NCCN Guidelines Add Novel Therapeutics to First-Line TNBC Armamentarium

The National Comprehensive Cancer Network (NCCN) updated the Clinical Practice Guidelines in Oncology to recommend sacituzumab govitecan-hziy (Trodelvy) as a category 1 preferred regimen for the first-line treatment of patients with metastatic triple-negative breast cancer (TNBC), according to a news release from the developer, Gilead.¹

This update followed the publication of data from the phase 3 ASCENT-03 (NCT05382299) and ASCENT-04/KEYNOTE-D19 trials (NCT05382286), which established sacituzumab govitecan, both as a monotherapy and in combination with pembrolizumab (Keytruda), as a significant therapeutic advancement.^2,3 The guideline update specifically included sacituzumab govitecan for patients with PD-L1-negative tumors or for those who were previously treated with a taxane in the neoadjuvant or adjuvant setting.

Supporting Efficacy Data

The guideline update was supported by significant survival and response data across 2 distinct patient populations. In the ASCENT-04/KEYNOTE-D19 trial, which evaluated the combination of sacituzumab govitecan and pembrolizumab in patients with PD-L1-positive, metastatic TNBC, the median progression-free survival (PFS) reached 11.2 months (95% CI, 9.3-16.7) with sacituzumab govitecan plus pembrolizumab vs 7.8 month (95% CI, 7.3-9.3) in the group receiving the standard combination of chemotherapy and pembrolizumab (HR, 0.65; 95% CI, 0.51-0.84; P <.001). Furthermore, the overall survival (OS) data were not mature at the time of analysis. The objective response rate (ORR) was reported at 60% (95% CI, 53%-66%) for the sacituzumab govitecan combination and 53% (95% CI, 46%-60%) for the control group.

In the ASCENT-03 study, which focused on sacituzumab govitecan as a monotherapy for patients with PD-L1-negative metastatic TNBC or those not eligible for PD-L1 therapy, the median PFS was 9.7 months (95% CI, 8.1-11.1) vs 6.9 months (95% CI, 5.6-8.2) for those receiving the treatment of physician’s choice (TPC; HR, 0.62; 95% CI, 0.50-0.77; P <.001). The ORR for the sacituzumab govitecan arm was 48% (95% CI, 42%-54%), while the TPC arm reached 46% (95% CI, 40%-52%).

Trial Design

The ASCENT-04/KEYNOTE-D19 trial was a phase 3, open-label, global study comparing the efficacy of sacituzumab govitecan in combination with pembrolizumab vs a control arm receiving investigator's choice of chemotherapy, which was gemcitabine plus carboplatin, nab-paclitaxel, or paclitaxel, plus pembrolizumab. Patients were randomly assigned to receive sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle with 200 mg of intravenous pembrolizumab on day 1 of 21-day cycles, or chemotherapy plus pembrolizumab.

The phase 3 ASCENT-03 trial compared sacituzumab govitecan monotherapy vs TPC. The TPC options available to investigators included paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin.

Both trials were designed to assess whether sacituzumab govitecan could provide a more effective first-line option for patients with locally advanced inoperable or metastatic TNBC.

The ASCENT-04 trial enrolled 443 patients with previously untreated locally advanced inoperable or metastatic TNBC whose tumors expressed PD-L1 with a combined positive score (CPS) of 10 or greater. The ASCENT-03 trial enrolled 558 patients with previously untreated locally advanced inoperable or metastatic TNBC who either had PD-L1-negative tumors or were not considered candidates for PD-L1-directed therapy. All patients across both trials had not received prior systemic therapy for metastatic disease.

The primary end point for both the ASCENT-04 and ASCENT-03 trials was PFS as determined by blinded independent central review. Secondary end points included OS, ORR, duration of response, and safety.

Safety Data

The safety profile of sacituzumab govitecan was consistent with prior studies of the agent. In the ASCENT-04 trial, grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 71% of patients in the combination arm and 70% of patients in the control group. The most frequent grade 3 or higher TRAEs in the combination arm were neutropenia (43% vs 45%), anemia (7% vs 16%), and diarrhea (10% vs 2%). Discontinuation of treatment due to AEs occurred in 12% of patients in the sacituzumab govitecan plus pembrolizumab group and 31% of patients in the control arm.

In the ASCENT-03 trial, grade 3 or higher TRAEs were reported in 66% of patients receiving sacituzumab govitecan monotherapy, compared with 62% of patients in the TPC arm.⁴ Neutropenia (67% vs 57%), diarrhea (54% vs 20%), and anemia (39% vs 50%) were among the most common AEs in the monotherapy and control arms, respectively. The rate of treatment discontinuation due to adverse effects was 4% for the sacituzumab govitecan group and 12% for the TPC group. No new safety signals were identified in either trial.

References

1. Trodelvy® added as preferred regimen within first-line metastatic triple-negative breast cancer in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). News release. Gilead. Updated February 27, 2026. Accessed March 18, 2026. https://tinyurl.com/ye28utcv
2. Cortés J, Punie K, Barrios C, et al. Sacituzumab govitecan in untreated, advanced triple-negative breast cancer. N Engl J Med. 2025;393(19):1912-1925. 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. Hurvitz A, Bardia A, Tolaney SM, et al. Safety analysis of ASCENT-03, a phase 3 study of sacituzumab govitecan vs chemotherapy for previously untreated advanced triple-negative breast cancer in patients who are not candidates for PD-(L)1 inhibitors. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; Houston, TX. Poster PS1-13-24.