid, for the ASCENT-04/KEYNOTE-D19 Clinical Trial Investigators.

Publication: The New England Journal of Medicine, 2026; volume 394, pages 354–366. DOI: 10.1056/NEJMoa2508959.

Trial registration: ClinicalTrials.gov number NCT05382286. Funded by Gilead Sciences, conducted in collaboration with Merck Sharp and Dohme (a subsidiary of Merck).

This patient-friendly article is based on peer-reviewed research published in The New England Journal of Medicine. It is intended for educational purposes and does not constitute medical advice. Always consult your healthcare team about diagnosis and treatment options.