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Immunotherapy Yields Response in Triple-Negative Breast Cancer

Immunotherapy Yields Response in Triple-Negative Breast Cancer

Results of the first phase I trials of programmed cell death 1 (PD-1) and PD-L1 inhibitors in breast cancer were presented at the 2014 San Antonio Breast Cancer Symposium (SABCS), held December 9–13 in San Antonio, Texas.

Pembrolizumab (Keytruda) an anti-PD-1 monoclonal antibody that releases the natural break on the immune system by blocking the interaction between the PD-1 receptor expressed on T cells and its two ligands, PD-L1 and PD-L2. PD-L1 has been shown to be upregulated on certain tumor cells, which allows continued blocking of the immune system from attacking tumor cells.

So far, these antibodies and other immunotherapies are most effective in tumors that have high levels of infiltrating immune cells including T cells, such as melanoma. Pembrolizumab was recently approved by the US Food and Drug Administration as a second-line therapy for metastatic melanoma.

Of the 27 advanced triple-negative breast cancer patients in the Keynote-012 trial who could be evaluated, 5 patients (18.5%) had an overall response including 1 complete response (3.7%) to pembrolizumab. The patient who had a complete response had one prior line of systemic therapy and two patients with a partial response each had five or more prior lines of therapy. Three of the five responders remained on therapy for at least 48 weeks and the other two patients who had discontinued treatment at the time of analysis received therapy for 40 weeks. “This speaks to the durability of the responses to therapy,” said study author Rita Nanda, MD, associate director of breast medical oncology at the University of Chicago, at a press conference.

Seven patients had stable disease and twelve patients had progressive disease. The median time to response was 18 weeks. Median progression-free survival was 1.9 months. Responses were durable, ranging from 15 to more than 40 weeks. The median duration of response has not yet been reached.

“Everyone continues to be quite excited about immunotherapy in breast cancer and what this shows is what we have seen in several other studies in other tumor types, that a small proportion respond, but for those that do, there tends to be long-term responses and durability that we don't often see with other therapies,” said Jennifer Litton, MD, of the University of Texas MD Anderson Cancer Center, who moderated the press conference.

All patients enrolled on the trial had tumors that expressed PD-L1. Pembrolizumab was administered every 2 weeks at a 10 mg/kg dose. The mean age of patients on the trial was 51.9. Of the 32 patients on the trial, 15 (47%) had at least three prior lines of therapy—mostly chemotherapy.

The most common adverse events were arthralgia, fatigue, myalgia, and nausea, occurring in at least 15% of patients. Four patients had grade 3 adverse events (anemia, headache, meningitis aseptic, and pyrexia), and one patient had a grade 4 adverse event of a decrease in blood fibrinogen. One patient on the trial died of disseminated intravascular coagulation that was attributed to administration of the therapy.

“The acceptable safety and tolerability profile, coupled with a promising antitumor activity, supports the further development of pembrolizumab in patients with advanced triple-negative breast cancer," said Nanda.

A phase II trial of pembrolizumab in patients with advanced triple-negative breast cancer is expected to start in the first half of 2015.

Also presented at the meeting, as a poster, were the results of the phase I study of MPDL3280A, a monoclonal antibody against PD-L1. Of the nine patients on the trial that could be evaluated, three had a response, including one complete response. Two additional patients had tumor shrinkage but were not included in the group of responders because they also had the appearance of new tumor lesions.

Median age of the patients on the trial was 55, and 92% of patients had two or more prior systemic therapies. While patients with both PD-L1–positive and PD-L1–negative tumors were enrolled in the trial, the nine patients evaluated were those with PD-L1-positive tumors.

Six patients (50%) experienced an adverse event and one patient (8%) had a high-grade adrenal insufficiency adverse event. The most frequent adverse events were fatigue and neutropenia, each in two patients. There were no treatment-related deaths.

The median duration of response has not been reached but the results are relatively recent with responses ranging from 6 to more than 8 weeks.

Advanced triple-negative breast cancer has no approved therapies in the United States and patients typically survival for about 12 months, making it a highly unmet need.

References

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. Presented at 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. 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. Presented at 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract PD1-6.

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