Antibody-drug combination outperforms standard treatment of advanced triple-negative breast cancer

In patients with an aggressive form of breast cancer, treatment with the antibody-drug conjugate sacituzumab govitecan plus pembrolizumab resulted in durable responses with improved progression free survival compared to the current standard treatment. The ASCENT-04 study presented today by Dana-Farber Cancer Institute investigators evaluated patients receiving their first treatment for advanced or metastatic triple negative breast cancer that tests positive for the immune checkpoint PD-L1.

The study results will be submitted to regulators and could change clinical practice for first-line treatment in this patient group.

Triple-negative breast cancer is an aggressive and difficult to treat form of breast cancer that accounts for about 15% of all breast cancer cases. The five-year survival rate for patients with metastatic triple-negative breast cancer is 12%.

“There is a huge unmet need for new therapies for patients with triple-negative breast cancer,” says Dr. Sara Tolaney, chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, who presented findings from the ASCENT-04/KEYNOTE-D19 study today at the American Society for Clinical Oncology (ASCO) annual meeting. “It is important that we work toward shifting these very effective novel drugs to the first line of therapy to move the needle and improve outcomes for these patients.”

Sacituzumab govitecan is an antibody-drug conjugate designed to direct a potent chemotherapy drug into cancer cells by targeting a protein called TROP-2 that is found on triple-negative breast cancer cells. It is currently approved as second line therapy for advanced triple-negative breast cancer. However, approximately half of the patients who receive the current standard first-line treatment for advanced triple-negative breast cancer do not survive long enough to receive a second line of therapy.

Pembrolizumab is an immune checkpoint inhibitor that targets PD-L1, an immune checkpoint that can help cancer cells evade immune system attack. Breast cancers expressing PD-L1 tend to be more aggressive and are associated with reduced survival time.

The global, open-label ASCENT-04/KEYNOTE-D19 study enrolled 443 patients who were randomized to receive either sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab. Patients were followed until their disease either worsened or they experienced unmanageable side effects.

After a median follow-up of 14 months, patients who received the sacituzumab govitecan combination were more likely to survive longer without progression, with an 11.2-month median progression free survival compared to 7.8 months among those who received the chemotherapy combination.

Nearly 60% of patients responded to the sacituzumab govitecan combination. Those who responded experienced durable responses with a median of 16.6 months compared to 9.2 months among those who responded to the chemotherapy combination.

Overall survival data is immature but is trending in the direction of favoring the sacituzumab govitecan combination. Ongoing patient follow-up and additional analyses are planned. The safety profile of sacituzumab govitecan in combination with pembrolizumab was consistent with the established profiles of either agent and treatment discontinuation due to side effects was less frequent among patients taking the sacituzumab govitecan combination.

“We hope this results in approval of sacituzumab govitecan plus pembrolizumab for first-line treatment in our patients with triple-negative breast cancer with tumors that are PD-L1-positive. Currently we sometimes see patients experience deterioration in their health during first-line treatment and they don’t always have an opportunity to benefit from these sacituzumab in later lines,” says Tolaney. “We need to move these agents up front so more patients can benefit.”

Dana-Farber investigators were involved in the first studies of sacituzumab govitecan in humans and participated in the pivotal clinical trials that led to its initial U.S. Food and Drug Administration approval for patients with pre-treated triple-negative breast cancer.

Tolaney also helped lead the TROPiCS-02 study, which led to the ADC’s approval in pre-treated patients with HR-positive, HER2-negative metastatic breast cancer. Dana-Farber also led investigator-initiated trials exploring the efficacy and safety of combining sacituzumab govitecan and pembrolizumab, providing evidence supporting the design of the phase 3 ASCENT-04/KEYNOTE-D19 trial.

The ASCENT-04/KEYNOTE-D19 trial was funded by Gilead Sciences, Inc.

In patients with an aggressive form of breast cancer, treatment with the antibody-drug conjugate sacituzumab govitecan plus pembrolizumab resulted in durable responses with improved progression free survival compared to the current standard treatment. The ASCENT-04 study presented today by Dana-Farber Cancer Institute investigators evaluated patients receiving their first treatment for advanced or metastatic triple negative breast cancer that tests positive for the immune checkpoint PD-L1.

The study results will be submitted to regulators and could change clinical practice for first-line treatment in this patient group.

Triple-negative breast cancer is an aggressive and difficult to treat form of breast cancer that accounts for about 15% of all breast cancer cases. The five-year survival rate for patients with metastatic triple-negative breast cancer is 12%.

“There is a huge unmet need for new therapies for patients with triple-negative breast cancer,” says Dr. Sara Tolaney, chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, who presented findings from the ASCENT-04/KEYNOTE-D19 study today at the American Society for Clinical Oncology (ASCO) annual meeting. “It is important that we work toward shifting these very effective novel drugs to the first line of therapy to move the needle and improve outcomes for these patients.”

Sacituzumab govitecan is an antibody-drug conjugate designed to direct a potent chemotherapy drug into cancer cells by targeting a protein called TROP-2 that is found on triple-negative breast cancer cells. It is currently approved as second line therapy for advanced triple-negative breast cancer. However, approximately half of the patients who receive the current standard first-line treatment for advanced triple-negative breast cancer do not survive long enough to receive a second line of therapy.

Pembrolizumab is an immune checkpoint inhibitor that targets PD-L1, an immune checkpoint that can help cancer cells evade immune system attack. Breast cancers expressing PD-L1 tend to be more aggressive and are associated with reduced survival time.

The global, open-label ASCENT-04/KEYNOTE-D19 study enrolled 443 patients who were randomized to receive either sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab. Patients were followed until their disease either worsened or they experienced unmanageable side effects.

After a median follow-up of 14 months, patients who received the sacituzumab govitecan combination were more likely to survive longer without progression, with an 11.2-month median progression free survival compared to 7.8 months among those who received the chemotherapy combination.

Nearly 60% of patients responded to the sacituzumab govitecan combination. Those who responded experienced durable responses with a median of 16.6 months compared to 9.2 months among those who responded to the chemotherapy combination.

Overall survival data is immature but is trending in the direction of favoring the sacituzumab govitecan combination. Ongoing patient follow-up and additional analyses are planned. The safety profile of sacituzumab govitecan in combination with pembrolizumab was consistent with the established profiles of either agent and treatment discontinuation due to side effects was less frequent among patients taking the sacituzumab govitecan combination.

“We hope this results in approval of sacituzumab govitecan plus pembrolizumab for first-line treatment in our patients with triple-negative breast cancer with tumors that are PD-L1-positive. Currently we sometimes see patients experience deterioration in their health during first-line treatment and they don’t always have an opportunity to benefit from these sacituzumab in later lines,” says Tolaney. “We need to move these agents up front so more patients can benefit.”

Dana-Farber investigators were involved in the first studies of sacituzumab govitecan in humans and participated in the pivotal clinical trials that led to its initial U.S. Food and Drug Administration approval for patients with pre-treated triple-negative breast cancer.

Tolaney also helped lead the TROPiCS-02 study, which led to the ADC’s approval in pre-treated patients with HR-positive, HER2-negative metastatic breast cancer. Dana-Farber also led investigator-initiated trials exploring the efficacy and safety of combining sacituzumab govitecan and pembrolizumab, providing evidence supporting the design of the phase 3 ASCENT-04/KEYNOTE-D19 trial.

The ASCENT-04/KEYNOTE-D19 trial was funded by Gilead Sciences, Inc.