Pembrolizumab Demonstrates Activity, Acceptable Safety in TNBC

Rita Nanda, MD

Rita Nanda, MD

The PD-1 inhibitor pembrolizumab (Keytruda) has demonstrated promising clinical activity and an acceptable safety profile in heavily pretreated patients with recurrent metastatic triple-negative breast cancer (TNBC). These phase Ib results were presented at the 2014 San Antonio Breast Cancer Symposium.

In the early-phase KEYNOTE-012 trial, treatment with pembrolizumab demonstrated an overall response rate of 18.5% in patients with PD-L1-positive TNBC. 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, MD, assistant professor of Medicine and associate director of the Breast Medical Oncology Program at the University of Chicago. "While 56% 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."

Pembrolizumab, a highly selective humanized IgG4-kappa monoclonal antibody, 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 FDA approved pembrolizumab 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," breast cancer expert Edith A. Perez, MD, the deputy director at large for the Mayo Clinic Cancer Center, 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 51.9 years received intravenous pembrolizumab at 10 mg/kg every 2 weeks. All patients enrolled in the trial had tumors that tested positive for PD-L1 expression by immunohistochemical assay in the stroma or in ≥1% of tumor cells. By these criteria, PD-L1-positivity was detected in 58% 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 21.9% having received ≥5 therapies. Additionally, 87.5% 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% of the patients participating in the study receiving three or more lines of therapy in the advanced cancer setting," Nanda said. "About 90% 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 (18.5%), including one complete response (3.7%), and four partial responses (14.8%). Additionally, seven patients (25.9%) had stable disease and 12 patients (44.4%) had progressive disease at a median follow-up of 9.9 months. Three patients whose disease progressed discontinued therapy prior to the first post-baseline scan.

The overall clinical benefit rate with pembrolizumab was 44%. The median PFS was 1.9 months. At 6 months, 23.3% 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% of patients experienced tumor shrinkage. In six patients who received ≥5 prior lines of therapy, the response rate and the stable disease rate was 33.3%.

"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% of patient treated with pembrolizumab, with grade 3/4 AEs occurring in 15.6% of patients. The most common AEs were arthralgia (18.8%), fatigue (18.8%), myalgia (15.6%), and nausea (15.6%). Grade 3 AEs included anemia, headache, meningitis aseptic, and pyrexia.

The only grade 4 AE was blood fibrinogen decrease, which was implicated in the death of one patient in the trial, as a result of disseminated intravascular coagulation (DIC). This was the only side effect leading to treatment discontinuation observed in the study.

"There was one death related to DIC 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 pembrolizumab 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 malignancies. 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."

Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.

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