Metastatic Triple-Negative Breast Cancer Responds to Immunotherapy

Megan Brooks

April 20, 2015

PHILADELPHIA — The high hopes for cancer immunotherapy have panned out in metastatic triple-negative breast cancer, a subtype that is particularly difficult to treat.

MPDL3280A, the investigational targeted immunotherapy under development by Genentech, has demonstrated durable clinical activity in patients with this type of advanced cancer.

"This is very exciting because longer responses are not typical of what occurs when patients with metastatic triple-negative breast cancer are treated with chemotherapy," Leisha A. Emens, MD, PhD, associate professor of oncology and member of the cancer immunology and the breast and ovarian cancer programs at the Johns Hopkins Kimmel Cancer Center in Baltimore, said in a news release.

She presented the results here at the American Association for Cancer Research (AACR) 2015 Annual Meeting.

Patients with triple-negative breast cancer have a worse prognosis than patients with other breast cancer subtypes, and in the United States, there is currently no targeted treatment available, Dr Emens reported.

MPDL3280A is an engineered monoclonal antibody that disrupts the programmed death (PD) pathway, which blocks the immune system's response to cancer. The anti-PD-L1 action of the drug removes this block, increasing the patient's immune response to cancer.

Lasting Responses

The phase 1a study involved 54 women with metastatic triple-negative breast cancer who were treated every 3 weeks with MPDL3280A 15 or 20 mg/kg or with a flat dose of 1200 mg. The level of PD-L1 expression on tumor-infiltrating immune cells was assessed using a proprietary assay.

All 21 patients evaluable for efficacy had levels of PD-L1 on immune cells of 5% or greater. The overall response rate was 19% (95% confidence interval [CI], 5% - 42%), and 24-week progression-free survival was 27% (95% CI, 7% - 47%).

There were two complete responses and two partial responses. "Importantly, three of four responses were ongoing at the time of the cutoff," Dr Emens said.

She added that three patients appeared to experience the phenomenon of "pseudoprogression" — an atypical response pattern seen in some patients treated with this class of agent — and were considered to have progressive disease. These are patients who experienced durable shrinkage of their target lesion while developing new lesions at other sites, which eventually responded to treatment, she reported.

The median duration of response has not yet been reached (range, 18 to at least 56 weeks), and the median duration of survival follow-up is approximately 40 weeks (range, 2 to at least 85 weeks). Further evaluation of MPDL3280A is ongoing.

In the 54 patients evaluable for safety, MPDL3280A was generally well tolerated. Fatigue, nausea, fever, decreased appetite, and asthenia were the most common treatment-related adverse events, Dr Emens reported. Grade 3 treatment-related adverse events were seen in 11% of patients. There was one case of grade 4 pneumonitis. The cause of two deaths is currently being investigated.

A Paradigm Shift in Breast Cancer

"When a cancer is developing, it faces really only one significant enemy, and that is the body's immune system," said Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, who moderated the AACR press briefing during which the data were presented.

This study is another "powerful indication" of the potential of targeted immune checkpoint blockade strategies to influence the outcome of several cancers, Dr Weiner said.

In fact, "the paradigm of understanding how breast cancer treatment works and what is involved in development of breast cancer is changing," said Robert Wesolowski, MD, a breast oncologist and researcher at the Ohio State University Comprehensive Cancer Center in Columbus, who was not involved in the study.

"We previously didn't think that the immune system was that important. Studies that were done some 20 years ago with immunotherapy didn't really show much promise in breast cancer," he told Medscape Medical News.

Now there is a new line of drugs that uncouples some of the inhibitor mechanisms of the immune system that the cancer is causing, leading to responses, Dr Wesolowski explained.

He noted that results from this study are particularly "promising," given that most of the patients had received at least 4 previous lines of chemotherapy. "These patients, on average, usually have a response rate of about 10% to 20% to standard cytotoxic chemotherapy, and the responses are usually not very long lasting — a few weeks to maybe a few months," he said.

The study is "very interesting," Dr Wesolowski said, "because they were measuring PD-L1 expression on the immune cells rather than PD-L1 expression on the tumor cells. We know that some immune cells, like natural killer cells, for example, can express PD-L1. It's cool that they were able to correlate responses with expression of PD-L1 on the immune system."

This study was funded by Genentech. Dr Emens reports receiving research funding from Genentech for another clinical trial, and from Merck, EMD Serono, Amplimmune, and Maxcyte; receiving a research grant from Roche; and serving as a consultant for Vaccinex, Celgene, Aveo, and Bristol-Myers Squibb.

American Association for Cancer Research (AACR) 2015 Annual Meeting: Abstract 6317. Presented April 20, 2015.

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