Sacituzumab Govitecan Plus Pembrolizumab in PD-L1-Positive Triple-Negative Breast Cancer

Key Clinical Summary:

• Sacituzumab govitecan plus pembrolizumab significantly improved progression-free survival compared with chemotherapy plus pembrolizumab in previously untreated, PD-L1–positive metastatic triple-negative breast cancer, representing a clinically meaningful frontline benefit.
• The trial validates the biologic rationale for combining Trop-2–directed antibody-drug conjugates with checkpoint inhibition, supporting synergistic activity through immunogenic cell death and immune activation mechanisms.
• With overall survival data still maturing but trending favorably, the combination has been incorporated into NCCN guidelines and is positioned to become a new first-line standard of care pending regulatory approval.

Sara Tolaney, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses results from the phase 3 ASCENT-04 trial evaluating sacituzumab govitecan plus pembrolizumab vs pembrolizumab plus chemotherapy in previously untreated patients with PD-L1–positive, locally advanced unresectable or metastatic triple-negative breast cancer (TNBC).

Results demonstrated that sacituzumab govitecan plus pembrolizumab significantly prolonged progression-free survival (PFS) and suggest that incorporation of a Trop-2–directed therapy into first-line immunotherapy-based treatment may improve disease control, supporting further evaluation of this combination in clinical practice.

Transcript: 

My name is Sara Tolaney and I’m a breast oncologist at Dana-Farber Cancer Institute. Today, we’ll be discussing the data from the ASCENT-04 trial. This is a phase 3, randomized study of sacituzumab govitecan in combination with pembrolizumab compared to chemotherapy and pembrolizumab in patients who have metastatic triple-negative breast cancer that has previously been untreated in the metastatic setting and patients who have tumors that are PD-L1 positive, those patients who aren’t candidates to receive immunotherapy.

Traditionally we've had chemotherapy and pembrolizumab as the first line standard of care for this particular patient population based on the KEYNOTE-355 study however, we have seen data for the use of sacituzumab govetecan, a Trop-2-directed antibody-drug conjugate that has a Topo1 payload, in patients who have pretreated metastatic triple negative disease where we've seen that when compared to standard chemotherapy, sacituzumab really has a dramatic improvement in both progression-free and overall survival. So there was a lot of interest in trying to move sacituzumab up from that pretreated population into the first line setting and we also knew that there was a lot of data suggesting that ADCs may actually work synergistically with checkpoint inhibition knowing that they can cause immunogenic cell death and enhance EDCC. The ASCENT-04 trial was really designed to test if sacituzumab and pembrolizumab would do better than chemotherapy in pembrolizumab in this upfront PD-L1-positive population.

In fact, what we saw was that the combination of sacituzumab and pembrolizumab led to a significant improvement in progression-free survival when compared to chemo/pembro going from 7.8 to 11.2 months with a hazard ratio of 0.65– really a 3.4 month improvement between the 2 arms and I think a very clinically meaningful improvement. The data for overall survival are still immature, but there is a slight trend favoring sacituzumab and pembrolizumab over chemotherapy and pembrolizumab. 

Currently the sacituzumab and pembrolizumab combination is now part of the NCCN guidelines and we are eagerly awaiting hopefully an FDA approval for this combination so that it will become a standard of care therapy in this first line setting.

Source: 

Tolaney SM, De Evandro A, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. Published online: January 21, 2026. doi:10.1056/NEJMoa2508959