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Checkpoint Inhibitors Show Promise in Triple-Negative Breast Cancer

Tony Hagen @oncobiz
Published: Friday, Aug 28, 2015

Rita Nanda, MD

Rita Nanda, MD

Immune checkpoint inhibitors can be of significant value in combatting recurrent and metastatic triple negative breast cancer (TNBC), Rita Nanda, MD, told physicians at the recent 14th Annual International Congress on the Future of Breast Cancer.

“Immunology has arrived. It’s going to remain an important tool in the fight against cancer for a variety of tumors, and I think breast cancer is certainly going to be one of them,” said Nanda, a medical oncologist at University of Chicago Medical Center and the lead author on one of the studies involving pembrolizumab (Keytruda).

Nanda said her conclusion was justified by the results of two trials involving PD-L1 inhibitors: the KEYNOTE-012 trial, in which patients were treated with pembrolizumab, and a second trial involving atezolizumab (MPDL3280A) led by Leisha A. Emens, MD, PhD, of the Cancer Immunology and the Breast and Ovarian Cancer Programs at the Johns Hopkins Kimmel Cancer Center.1,2

The checkpoint inhibitors were used in heavily pretreated populations, and demonstrated safety and low toxicity while achieving good responses, Nanda said. “They certainly demonstrated single-agent activity, and I think the question now is what combinations can further build on this promise,” Nanda said.

TNBCs are associated with worse clinical outcomes and continue to represent an important clinical challenge, Nanda said. Lending support to the use of immunotherapy in TNBC is the fact that estrogen receptor (ER)–negative tumors have a higher density of tumor infiltrating lymphocytes (TIL) than ER positive tumors, Nanda said. TILs play an important role in killing tumor cells.

In addition, Vanderbilt University researcher Brian D. Lehmann, PhD, and his colleagues have identified TNBC subtypes that may aid in guiding patients toward targeted therapies, Nanda said. Furthermore, TNBCs “are generally unstable, are prone to genetic mutations, and produce neoantigens, which in turn can stimulate immunity,” she said.

The high expression of PD-L1 in TNBC tumor cells leads to suppression of T-cell function. Pembrolizumab binds to PD-1 on inactive T cells and blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby enabling T cells to activate in the fight against tumor cells.

KEYNOTE-012 enrolled patients with a variety of different tumor types. Patients in the TNBC portion had metastatic or recurrent TNBC, an ECOG performance status of 0 or 1, and tumors testing positive for PD-L1 expression. Patients were not on systemic steroid therapy, and they did not have autoimmune disease or active brain metastases. They received intravenous pembrolizumab at 10 mg/kg every 2 weeks. Nanda originally reported on the phase 1b study in December at the 2014 San Antonio Breast Cancer Symposium.

Statistics on durability of response and survival were impressive, Nanda said, though 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.

The trial enrolled 32 females with a mean age of 51.9 years. The prior treatment statistics were taxane, 93.8%; anthracycline, 78.1%; capecitabine, 65.6%; platinum, 59.3%; and eribulin, 21.9%. “Just under half of patients had had 3 or more prior lines of therapy for metastatic disease and almost 90% had previously received treatment in the early stage setting,” Nanda said.

The most common treatment-related adverse events of any grade included arthralgia, fatigue, myalgia, and nausea. “These were generally grade 1 to 2 and were very mild and easily managed,” Nanda said. Adverse events (AE) of a potentially immune-mediated nature, regardless of attribution, included pruritus (n = 3; all grade 1-2), hepatitis (n = 1; grade 3), and hypothyroidism (n = 1; grade 2).

There were four grade 3 events and one grade 4 event. There was one AE related to treatment that resulted in death, attributed to disseminated intravascular coagulation. “While it was certainly possible this was related to study-based therapy, I will mention that there are thousands of patients who received pembrolizumab for other tumor types. This hasn’t been a recurrent theme, so it’s certainly reassuring to us,” Nanda said.

Among 27 patients evaluable for response, the overall response rate was 18.5% (n = 5). The responses included 1 complete response, 4 partial responses (14.8%), 7 instances of stable disease (25.9%), and 12 instances of progressive disease (44.4%) at a median follow-up of 9.9 months.

“Responses were actually not limited to patients who had very few treatments,” Nanda said. “In fact, 4 of the 5 responders had had 3 or more lines of therapy for advanced breast cancer. Also the majority of these patients had also had neoadjuvant or adjuvant chemotherapy.”




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