Sacituzumab or Chemotherapy for First-Line Treatment of Triple-Negative Breast Cancer?

First-Line Treatment Options in Triple-Negative Breast Cancer Are Being Reshaped

The breast cancer subtype known as triple-negative breast cancer – TNBCis among the more difficult subtypes to treat because of its aggressive biology, tendency to metastasize rapidly and lack of hormone receptors and HER2 targets. Treatment options are particularly limited in advanced disease.

The KEYNOTE-355 study, published in 2020, marked a turning point for this patient population. In the study, pembrolizumab (anti–PD-1) combined with chemotherapyprovided significantly longer progression-free survival (PFS) than chemotherapy alone. In PD-L1-positive advanced TNBC, this combination therefore became the first-line standard of care . However, even with this treatment:

• Median PFS was only 9.7 months approximately

• The 3-year survival rate was approximately 36% overall

• Furthermore, severe chemotherapy-related toxicities prevented many patients from continuing treatment.

Against this background, findings presented at ASCO 2025 as abstract LBA109 from the ASCENT-04 / KEYNOTE-D19 studyprovided strong data that could usher in a new era in the treatment of PD-L1-positive advanced TNBC.

The study showed that replacing chemotherapy with sacituzumab govitecan , an antibody-drug conjugate (ADC), significantly improved progression-free survival and nearly doubled the duration of response . Moreover, this came with fewer treatment discontinuations and manageable side effects...

Let us take a closer look at this striking study.

Study Design: SG + Pembro vs Chemo + Pembro

In this phase 3 randomized study, patients who had not previously received systemic treatment and had PD-L1-positive (CPS ≥10) advanced TNBC were assigned to two arms, with 443 patients in total:

• 221 patients: Sacituzumab govitecan (SG) + pembrolizumab

• 222 patients: Investigator's choice of chemotherapy (gemcitabine + carboplatin, paclitaxel or nab-paclitaxel) + pembrolizumab

Key Findings: A Clear Difference in Progression-Free Survival

• Median PFS:

  • SG + Pembro: 11.2 months

  • Chemo + Pembro: 7.8 months

  • HR: 0.65 (95% CI: 0.51–0.84, p = 0.0009)

• Median Duration of Response (DOR):

  • SG + Pembro: 16.5 months

  • Chemo + Pembro: 9.2 months

• Objective Response Rate (ORR):

  • SG + Pembro: 59.7%

  • Chemo + Pembro: 53.2%

These data show that sacituzumab + pembrolizumab not only provided longer disease control, but also nearly doubled the duration of response.

Safety Profile and Treatment Continuation

• Grade ≥3 adverse events:

  • SG + Pembro: neutropenia (43%), diarrhea (10%)

  • Chemo + Pembro: neutropenia (45%), anemia (16%), thrombocytopenia (14%)

• Treatment discontinuation rate:

  • SG + Pembro: 12%

  • Chemo + Pembro: 31%

The sacituzumab combination therefore stands out for fewer treatment discontinuations and a more manageable toxicity profile.

Does Trop-2 Expression Matter?

Sacituzumab govitecan is an antibody-drug conjugate (ADC) targeting the Trop-2 protein on tumor cells. Although progression-free survival was longer in Trop-2-positive tumors, in the study the SG combination provided benefit regardless of Trop-2 level. This indicates that the treatment could be applicable to a broad patient population.

Clinical Applications and Future Perspective

Presenting the study, Dr. Sara Tolaney said, “This combination could be a turning point in oncology practice,” emphasizing that it could find a place in first-line treatment.

Conclusion: A New First-Line Standard?

The current results strongly support the possibility that sacituzumab govitecan + pembrolizumab could become a new first-line standard of care in PD-L1-positive advanced TNBC. Following FDA approval, this combination is expected to be rapidly integrated into clinical practice.