First-Line Sacituzumab Govitecan Plus Pembrolizumab Delivers Efficacy Benefit in mTNBC

The combination of sacituzumab govitecan-hziy (Trodelvy) and pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) compared with chemotherapy plus pembrolizumab as a frontline treatment for patients with PD-L1–positive, locally advanced unresectable or metastatic triple-negative breast cancer (mTNBC), according to findings from the phase 3 ASCENT-04/KEYNOTE-D19 trial (NCT05382286) published in the New England Journal of Medicine.¹

At a median follow-up of 14.0 months (range, 0.1-28.6), the median PFS as assessed by blinded independent central review (BICR) was 11.2 months (95% CI, 9.3-16.7) in the sacituzumab govitecan/pembrolizumab arm (n = 221) vs 7.8 months (95% CI, 7.3-9.3) in the chemotherapy/pembrolizumab arm (n = 222; HR, 0.65; 95% CI, 0.51-0.84; P < .001). The 12-month PFS rate was 48% (95% CI, 41%-56%) in the investigational arm vs 33% (95% CI, 26%-40%) in the control arm. Overall survival (OS) data were immature at the time of the primary analysis.

“The benefit with respect to PFS, along with a longer duration of response [DOR] and a lower likelihood of treatment discontinuation than with chemotherapy plus pembrolizumab, highlights sacituzumab govitecan plus pembrolizumab as an advancement in improving treatment outcomes for this difficult-to-treat patient population,” lead study author Sara M. Tolaney, MD, MPH, and coauthors wrote in the discussion of the data.

Tolaney is chief of the Division of Breast Oncology and associate director of the Susan F. Smith Center for Women's Cancers, as well as a senior physician, at Dana-Farber Cancer Institute in Boston, Massachusetts. She is also an associate professor of medicine at Harvard Medical School.

What was the design of the ASCENT-04 trial?

This open-label, international trial enrolled adult patients with locally advanced unresectable or metastatic TNBC who had received no prior therapy for advanced disease and whose tumors were PD-L1 positive (defined as having a combined positive score ≥ 10). Patients were randomly assigned 1:1 to receive:

• sacituzumab govitecan at 10 mg/kg intravenously (IV) on days 1 and 8 plus pembrolizumab at 200 mg IV on day 1 of each 21-day cycle; or
• physician’s choice of chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) plus pembrolizumab at 200 mg on day 1 of each 21-day cycle.

Treatment continued until disease progression, unacceptable toxicity, or death. PFS by BICR served as the primary end point. Secondary end points included OS, objective response rate (ORR), DOR, time to response (TTR), and safety.

What were the baseline characteristics of the ASCENT-04 trial population?

Between October 17, 2022, and August 21, 2024, a total of 443 patients were enrolled. The median age was 54 years (range, 23-88) in the sacituzumab govitecan arm vs 55 years (range, 27-82) in the chemotherapy arm. All patients were women and had PD-L1–positive disease, and most patients in the respective arms had an ECOG performance status of 0 (71% vs 69%). Disease status at random assignment in both arms included metastatic at initial diagnosis (34%), recurrent within 6 to 12 months after curative-intent treatment (18%), and recurrent more than 12 months after curative-intent treatment (48%).

What additional efficacy findings were observed with sacituzumab govitecan plus pembrolizumab in TNBC?

The ORR was 60% (95% CI, 53-66) in the sacituzumab govitecan/pembrolizumab group, including a complete response (CR) rate of 13% and a partial response (PR) rate of 47%. In the chemotherapy/pembrolizumab group, the ORR was 53% (95% CI, 46-60; OR, 1.3; 95% CI, 0.9-1.9), with a CR rate of 8% and a PR rate of 45%.

Among responders, the median DOR was significantly longer with sacituzumab govitecan plus pembrolizumab, at 16.5 months (95% CI, 12.7-19.5) compared with 9.2 months (95% CI, 7.6-11.3) in the chemotherapy arm. The median TTR was 1.9 months in both treatment groups. Subgroup analyses showed that the PFS benefit with the antibody-drug conjugate (ADC)-based combination was consistent across predefined patient subgroups, including age, geographic region, and disease status.

What was the safety profile of sacituzumab govitecan plus pembrolizumab in ASCENT-04?

The safety profile of the combination was consistent with the known toxicities of each individual agent. Grade 3 or higher adverse effects (AEs) were reported in 71% of patients who received the sacituzumab govitecan–based combination and 70% of those who received chemotherapy plus pembrolizumab. Notably, the incidence of treatment discontinuation due to AEs was lower in the sacituzumab govitecan arm (12%) than in the chemotherapy arm (31%).

The most common AEs in the sacituzumab govitecan/pembrolizumab arm included the following:

• Diarrhea (any grade, 70%; grade ≥ 3, 10%)
• Nausea (68%; 3%)
• Neutropenia (63%; 43%)
• Fatigue (58%; 8%)
• Alopecia (52%; 0%)

Serious AEs occurred in 38% of patients in the sacituzumab govitecan arm vs 31% of those in the chemotherapy arm. Immune-mediated AEs were reported less frequently with the ADC-based combination (30%) than with chemotherapy plus pembrolizumab (40%).

“What we saw with the [sacituzumab govitecan/pembrolizumab] combination was that there was really no additive toxicity,” Tolaney said in an interview with OncLive following the presentation of updated safety data from ASCENT-04 at the 2025 San Antonio Breast Cancer Symposium.² “Numerically, there were fewer immune-related AEs with sacituzumab govitecan plus pembrolizumab compared with chemotherapy plus pembrolizumab, [which] was reassuring.”

What additional findings have been seen with first-line sacituzumab govitecan in TNBC?

Notably, in the phase 3 ASCENT-03 trial (NCT05382299), sacituzumab govitecan monotherapy elicited a median PFS by BICR of 9.7 months (95% CI, 8.1-11.1) vs 6.9 months (95% CI, 5.6-8.2) with chemotherapy (HR, 0.62; 95% CI, 0.50-0.77; P < .001) in patients with previously untreated, locally advanced unresectable mTNBC who were not eligible to receive PD-1/PD-L1 inhibition.³ The 12-month PFS rates in these respective arms were 41% (95% CI, 34%-47%) and 24% (95% CI, 19%-30%).

Notably, based on the ASCENT-03 and ASCENT-04 data, the National Comprehensive Cancer Network updated its Clinical Practice Guidelines in Oncology for breast cancer to include sacituzumab govitecan monotherapy as a category 1 preferred regimen for the first-line treatment of patients with mTNBC whose disease is PD-L1 negative and has no germline BRCA1/2 pathogenic variants, as well as in combination with pembrolizumab for the treatment of patients with mTNBC whose disease is PD-L1 positive.⁴

What are the next steps for evaluating sacituzumab govitecan in breast cancer?

“The findings from the ASCENT-04/KEYNOTE-D19 and ASCENT-03 trials support the use of sacituzumab govitecan as a potential backbone treatment option, with or without pembrolizumab, for patients with previously untreated, locally advanced unresectable or metastatic [TNBC],” the ASCENT-04 authors concluded.¹

Ongoing phase 3 trials, such as ASCENT-05 (NCT05633654) and SASCIA (NCT04595565), are further evaluating the role of sacituzumab govitecan in earlier high-risk breast cancer settings, including as adjuvant and neoadjuvant treatment.

References

1. 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
2. Tolaney SM. Dr Tolaney on updated safety findings with sacituzumab govitecan plus pembrolizumab in PD-L1–positive TNBC. OncLive. December 23, 2025. Accessed March 18, 2026. https://www.onclive.com/view/dr-tolaney-on-updated-safety-findings-with-sacituzumab-govitecan-plus-pembrolizumab-in-pd-l1-positive-tnbc
3. Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Ann Oncol. 2025;36(suppl 2):S1565-S1566. doi:10.1016/j.annonc.2025.09.030
4. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2026. Accessed March 18, 2026. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf