Checkpoint Inhibitors Show Promise in Triple-Negative Breast Cancer

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.”

The overall clinical benefit rate with pembrolizumab was 44%. The median progression-free survival (PFS) was 1.9 months. At 6 months, 23.3% of patients remained progression free. The median time to response was 18 weeks.

“You can see how durable these responses were,” Nanda said. “At the time of last data analysis, 3 of the patients who responded to study-based therapy remained on treatment, 2 had discontinued, and at the median follow-up of 10 months, the median duration of response had not yet been achieved.”

Nanda described the PFS in this very heavily pretreated patient population with a new checkpoint inhibition monotherapy as “quite impressive,” adding, “When we’re thinking about a relatively aggressive form of breast cancer in patients who have been heavily pretreated, that’s not generally what we see with chemotherapy in this setting.”

She said the trial of atezolizumab was similarly exciting. It demonstrated a 19% objective response rate, with 75% of responses ongoing in pretreated patients with metastatic TNBC, at the analysis. “Much like pembrolizumab, the goal of inhibition here was to stimulate the T cells to become active, to recognize cancer and to destroy it,” Nanda said.

In the multicenter phase Ia study, 54 patients with mTNBC received IV atezolizumab at 15 mg/kg, 20 mg/kg, or a flat 1200 mg dose every 3 weeks. At baseline, 69% of patients tested positive for PD-L1 expression.

The median age of patients enrolled in the study was 48 years. Patients had an ECOG PS of 0 or 1; 59% had visceral metastases; and 11% had bone metastases, according to the abstract. In addition, 85% received ≥4 prior systemic regimens, including taxanes (82%), anthracyclines (78%), carboplatin (41%), and cisplatin (15%).

Among 21 evaluable patients who were PD-L1¬—positive, 9.5% had complete responses, and 9.5% had partial responses. At the analysis, 75% of responses were ongoing, with a median not yet reached (range: 18-56+ weeks).

“Patients had an excellent performance, as approximately 70% had visceral disease, and again, we’re looking at a very heavily pretreated population,” Nanda said. “One in 10 patients did experience a grade 3 adverse event, and there were 2 deaths that occurred while on study therapy. The etiology of these deaths was ongoing at the time of the presentation [at the 2015 AACR annual meeting].”

Based on the durable responses and the safety and tolerability of the checkpoint inhibitors in these trials, Nanda said, the stage is set for further investigation.

“There are a lot of therapies that immune checkpoint inhibition can be combined with. You could potentially combine immune checkpoint inhibitors with each other or with chemotherapy, radiation therapy, and targeted therapies.”

She said vaccines up until now have been disappointments, but that in combination with other therapies, it may be possible to make vaccines work.

1. 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.
2. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 6317.