Patients with triple-negative breast cancer (TNBC) — a subtype which accounts for 10 to 20% of all breast cancers— have very few treatment options. Targeted therapies, which are used to treat many other forms of breast cancer, do not work in this patient population because it is characterized by the absence of hormone and HER2 receptors.
The only remaining options for most TNBC patients is chemotherapy; however many patients develop resistance to this therapy. The median overall survival for metastatic TNBC is only nine to 12 months.
Single-agent atezolizumab (Tecentriq) — a type of immunotherapy agent that harnesses the body’s own immune system to fight disease— recently showed early promise, demonstrating durable responses and long-term survival in patients with TNBC who responded to the therapy, in a phase I study, presented April 3 at the American Association for Cancer Research (AACR) Annual Meeting. 1
The study involved the largest cohort of patients with metastatic breast cancer treated with immunotherapy presented to date, and is the first study to report data on survival for this subgroup of TNBC.
“This is a small but significant signal,” said study lead another Dr. Peter Schmid, M.D, Ph.D., director of the St. Bartholomew’s Breast Centre at St. Bartholomew’s Hospital and Barts Cancer Institute in London, during a presentation at AACR. “The fact that we have a group—while it is a small group that benefits— from single-agent immunotherapy that has had such a substantial benefit in terms of long-duration of response and also a long survival time gives me hope, but it is obviously not the solution for all patients.”
In the study, 112 patients with metastatic TNBC were evaluated for response. Patients included in this study had zero, one, two, or three or more previous treatments. The median age of patients in the study was 53 years old (range 29 to 82).
At the time of enrollment, patients’ tumors were evaluated for the presence of the programmed death-ligand 1 (PD-L1) protein on immune cells inside the tumor, which has been investigated in other tumor types as a potential indicator of response to immunotherapies similar to atezolizumab. The study initially enrolled patients only with high levels of PD-L1, but later expanded to include all-comers.
The primary endpoint of the study was safety, with overall response rate (ORR), duration of response and progression-free survival as key secondary endpoints.
Early promise
ORR was higher in patients that had received fewer previous treatments. ORR was 26 percent among the nineteen patients in the study that received atezolizumab as a first line (initial) treatment, four percent among the 28 patients that received atezolizumab as a second line treatment, and eight percent in the 65 patients that received atezolizumab in the third line or later setting.
In the overall patients population the ORR was 10%, with 11 of the 112 patients responding to treatment.
The median duration of response was 21.1 months in all response-evaluable patients in the trial.
“If you take this in context knowing the median overall survival normally observed in this group is nine to 12 months, a median duration of response of 21 months is in my opinion significant,” said Schmid.
Higher levels of PD-L1 were moderately associated with better clinical outcomes with atezolizumab monotherapy, although more investigation is necessary, said Schmid.
Patients in the study fell into two categories, those with PD-L1 on fewer than 5 percent of immune cells and those with PD-L1 on 5 percent or more of immune cells as assessed by an investigational immunohistochemistry test based on the SP142 antibody being developed by Roche Tissue Diagnostics.
The ORR in those with PD-L1 on fewer than 5 percent of immune cells was 5 percent, while the ORR in those with PD-L1 on 5 percent or more of immune cells was 13 percent.
Results among responders
All 11 patients who responded were alive after one and two years, while for non-responders, OS rates were 33 percent after one year and 11 percent after two years.
Of patients who responded, five received atezolizumab as first line therapy, and nine had disease with high PD-L1 expression.
One- and two-year OS for patients who received atezolizumab as first line treatment were 63 percent and 47 percent respectively; for those who were previously treated, OS rates were 37 percent and 18 percent respectively. One-year OS for patients with high PD-L1 expression was 45 percent, versus 37 percent for those with low to no PD-L1 expression.
The study demonstrated a median overall survival (OS) of 9.3 months in all patients after a median follow-up of 15.2 months.
“The overall survival was longer than what we see with other therapies at the moment,” said Schmid.
With extended follow-up, atezolizumab monotherapy was shown to be generally well tolerated.
“The safety data in this study are very much consistent to what we know with atezolizumab in other diseases,” Schmid added.
Next steps
A randomized phase III study known as IMpassion130 is investigating atezolizumab plus chemotherapy in the first line TNBC to see if is possible to broaden the cancer immune response to a greater number of patients. This study is nearing completion
“That will hopefully enable us to better define the roles of immune checkpoint inhibitors in triple negative breast cancer,” said Schmid.
While the phase I results are promising, much is still unknown, he adds.
“We cannot say that every patient should have single agent immune checkpoint inhibitor therapy because the response rates at the moment are too low,” said Schmid. “For me this is the start of immunotherapy in triple negative breast cancer, and our goal has to be to improve the number of patients that respond to this therapy and have higher response rates, and find more patients that benefit.”
Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic triple-negative breast cancer: long-term clinical outcomes and biomarker analyses. Abstract presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington DC. Abstract 2986.
Filed Under: Drug Discovery
