Triple-negative breast cancer (TNBC) represents one of the cancer subtypes with the poorest prognosis today. Its name comes from its lack of expression of estrogen receptors, progesterone receptors, and HER2. This absence limits the use of hormonal therapies or anti-HER2 treatments, historically leaving chemotherapy as one of the main tools to try to combat this disease. However, patients who respond to chemotherapy still have a high risk of relapse within 5 years, which is why TNBC remains, to this day, one of the greatest challenges in modern oncology.
Recently, in June 2026, the FDA approved sacituzumab govitecan-hziy, commercially known as Trodelvy, for two indications in adults with unresectable locally advanced or metastatic triple-negative breast cancer. One was as first-line monotherapy for patients who are not candidates for PD-1 or PD-L1 inhibitors. The other, more relevant to this discussion, was its use in combination with pembrolizumab for patients whose tumors express PD-L1. This approval was mainly supported by the ASCENT-04/KEYNOTE-D19 clinical trial, where the combination of sacituzumab govitecan plus pembrolizumab showed a positive effect by increasing patients’ progression-free survival to 11.2 months, compared with 7.8 months with another treatment regimen.
To understand the basis of this combination, we first need to look at sacituzumab govitecan. This drug belongs to a family known as antibody-drug conjugates, or ADCs. An ADC works like a therapeutic “Trojan horse”: it has one part that recognizes a molecule on the tumor and another part that carries a therapeutic payload. In this case, the antibody targets TROP-2, a membrane protein frequently expressed in epithelial tumors and particularly relevant in triple-negative breast cancer. The payload it carries is SN-38, the active metabolite of irinotecan, a topoisomerase I inhibitor.
Topoisomerase I is an enzyme that helps the cell manage DNA tension during replication. When SN-38 inhibits this enzyme, DNA becomes damaged, the tumor cell loses its ability to divide properly, and it may undergo cell death. Importantly, sacituzumab govitecan does not release this payload in a completely indiscriminate way: by binding to TROP-2, it helps deliver the drug to tumor cells that express this target, releasing it inside the tumor and also affecting nearby tumor cells that may express TROP-2.
This is especially valuable in triple-negative breast cancer, since different cells within the same lesion can have different levels of TROP-2, distinct metabolic states, and varying degrees of treatment sensitivity. A therapy that depends too heavily on perfect target expression could allow resistant subpopulations to escape. However, because of its potent and diffusible cytotoxic activity, sacituzumab govitecan-hziy offers a more flexible way to attack a biologically heterogeneous tumor.
But the FDA-approved combination does not only focus on killing tumor cells. The second drug, pembrolizumab, acts on another layer of the disease: the relationship between the tumor and the immune system. Pembrolizumab is an antibody against PD-1, a receptor present on activated T cells that acts as an immune brake. Under normal conditions, this brake prevents excessive immune responses. In cancer, however, many tumor cells or cells within the microenvironment express PD-L1, which binds to PD-1 and reduces T-cell activity. In simple terms, the tumor learns how to partially “turn off” the immune cells that should be attacking it.
By blocking PD-1, pembrolizumab helps release this brake. It does not create an immune response from scratch, but it can enhance or reignite an existing antitumor response, especially in tumors where there are already signs of immune interaction.
Figure 1. Sacituzumab govitecan delivers SN-38 into tumor cells, causing DNA damage and immunogenic tumor cell death, while pembrolizumab helps reactivate T cells by blocking PD-1, enhancing immune-mediated tumor destruction.
So, what does sacituzumab govitecan add to pembrolizumab?
The key is that tumor damage is not only destruction; it can also be immunological information. When a tumor cell dies from DNA damage, it can release antigens, stress signals, and molecules associated with cellular damage. These signals can be captured by immune cells such as dendritic cells, which process tumor antigens and present them to T cells. In other words, killing tumor cells in an immunologically active way can make the tumor more visible to the immune system.
This concept is known as immunogenic cell death, or ICD. Not all forms of cell death awaken the immune system in the same way. In the case of sacituzumab govitecan, it has been proposed that its SN-38 payload and DNA damage may contribute to generating ICD. Therefore, this combination can be understood as a two-step strategy. First, sacituzumab govitecan acts as a targeted therapy with a cytotoxic payload: it recognizes TROP-2, delivers SN-38, induces DNA damage, and reduces tumor burden. Second, pembrolizumab attempts to sustain the immune response by preventing the PD-1/PD-L1 pathway from turning off T cells. If the ADC increases the release of antigens and inflammatory signals, pembrolizumab may help prevent that response from becoming blocked within the tumor microenvironment.
This does not mean that the combination is a cure or that all patients will respond. Triple-negative breast cancer remains heterogeneous, aggressive, and capable of developing resistance. For this reason, the future will likely depend on more refined biomarkers: not only PD-L1, but also immune infiltration, TROP-2 expression, DNA repair status, mutational burden, interferon signatures, and the composition of the tumor microenvironment.
It is also important to discuss safety. Sacituzumab govitecan has relevant warnings, especially diarrhea and neutropenia, as well as nausea, vomiting, hypersensitivity reactions, and considerations for patients with reduced UGT1A1 activity. Pembrolizumab, on the other hand, can cause immune-mediated adverse events because, by releasing the immune brake, it can also promote inflammation in healthy tissues. This may involve the skin, thyroid, lungs, liver, colon, or other organs. The therapeutic promise must always be accompanied by careful clinical monitoring.
Overall, sacituzumab govitecan plus pembrolizumab represents an important evolution in the treatment of advanced PD-L1-positive triple-negative breast cancer. It is not simply about replacing one chemotherapy with another. It is about integrating molecular precision, targeted tumor damage, and immunotherapy into a single strategy.
Main reference:
FDA approves sacituzumab govitecan-hziy as monotherapy and in combination with pembrolizumab for first-line treatment of triple-negative breast cancer. (2026, junio 24). U.S. Food and Drug Administration; FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sacituzumab-govitecan-hziy-monotherapy-and-combination-pembrolizumab-first-line
Other references:
Tolaney, S. M., de Azambuja, E., Kalinsky, K., Loi, S., Kim, S. B., Yam, C., Rapoport, B., Im, S. A., Pistilli, B., Mchayleh, W., Cescon, D. W., Watanabe, J., Bañuelas, M. A. L., Freitas-Junior, R., Salvador Bofill, J., Afshari, M., Gary, D., Wang, L., Lai, C., Schmid, P., … ASCENT-04/KEYNOTE-D19 Clinical Trial Investigators (2026). Sacituzumab Govitecan plus Pembrolizumab for Advanced Triple-Negative Breast Cancer. The New England journal of medicine, 394(4), 354–366. https://doi.org/10.1056/NEJMoa2508959
Bardia, A., Hurvitz, S. A., Tolaney, S. M., Loirat, D., Punie, K., Oliveira, M., Brufsky, A., Sardesai, S. D., Kalinsky, K., Zelnak, A. B., Weaver, R., Traina, T., Dalenc, F., Aftimos, P., Lynce, F., Diab, S., Cortés, J., O’Shaughnessy, J., Diéras, V., Ferrario, C., … ASCENT Clinical Trial Investigators (2021). Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. The New England journal of medicine, 384(16), 1529–1541. https://doi.org/10.1056/NEJMoa2028485
