Nick Mulcahy

April 03, 2017

WASHINGTON, DC — The proportion of patients with metastatic triple-negative breast cancer who respond to the immunotherapy atezolizumab (Tecentriq, Genentech) is only 10% to 13%, but the responses tend to last a long time, according to new results from an ongoing phase 1 study.

The median duration of response was 21 months, which is "significant" in this setting, said Peter Schmid, MD, PhD, director of the St. Bartholomew’s Breast Centre at St. Bartholomew’s Hospital and Barts Cancer Institute in London, United Kingdom.

"All responding patients achieved a long-term survival benefit," he told reporters during a press conference here at the American Association for Cancer Research (AACR) 2017 Annual Meeting.

The new findings are the first overall survival results reported among patients with metastatic breast cancer treated with a immunotherapy checkpoint inhibitor, said Suzanne Topalian, MD, from the Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, who moderated the press conference.

The landmark overall survival rates were 41% at 1 year and 22% at both year 3 and year 3.

The trial is the "largest of its kind," said Dr Topalian, referring to the fact that there are smaller early-phase studies of other checkpoint inhibitors in triple-negative breast cancer.

However, that is good news. Less promising was the fact that median overall survival among the 115 patients in the phase 1a trial was only 9.3 months. That's not an improvement upon the current state of affairs in metastatic triple-negative breast cancer. Median survival is 9 to 12 months among these patients, who are treated with chemotherapy, said Dr Schmid.

Patients with triple-negative breast cancer have a worse prognosis than patients with other breast cancer subtypes, and in the United States, no targeted treatment is available, he added.

But there has been a hypothesis that triple-negative disease would respond to immunotherapy because, compared with other breast cancers,  it has a high rate of mutations, relatively high levels of programmed cell death (PD) ligand 1 (L1) expression, and infiltration of tumor-infiltrating lymphocytes, Dr Schmid explained.

Atezolizumab is an engineered monoclonal antibody that disrupts the 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.

In the current study, exploratory biomarker analyses suggested that higher CD8 T cell and tumor-infiltrating lymphocyte counts, and, to a lesser extent, PD-L1 status (on immune cells) are associated with better clinical outcomes with atezolizumab.

"But all of these markers were not black or white in a way we can say we can select all of the responders based on this or can deselect them," Dr Schmid said.

Another expert agreed. "The biomarkers that were examined in this trial did not predict who would respond to the drug," said Amy Clark, MD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, who was not involved in the study.

"The critical issue will be our ability to identify the subset of patients who will benefit," Dr Clark told Medscape Medical News. Future research with atezolizumab should examine additional novel predictive biomarkers, she added.

Response rates were numerically higher in the patients with PD-L1 immune cell counts of 5% or greater and in the first-line setting.

However, most of the patients in the trial were receiving their second line of therapy or more (83%). Only 17% were being treated with immunotherapy first-line, and they were more likely to be responders.

There is a need to find biomarkers that are predictive of response to therapy because approximately 90% of patients in the trial were not responders, but there is no definitive marker at this point.

By using standard RECIST (response evaluation criteria in solid tumors)  criteria, the investigators reported that the objective response rate was 10%.

However, they also used the immune-related response criteria and  reported a response rate of 13% with that measure. The additional criteria allow for the time gap in many cancer patients between initial treatment and the apparent action of the immune system to reduce the tumor burden; some patients who have this time gap will experience the phenomenon of "pseudoprogression," said Dr Schmid: that is, these patients experienced durable shrinkage of their target lesion while developing new lesions at other sites or have spread at a lymph node, which eventually responded to treatment.

In the trial, patients were treated every 3 weeks with atezolizumab, 15 or 20 mg/kg, or a flat dose of 1200 mg. The level of PD-L1 expression on tumor-infiltrating immune cells was assessed by using a proprietary assay.

Only 11% of patients experienced treatment-related grade 3 or greater adverse events, and side effects led to treatment discontinuation in 3% of patients.

Triple-negative breast cancer counts for 10% to 20% of all breast cancers, said Dr Schmid. Single-agent checkpoint inhibitors have been "relatively disappointing" in this setting, he acknowledged. Therefore, the next step in this area is to combine these immunotherapies with other agents.

The ongoing randomized phase 3 study Impassion130 is investigating the idea that chemotherapy plus atezolizumab in the first line of triple-negative breast cancer "can broaden the cancer immune response to a greater number of patients," he commented.

This study was funded by Genentech/Roche. Dr Schmid’s spouse is a consultant to Roche/Genentech. Dr Topalian reports financial relationships with AbbVie, Bristol-Myers Squibb, Five Prime Therapeutics, ImaginAb, Amgen, Aduro, Compugen, Jounce Therapeutics, MedImmune, Merck, Nextimmune, Pfizer, Potenza Therapeutics, Sanofi, and Tizona.

American Association for Cancer Research (AACR) 2017 Annual Meeting. Abstract 2986. Presented April 3, 2017.

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