Triple-negative breast cancer is an aggressive disease with no approved targeted therapy, and it remains challenging to treat. Early data from a phase I study suggest that the PD-L1 inhibitor atezolizumab (Tecentriq) can extend the lives of a subset of women who respond to this checkpoint inhibitor.

Median overall survival in metastatic triple-negative breast cancer with current treatments ranges from 9 to 12 months. In the phase I study, 100% of patients who responded to atezolizumab were alive at 1 year vs 38% of nonresponders.

This study has the largest cohort of patients with metastatic breast cancer treated with immunotherapy to be presented to date, and it is the first study to report data on survival for this subgroup. Results were presented at the 2017 American Association for Cancer Research Annual Meeting.¹

A small group of patients will benefit from single-agent immune checkpoint inhibitor therapy, with a long duration of response and longer survival.

— Peter Schmid, MD, PhD

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“The most significant finding is the difference in overall survival between patients who responded to atezolizumab and patients who did not respond. While all responders were alive after 1 year, the 1-year survival rate for nonresponders was only 38%,” said lead author Peter Schmid, MD, PhD, Director of St. Bartholomew’s Breast Centre at St. Bartholomew’s Hospital and Barts Cancer Institute, London.

Triple-negative breast cancer accounts for 10% to 20% of all breast cancers. Dr. Schmid told listeners that triple-negative breast cancer is a rational target for immunotherapy—perhaps the best breast cancer subtype for selecting patients to receive such treatment—due to its high rate of mutations, high levels of programmed cell death ligand 1 (PD-L1) expression, and tumor-infiltrating lymphocyte invasion.

Atezolizumab selectively targets PD-L1 and is currently approved by the U.S. Food and Drug Administration for the treatment of metastatic non–small cell lung cancer and locally advanced or metastatic urothelial bladder cancer that has progressed on platinum-containing chemotherapy. In addition to breast cancer, the drug is also being investigated in other tumor types.

Study Details

The results Dr. Schmid presented at the AACR meeting focused on a cohort of 115 patients with metastatic triple-negative breast cancer treated with atezolizumab every 3 weeks at 15 or 20 mg/kg intravenously or a flat dose of 1,200 mg. Initially patients were treated for up to 16 cycles, but the protocol was amended to allow for newly enrolled patients to be treated past progressive disease, until loss of benefit according to the investigators. About 65% had visceral metastasis, and 30% had bone metastasis.

Patients were heavily pretreated, having received a median of seven prior systemic therapies. Fifty-eight percent were being treated in the third-line or later setting. Two-thirds of tumors had high levels of PD-L1 expression, defined as ≥ 5% positive immune-infiltrating cells.

The overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) was 10% overall and 13% in the group with PD-L1 expression ≥ 5%. Overall response rate was 26% in patients who were treated in the first-line setting and 11% for the second-line group. Disease control (response plus stable disease) was achieved in 30% of patients overall and 58% of those treated in the first line.

“Atezolizumab did not benefit a relatively large proportion of patients whose disease progressed relatively quickly,” Dr. Schmid acknowledged. “But among responders, median duration of response was 21.1 months. In the context of a median overall survival of 9 to 12 months in this disease, the duration of response is substantially longer than what has been seen with any other treatment to date for this population.”

Survival and Biomarkers

Median overall survival in the study was 9.3 months in all patients. The 1-year overall survival rate was 41%, and the 2-year survival rate was 22%. Among responders, 1- and 2-year survival rates were 100%, vs 33% and 11%, respectively, for nonresponders. “Overall survival was substantially longer than what we see with other therapies in this disease,” he emphasized.

With an extended follow-up of 15 months, atezolizumab continues to be generally well tolerated.

Exploratory analysis evaluated biomarkers and found that higher response rates seemed to be associated with higher levels of tumor-infiltrating lymphocytes, CD8 T cells, and PD-L1 expression.

“We saw a higher response rate in earlier lines of therapy and a slightly higher response rate in association with higher PD-L1 expression, but patients with lower PD-L1 expression also benefited from atezolizumab,” Dr. Schmid stated. “We cannot use PD-L1 expression alone as a biomarker for atezolizumab.”

Study Implications

The phase III IMpassion 130 trial is investigating the combination of atezolizumab plus nab-paclitaxel (Abraxane) in the first-line setting for triple-negative breast cancer. The hope is that the combination will broaden the cancer immune response among a greater number of patients.

“The study gives us a small but significant signal. A small group of patients will benefit from immune checkpoint inhibitor therapy alone, with a long duration of response and longer survival. It gives me hope. It is obviously not a solution, and not every triple-negative breast cancer patient should have this treatment, but it is a start,” Dr. Schmid said. “The goal of future studies of combination therapy will be to improve response rates.

Suzanne Topalian, MD

Moderator of a press conference where these data were presented, Suzanne Topalian, MD, said, “This study shows evidence of an ongoing immune response in a subpopulation of women with metastatic triple-negative breast cancer. This may be a new treatment option. Triple-negative breast cancer is a likely target to move forward for immune checkpoint inhibitors. This is a start, but the next step is to study combinations and to identify biomarkers. We need to build on this observation.” Dr. Topalian said. We need to build on this observation.” Dr. Topalian is Professor of Surgery and Oncology, Johns Hopkins Medicine; Associate Director of the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy; and Melanoma Program Director at Hopkins’ Sidney Kimmel Comprehensive Cancer Center, Baltimore. ■

Disclosure: Dr. Schmid reported no conflicts of interest. Dr. Topalian has been a consultant for, received research support from, or owned stock in AbbVie, Bristol-Myers Squibb, Five Prime Therapeutics, Amgen, Compugen, Jounce Therapeutics, MedImmune, Merck, Pfizer, Potenza Therapeutics, Sanofi, and Tizona.

Reference

1. Schmid P, Cruz C, Braiteh FS, et al: Atezolizumab in metastatic TNBC: Long-term clinical outcomes and biomarker analysis. 2017 AACR Annual Meeting. Abstract 2986. Presented April 3, 2017.