Gilead Sciences and Merck & Co. have announced promising results from their phase 3 ASCENT-04/KEYNOTE-D19 trial evaluating the combination of Trodelvy (sacituzumab govitecan) and Keytruda (pembrolizumab) as a first-line treatment for patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC).
The study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared to the current standard of Keytruda plus chemotherapy in patients whose tumors express PD-L1. While overall survival data were not mature at the time of analysis, researchers noted an early trend showing improvement in this critical endpoint.
"These findings are the first to show the transformative potential of an antibody-drug conjugate combined with an immuno-oncology agent in early treatment lines of metastatic breast cancer," said Dr. Dietmar Berger, Chief Medical Officer of Gilead Sciences. "For patients with this difficult to treat type of breast cancer, these results potentially offer a new pathway that may redefine their treatment options."
Strategic Collaboration Targets Aggressive Cancer
The partnership between Gilead and Merck represents a strategic effort to improve outcomes for patients with triple-negative breast cancer, an aggressive form of the disease with limited treatment options. Trodelvy has already established itself as a go-to therapy for TNBC patients whose disease has progressed after prior treatments, while Keytruda is approved as a first-line therapy in combination with chemotherapy for patients with PD-L1 scores of 10 or more.
Dr. Sara Tolaney, primary investigator of the study and Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, emphasized the significance of these findings: "For patients with metastatic triple-negative breast cancer, there is a critical need for more effective treatment options. These data suggest that the combination of Trodelvy and Keytruda may offer a new treatment approach — bringing together a potent antibody drug conjugate with immunotherapy to improve outcomes for patients."
Study Design and Patient Population
The ASCENT-04/KEYNOTE-D19 trial enrolled 443 patients across multiple study sites. Participants received either 10 milligrams per kilogram of Trodelvy intravenously on days 1 and 8 of a 21-day cycle plus 200 milligrams of Keytruda intravenously on day 1 of a 21-day cycle, or chemotherapy plus Keytruda. Treatment continued until disease progression or unacceptable toxicity.
Importantly, the safety profile of Trodelvy plus Keytruda was found to be consistent with the known safety profiles of each individual treatment. Patients randomized to receive chemotherapy were allowed to switch to Trodelvy if they experienced disease progression.
The study remains active and is estimated to be completed in February 2027, with detailed results to be presented at future medical meetings and discussed with regulatory authorities.
Innovative Mechanism of Action
Trodelvy belongs to a class of medications known as antibody-drug conjugates (ADCs), which represent a targeted approach to cancer treatment. Dr. Yuan Yuan, Professor of Medicine and Director of Breast Oncology at Cedars-Sinai Medical Center, describes ADCs as "a new class of designer drug, where the target-specific antibody was attached to a small amount of chemotherapy [payload], in contrast to conventional chemotherapy with a larger amount of drug to enter the body."
Specifically, Trodelvy targets Trop-2, a protein highly expressed in many solid tumors including TNBC. The antibody component delivers the cytotoxic payload directly to cancer cells, potentially reducing systemic toxicity while maintaining efficacy.
Keytruda, meanwhile, works by blocking the PD-1 pathway, helping the immune system recognize and attack cancer cells. The combination approach aims to simultaneously deliver targeted cytotoxic therapy while enhancing immune response against the tumor.
Commercial Implications
For Gilead, the positive results support the company's strategic vision for Trodelvy. "This helps further our ambition of displacing chemotherapy with Trodelvy to improve outcomes for people living with cancer," said Gilead's Chief Medical Officer Merdad Parsey.
Trodelvy is a key growth product for Gilead as it faces pressure on its HIV franchise, which has been affected by reduced diagnoses and therapy initiations during the COVID-19 pandemic. The company reported third-quarter sales of $101 million for Trodelvy, which is also approved to treat metastatic urothelial cancer in the US.
Merck's Keytruda continues to strengthen its position in the TNBC treatment landscape, having recently secured FDA approvals for use in neoadjuvant settings alongside chemotherapy before surgery, as well as in the adjuvant setting as a monotherapy to prevent tumor recurrence.
Unmet Need in Triple-Negative Breast Cancer
Triple-negative breast cancer, which accounts for approximately 15-20% of all breast cancers, lacks expression of estrogen receptors, progesterone receptors, and HER2 protein. This molecular profile makes the disease particularly challenging to treat, as it does not respond to hormonal therapies or HER2-targeted treatments.
Patients with metastatic TNBC typically face a poor prognosis, with median survival historically ranging from 12 to 18 months. The disease disproportionately affects younger women and those of African American or Hispanic descent.
The potential to move Trodelvy earlier in the treatment pathway, particularly in combination with immunotherapy, represents a significant advancement in addressing this substantial unmet medical need.
Looking Forward
If approved for first-line treatment of metastatic TNBC, the Trodelvy-Keytruda combination could significantly alter the treatment landscape. The approach aligns with the broader oncology trend toward targeted therapies and immunotherapy combinations that aim to improve efficacy while reducing the toxicity associated with conventional chemotherapy.
As the ASCENT-04/KEYNOTE-D19 trial continues, the medical community eagerly awaits mature overall survival data and additional safety information that will further clarify the role of this promising combination in the management of triple-negative breast cancer.
