Keytruda Produces Antitumor Responses in Triple-Negative Breast Cancer

The PD-1 inhibitor Keytruda (pembrolizumab) has demonstrated promising clinical activity with an acceptable safety profile in heavily pretreated patients with recurrent metastatic triple-negative breast cancer (TNBC).

The results from the phase 1b KEYNOTE-012 trial were presented at the 2014 San Antonio Breast Cancer Symposium. Data showed that treatment with Keytruda demonstrated an overall response rate of 18.5 percent in patients with TNBC that strongly expressed the PD-L1. At the time of the analysis, the median duration of response was not yet reached. The findings from the study were described as the first to demonstrate clinical activity for an immune checkpoint inhibitor in breast cancer.

"Pembrolizumab showed an acceptable safety and tolerability profile in heavily pretreated PD-L1-positive advanced triple-negative breast cancer patients," said lead author Rita Nanda, assistant professor of medicine and associate director of the Breast Medical Oncology Program at the University of Chicago. "While 56 percent of patients did experience a therapy-related adverse event, the vast majority of these toxicities were easily managed, well tolerated and did not require treatment discontinuation."

Keytruda is designed to inhibit PD-1 interaction with its ligands PD-L1 and PD-L2. Cancer cells commonly express PD-1 to evade the immune system, and blocking this pathway causes the reactivation of the immune system against cancer cells. The Food and Drug Administration (FDA) approved Keytruda in September 2014 as a treatment for patients with unresectable or metastatic melanoma whose disease has progressed after prior therapies.

The novel agent has also received a breakthrough therapy designation from the FDA as a potential treatment for patients with non-small cell lung cancer. "Breast cancer has not typically been found to be a disease that we can target with immune-modulating therapies, which is why it has been explored in other tumor types first," Edith A. Perez, deputy director-at-large for the Mayo Clinic Cancer Center and breast cancer expert, said during a press briefing. "I am very gratified that now we have the first proof-of-principle study showing that in a group of patients with refractory, advanced, metastatic breast cancer that there was a signal of some activity to immune-modulating therapy."

In the ongoing trial, 32 patients with a median age of 52 years received intravenous Keytruda at 10 mg/kg every two weeks. All patients enrolled in the trial had tumors that tested positive for PD-L1 expression. PD-L1-positivity was detected in 58 percent of patients screened for the trial. Patients on the study were not on systemic steroid therapy and did not have an autoimmune disease or active brain metastases. Those enrolled had received several prior lines of treatment, with 22 percent having received at least five previous therapies. Additionally, 87.5 percent of patients had received neoadjuvant or adjuvant therapy.

The primary endpoints of the study were focused on safety, tolerability and clinical activity. Secondary objectives included assessments of progression-free survival (PFS), overall survival and response duration.

"This patient population was relatively heavily pretreated with almost 50 percent of the patients participating in the study receiving three or more lines of therapy in the advanced cancer setting," Nanda said. "About 90 percent of patients who participated in this study had received therapy in the early-stage setting and had received either adjuvant or neoadjuvant therapy."

Among 27 evaluable patients, five responded to treatment, including one complete response, and four partial responses. Additionally, seven patients had stable disease and 12 patients had progressive disease at a median follow-up of 9.9 months.

The overall clinical benefit rate with Keytruda was 44 percent. The median PFS was 1.9 months. At six months, 23.3 percent of patients remained progression free.

"Everyone continues to be quite excited about immunotherapy in breast cancer," explained session moderator Jennifer K. Litton, MD, an associate professor at The University of Texas MD Anderson Cancer Center. "This shows what we've seen in several other studies in other tumor types—that a small portion may respond, but for those who do, there tends to be some long-term responders with durability that we don't see with other therapies."

The median time to response was 18 weeks and the median duration of response was not yet reached, with many responses lasting longer than 40 weeks. Additionally, 30 percent of patients experienced tumor shrinkage. In six patients who received at least 5 prior lines of therapy, the response rate and the stable disease rate was 33.3 percent.

"At the time of analysis, three of the five responders remained on therapy. These patients were on therapy for 40 weeks or longer," Nanda explained. "Two of the patients who discontinued by the time of the analysis had received treatment for 40 weeks. This speaks to the durability of responses to therapy."

Adverse events (AEs) of any grade occurred in 56.3 percent of patient treated with Keytruda, with serious AEs occurring in 15.6 percent of patients. The most common AEs were arthralgia, fatigue, myalgia and nausea. Serious side effects included anemia, headache, meningitis aseptic and fever. "There was one death related to DIC (disseminated intravascular coagulation, a bleeding disorder) in a patient who had rapidly progressive triple-negative breast cancer; that incidence seems to be an outlier," Nanda said. "In patients who have been exposed to Keytruda for a variety of other disease, it doesn't appear to be a recurring theme."

Clinical trials are currently exploring the promising therapy across a variety of settings for patients with solid tumors and hematological cancers. In patients with TNBC, further studies are planned to explore the drug as a monotherapy and potentially in combinations. However, at this point, an optimal combination has not yet been identified.

"Certainly, it would be fantastic to expand on this study to figure out whether staining for PD-L1 is relevant; to determine the true activity of the single agent; and, most important, to see how we can combine this agent with other strategies for triple-negative breast cancer," said Perez. "These patients have so few options that the slightest glimpse of activity provides us cause for a lot of enthusiasm."