1. Eastman, Peggy

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WASHINGTON, D.C.-Patients with metastatic triple negative breast cancer (TNBC) who responded to the anti-PD-L1 immunotherapy atezolizumab had higher overall survival than non-responders, as demonstrated in a phase I trial presented at the annual meeting of the American Association for Cancer Research, held April 1-5.

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This study contains the largest number of patients with metastatic breast cancer treated with immunotherapy to date, and it is the first to report data on survival for the TNBC cohort, according to lead author Peter Schmid, MD, PhD, Director of the St. Bartholomew's Breast Centre at St. Bartholomew's Hospital and Barts Cancer Institute in London.


The subgroup of patients with metastatic TNBC treated with atezolizumab monotherapy had a prolonged median duration of response of 21 months, which Schmid noted "is substantially longer than what has been seen with any other treatment to date for this patient population.


"All responding patients achieved long-term survival benefit," he continued. "With extended follow-up (a median of 15 months) in the TNBC cohort, atezolizumab monotherapy continues to be well-tolerated."


Speaking at a news conference on his findings, Schmid explained atezolizumab has demonstrated efficacy and safety in a broad range of cancer types; it is approved in the U.S. for previously treated metastatic urothelial carcinoma and non-small cell lung cancer. The drug is a humanized engineered monoclonal antibody that selectively inhibits PD-L1 interactions with its receptors PD-1 and B7.1, "thereby reinvigorating and enhancing anti-cancer immunity," he stated.


If other studies confirm its efficacy for metastatic TNBC, atezolizumab would be a welcome addition to oncologists' armamentarium, Schmid said. "In terms of survival in breast cancer, we have made significant progress...unfortunately, we have not made such progress in triple negative breast cancer. TNBC is an aggressive breast cancer subtype with a high unmet need."


TNBC tends to strike younger women and, in the metastatic setting, limited therapy options are available; median overall survival is about 9-12 months, Schmid explained.


Atezolizumab Study Details

Schmid and his colleagues recruited and enrolled 115 patients with metastatic TNBC to one of the expansion cohorts of the phase I trial. The median age was 53, with an age range of 29 to 82. Visceral metastatic sites were present in 65 percent, and bone metastastic sites were present in 30 percent. Of the 112 patients who could be evaluated for response, 19 received atezolizumab as first-line treatment, while 93 patients received at least two lines of prior therapy. Prior therapies included anthracycline, taxane, platinum, and bevacizumab.


At the time of enrollment, TNBC patients' tumors were evaluated for the presence of the PD-L1 protein on immune cells inside the tumor. Patients fell into one of two categories: those with PD-L1 on less 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. Per RECIST v1.1, 11 patients responded to treatment for an overall response rate (which included complete and partial responses) of 10 percent.


Both 1- and 2-year overall survival rates for responders were 100 percent, while for nonresponders the 1-year survival rate was 33 percent and the 2-year survival rate was 11 percent. Of the 11 RECIST v1.1 responders, five received atezolizumab as first-line therapy, and nine had metastatic disease with high PD-L1 expression.


One-year overall survival for TNBC patients who received atezolizumab as first-line treatment was 63 percent, while 2-year overall survival in this group was 47 percent. For patients who received the drug as second-line treatment, the 1-year overall survival rate was 37 percent and the 2-year overall survival rate was 18 percent. One-year overall survival for patients with high PD-L1 expression was 45 percent, compared to an overall survival rate of 37 percent for those with low to no PD-L1 expression.


Schmid stated the drug was generally well-tolerated in the TNBC cohort; 11 percent of patients experienced treatment-related grade 3 or 4 side effects. Side effects led to discontinuation of treatment in 3 percent of patients.


Immunotherapy Options

TNBC is probably the best breast cancer subgroup in terms of response to immunotherapy, said Schmid, because it has a high rate of mutations, high levels of PD-L1 expression, and high levels of tumor-infiltrating lymphocytes (TILs). "Atezolizumab has yielded durable responses in a small population of both previously untreated and pre-treated TNBC patients and is associated with an excellent safety profile," he noted. "The results provide further evidence that immunotherapy may play a significant role in the treatment of breast cancer. This is a small but significant signal. That gives me hope."


Schmid said it will now be up to "other ongoing and future studies to further improve on these treatment outcomes by optimizing treatment regimens and combinations for this hard-to-treat group of patients. Exploratory biomarker analyses suggested that higher levels of TILs and CD8 cells, and to a lesser extent PD-L1 on immune cells, are associated with better clinical outcomes with atezolizumab monotherapy."


Currently, the randomized phase III study IMpassion 130 is "investigating the hypothesis that atezolizumab plus chemotherapy in the 1L TNBC setting can broaden the cancer immune response to a greater number of patients," noted Schmid. The IMpassion 130 trial is evaluating atezolizumab combined with nab-paclitaxel for previously untreated metastatic TNBC. For breast cancer in general, "the way forward is clearly combinations."


A limitation of this study is that it did not have a randomized control group treated with standard therapy; therefore, the survival data in the study could only be seen in the context of the survival of historical TNBC controls.


Peggy Eastman is a contributing writer.