European Commission Broadens Trodelvy’s First-Line Use in Metastatic Triple-Negative Breast Cancer Regardless of PD-L1 Status
Gilead Sciences, Inc.announced that the European Commission (EC) has granted marketing authorization for Trodelvy® (sacituzumab govitecan-hziy) in combination with Keytruda® (pembrolizumab) for the first-line treatment of adults with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 at a combined positive score (CPS) of 10 or higher.
The approval applies to patients who have not previously received systemic therapy for metastatic disease. It represents an important development in the European treatment landscape for TNBC, one of the most aggressive forms of breast cancer and a disease associated with significant treatment challenges and a substantial unmet medical need.
According to Gilead, the Trodelvy and Keytruda combination is the first and only antibody-drug conjugate (ADC) plus immunotherapy regimen approved for first-line metastatic TNBC across the European Union’s 27 member states, as well as Norway, Iceland and Liechtenstein.
The regulatory decision expands the role of Trodelvy in earlier-line treatment and follows a recent EC authorization of Trodelvy as a single-agent therapy for adults with unresectable, locally advanced or metastatic TNBC who have not received prior systemic treatment for metastatic disease and are not candidates for PD-1 or PD-L1 inhibitor therapy.
Taken together, the two European approvals establish Trodelvy-based treatment options for eligible patients with first-line metastatic TNBC regardless of PD-L1 status, providing physicians with additional flexibility when selecting treatment according to individual patient characteristics.
New First-Line Option for Metastatic TNBC
Triple-negative breast cancer is defined by the absence of three commonly targeted receptors: estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2). Because TNBC lacks these molecular targets, treatment options can be more limited than for some other forms of breast cancer.
The disease can progress rapidly, and patients with metastatic TNBC require effective therapies that can control disease progression while maintaining quality of life for as long as possible. The first-line setting is particularly important because it represents the initial opportunity to control metastatic disease after it has spread beyond the primary tumor.
The approval of Trodelvy in combination with Keytruda provides a new approach for patients whose metastatic tumors express PD-L1 with a CPS of at least 10. The regimen combines two different therapeutic mechanisms: an ADC designed to selectively deliver chemotherapy to cancer cells and an immune checkpoint inhibitor designed to enhance the immune system’s ability to recognize and attack tumor cells.
Evandro de Azambuja, MD, PhD, Head of the Medical Support Team at the Jules Bordet Institute and an investigator in the ASCENT-04 study, described the approval as an important advancement for people with PD-L1-positive metastatic TNBC.
He emphasized that the regimen has the potential to influence the treatment standard in the first-line setting by offering a new therapeutic option for patients facing an aggressive form of metastatic breast cancer.
Phase 3 ASCENT-04/KEYNOTE-D19 Data Support Approval
The European Commission’s decision is based on results from the Phase 3 ASCENT-04/KEYNOTE-D19 clinical trial. The study evaluated Trodelvy in combination with Keytruda compared with standard-of-care chemotherapy plus Keytruda as first-line treatment for patients with PD-L1-positive metastatic TNBC.
The trial demonstrated a highly statistically significant and clinically meaningful improvement in progression-free survival for patients receiving the Trodelvy and Keytruda combination compared with those receiving standard chemotherapy plus Keytruda.
According to Gilead, treatment with Trodelvy resulted in a 35% reduction in the risk of disease progression or death among patients with PD-L1-positive metastatic TNBC.
Progression-free survival is an important measure in metastatic cancer studies because it reflects the length of time patients live without their disease worsening. A reduction in the risk of progression or death can therefore represent a meaningful benefit for patients and their treating physicians.
The ASCENT-04/KEYNOTE-D19 results provided evidence supporting the use of Trodelvy alongside pembrolizumab earlier in the treatment journey. The findings also build on previous clinical experience with Trodelvy in TNBC and other breast cancer treatment settings.
The study’s results helped establish the scientific basis for expanding Trodelvy into the first-line metastatic setting for patients whose tumors meet the specified PD-L1 criteria.
Combining an ADC With Immunotherapy
Trodelvy is an antibody-drug conjugate designed to deliver an active chemotherapy payload directly to cancer cells through a targeted antibody component. ADCs are increasingly being investigated across oncology because they are designed to combine the targeting capabilities of antibodies with the cancer-killing effects of cytotoxic medicines.
Keytruda, meanwhile, is an immunotherapy that targets the PD-1 pathway. By blocking PD-1 signaling, pembrolizumab can help restore or enhance certain immune responses against cancer cells.
The combination of an ADC and an immune checkpoint inhibitor represents an approach intended to attack cancer through complementary mechanisms. Trodelvy is designed to deliver its cytotoxic payload to tumor cells, while Keytruda works through the immune system.
The potential value of this combination is particularly relevant in TNBC, where treatment strategies have increasingly incorporated immunotherapy for appropriate patients. The ASCENT-04/KEYNOTE-D19 results provide clinical evidence for combining these two treatment approaches in the first-line metastatic setting.
Trodelvy’s Expanding Role in TNBC
The latest European approval adds to the clinical development history of Trodelvy and further expands its role in breast cancer treatment.
Trodelvy has already established a significant presence in later-line TNBC treatment, giving Gilead extensive clinical and real-world experience with the medicine. The company reports that more than 75,000 patients have been treated with Trodelvy globally across its approved uses and clinical development programs.
By moving Trodelvy into the first-line metastatic TNBC setting, Gilead is seeking to provide patients with access to the therapy earlier in their treatment journey.
The company’s strategy also means that Trodelvy-based options can now address eligible first-line metastatic TNBC patients across PD-L1 status in Europe. Patients with PD-L1-positive tumors may be eligible for the Trodelvy plus Keytruda combination under the newly approved indication, while Trodelvy monotherapy provides an option for patients who are not candidates for PD-1 or PD-L1 inhibitor therapy.
This creates a broader treatment framework centered on Trodelvy for different patient groups.
Addressing an Unmet Need in Metastatic Breast Cancer
Metastatic TNBC remains one of the most challenging forms of breast cancer to manage. Once breast cancer becomes metastatic, treatment generally focuses on controlling the disease, delaying progression and maintaining quality of life rather than achieving a cure.
Historically, patients with metastatic TNBC have faced limited treatment options compared with patients whose tumors express hormone receptors or HER2. The lack of these established therapeutic targets makes the development of new treatment strategies especially important.
The European approval of Trodelvy plus Keytruda provides another option for patients with PD-L1-positive disease at the beginning of metastatic treatment. The availability of a new first-line regimen may help clinicians individualize therapy and potentially delay disease progression.
For patients and families, access to new treatment options earlier in the course of metastatic disease can be particularly meaningful because first-line therapy plays a central role in determining how the disease is managed over subsequent lines of treatment.
Gilead’s Oncology Strategy
Mika Kakefuda Derynck, MD, Senior Vice President of Clinical Development, Oncology at Gilead Sciences, characterized the EC decision as a significant milestone for patients with metastatic TNBC.
The company believes that the approval transforms the treatment landscape by expanding Trodelvy-based treatment options to eligible patients with first-line metastatic TNBC across PD-L1 status. Gilead views Trodelvy as a potential backbone therapy within this setting, building on the medicine’s established clinical history.
The decision also demonstrates Gilead’s broader commitment to advancing oncology therapies into earlier stages of disease. By leveraging the existing clinical experience with Trodelvy while evaluating new combinations and treatment settings, the company is working to expand the medicine’s potential impact across cancer populations.
The first-line metastatic TNBC approval is particularly significant because it places Trodelvy earlier in the treatment pathway, when patients and physicians are seeking effective strategies to control metastatic disease.
Implications for Patients and Physicians
For European healthcare professionals, the new authorization provides an additional treatment option for adults with unresectable, locally advanced or metastatic TNBC who meet the specified eligibility criteria.
The treatment decision will continue to depend on factors including tumor characteristics, PD-L1 expression, previous treatment history, overall health and individual patient circumstances. The approval specifically identifies patients whose tumors have a PD-L1 combined positive score of at least 10 and who have not previously received systemic therapy for metastatic disease.
The availability of the combination may also contribute to a broader evolution in the way metastatic TNBC is treated. Rather than relying exclusively on conventional chemotherapy, treatment strategies increasingly incorporate targeted therapies, ADCs and immunotherapies based on the biological characteristics of individual tumors.
A Significant European Regulatory Milestone
The European Commission authorization of Trodelvy plus Keytruda represents a major milestone for Gilead and for patients with PD-L1-positive metastatic TNBC. The decision is supported by Phase 3 evidence demonstrating a clinically meaningful progression-free survival benefit compared with chemotherapy plus Keytruda.
It also expands the role of Trodelvy from later-line treatment into the first-line metastatic setting, allowing the therapy to become part of treatment planning earlier in the disease course.
With Trodelvy monotherapy recently authorized for certain patients who are not candidates for PD-1 or PD-L1 inhibitor therapy, and the combination with Keytruda now approved for eligible PD-L1-positive patients, Gilead has established a broader Trodelvy-based treatment strategy for first-line metastatic TNBC in Europe.
The approvals come at a time when patients with metastatic TNBC continue to need more effective and durable treatment options. By combining the targeted drug-delivery approach of an antibody-drug conjugate with the immune-modulating activity of a checkpoint inhibitor, the Trodelvy-Keytruda regimen represents a new strategy for addressing this aggressive disease.
As the new authorization is implemented across the European markets covered by the decision, physicians and patients will have access to an additional first-line treatment option supported by Phase 3 clinical evidence. The approval further strengthens Trodelvy’s position in the breast cancer treatment landscape and underscores the continuing evolution of therapeutic approaches for metastatic triple-negative breast cancer.
About Triple-Negative Breast Cancer
TNBC is the most aggressive type of breast cancer and has historically been difficult to treat, accounting for approximately 15% of all breast cancers. TNBC disproportionally impacts younger, premenopausal, and Black and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER2 expression. Due to the nature of TNBC, treatment options are extremely limited compared with other breast cancer types.
TNBC has a higher chance of recurrence and metastases than other breast cancer types. The average time to metastatic recurrence for TNBC is approximately 2.6 years compared with 5 years for other breast cancers, and the relative five-year survival rate is much lower. Among women with metastatic TNBC, the five-year survival rate is 12%, compared with 28% for those with other types of metastatic breast cancer.
About Trodelvy
Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2-directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and lung cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the tumor microenvironment through a bystander effect.
The U.S. FDA and the European Commission have approved the use of Trodelvy alone or in combination with pembrolizumab in first-line metastatic TNBC, across PD-L1 status. It is also globally approved for second-line and later metastatic TNBC and pre-treated HR+/HER2- metastatic breast cancer.
Healthcare professionals have substantial clinical experience with Trodelvy, with more than 75,000 breast cancer patients treated since 2020. It is the only ADC with four positive Phase 3 trials in HER2-negative metastatic breast cancer and the only Trop-2-directed ADC to demonstrate a meaningful overall survival benefit in two distinct types of metastatic breast cancer.
Trodelvy is currently being evaluated in multiple ongoing Phase 3 trials across a range of tumor types with high Trop-2 expression, including in lung and gynecologic cancers, where previous proof-of-concept studies have demonstrated clinical activity.