Sacituzumab Govitecan + Pembrolizumab: A New First-Line Standard in PD-L1-Positive Metastatic TNBC
At the 2025 ASCO Annual Meeting, new results from the ASCENT-04/KEYNOTE-D19 trial marked a potential paradigm shift in the treatment of PD-L1-positive, locally advanced or metastatic triple-negative breast cancer (TNBC). The combination of sacituzumab govitecan (SG) — an antibody-drug conjugate targeting Trop-2 — with pembrolizumab significantly improved progression-free survival (PFS) compared to the current standard of pembrolizumab plus chemotherapy.
Study Overview: ASCENT-04
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Patient population: 443 women
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Inclusion criteria: De novo metastatic TNBC or relapse ≥6 months after completing systemic therapy for early-stage disease
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PD-L1 status: All patients had a combined positive score (CPS) ≥10
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~40% of tumors expressed Trop-2, the target of SG
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Randomized groups:
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SG + Pembrolizumab group (n = 221): SG 10 mg/kg on day 1 and 8 + pembrolizumab 200 mg on day 1 every 21 days, for up to 35 cycles
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Chemo + Pembrolizumab group (n = 222): Pembrolizumab + physician’s choice of chemo (gemcitabine/carboplatin or paclitaxel/nab-paclitaxel)
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Key Efficacy Results
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Median PFS:
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SG + pembrolizumab: 11.2 months
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Chemo + pembrolizumab: 7.8 months
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➤ 35% reduction in risk of progression (HR: 0.65; P = .0009)
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Median duration of response (DoR):
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SG group: 16.5 months
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Chemo group: 9.2 months
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Overall survival (OS):
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Still maturing, but shows favorable trend for SG group (HR: 0.89)
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Trop-2 expression:
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Greater Trop-2 expression enhanced SG benefit, but efficacy was observed regardless of Trop-2 status, eliminating the need for biomarker pre-selection
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Safety and Tolerability
|
Adverse Events (Grade 3–4, ≥10%) |
SG + Pembrolizumab |
Chemo + Pembrolizumab |
|
Neutropenia |
43% |
45% |
|
Diarrhea |
10% |
<10% |
|
Anemia |
<10% |
16% |
|
Thrombocytopenia |
<10% |
14% |
|
Serious adverse events (SAEs) |
38 patients |
31 patients |
Although SAEs were slightly higher in the SG group, there were fewer dose reductions and discontinuations compared to the chemo group. No new safety signals were reported.“We’ve used both agents independently, and with this combination showing such promise — and no new safety concerns — oncologists will likely feel confident implementing it in practice,”— Dr. Jane Meisel, Emory University
Expert Commentary
“I believe this regimen should become the new standard of care for PD-L1-positive metastatic TNBC in the first-line setting.”— Dr. Sara Tolaney, Dana-Farber Cancer Institute
“This is truly a game-changer. I look forward to seeing this approach make its way into clinical guidelines.”— Dr. Jane Meisel, Emory University
“Sacituzumab govitecan is already approved in later-line metastatic settings, and these data will likely shift it earlier in treatment.”— Dr. Julie Gralow, University of Washington
Clinical Implications
Sacituzumab govitecan is currently FDA-approved for third-line treatment of metastatic TNBC. Based on the compelling ASCENT-04 results, experts anticipate this combination with pembrolizumab will become a new first-line treatment standard for PD-L1-positive TNBC.
This shift could help address the unmet need in this aggressive breast cancer subtype, where current 3-year survival rates remain below 40%.
Conclusion
The ASCENT-04 trial represents a critical advancement in metastatic TNBC care. With improved PFS, a longer duration of response, a manageable safety profile, and activity regardless of Trop-2 status, the SG + pembrolizumab combination stands poised to redefine front-line treatment for patients with PD-L1-positive disease.
Source
Sacituzumab or Chemo in First-Line TNBC: Which Is Better? - Medscape - May 31, 2025.
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