Based on these data, we believe that further investigation of immune therapies in HER2-positive, estrogen receptor–negative breast cancer is warranted, particularly if combination therapies can expand the T-cell compartment.
—Hope Rugo, MD
Despite the modest overall response rate in unselected metastatic breast cancer patients, there were signs of greater clinical activity...among patients with triple-negative breast cancer and patients expressing PD-L1. Further analysis of PD-L1 expression and clinical activity of avelumab is ongoing.
—Luc Dirix, MD
Immunotherapy is at the forefront of exciting new approaches to cancer, with excellent and long-lasting responses in metastatic melanoma and non–small cell lung cancer (NSCLC) and several immunotherapy agents now approved for those malignancies by the U.S. Food and Drug Administration (FDA). The hope is that other tumors will follow suit. However, at the 2015 San Antonio Breast Cancer Symposium (SABCS), two separate preliminary studies of immunotherapy presented lackluster results, but it is still early in the days of immunotherapy for breast cancer.
The JAVELIN trial explored the use of the investigational IgG1 anti–PD-L1 (anti–programmed cell death ligand 1) antibody avelumab in patients with locally advanced or metastatic breast cancer and showed a low overall response rate of 4.8%.1 However, there was an early signal for hope in triple-negative breast cancer; of the eight patients who responded in this trial, five had triple-negative breast cancer. Tumor shrinkage of 30% or more was observed in 16 patients (9.5%) in the overall study population.
“Despite the modest overall response rate in unselected metastatic breast cancer patients, there were signs of greater clinical activity among patients with triple-negative breast cancer and patients expressing PD-L1 [PD-1 ligand]. Further analysis of PD-L1 expression and clinical activity of avelumab is ongoing,” said presenting author Luc Dirix, MD, of Sint Augustinus–University of Antwerp, Belgium.
The study enrolled 168 patients unselected for PD-L1 expression. A total of 58 had triple-negative breast cancer, 72 had estrogen receptor–positive/HER2-negative or progesterone receptor–positive disease, and 26 had HER2-positive disease (another 12 patients had disease of an unknown molecular subtype). Avelumab was given at 10 mg/kg intravenously every 2 weeks until disease progression.
Response to avelumab appeared to be related to PD-L1 expression on immune cells within the tumor: 33% for those with positive PD-L1 expression vs 2.4% for tumors that were PD-L1–negative. Of the five triple-negative breast cancer responders, four had PD-L1–positive immune cells.
The safety profile of avelumab was acceptable. Grade 3 or higher treatment-related adverse events were reported in 13.7%. Immune-related side effects were reported in 17 patients (ie, hypothyroidism, thrombocytopenia, and/or autoimmune hepatitis). Eight patients discontinued treatment with avelumab (4.8%). Treatment-related deaths were reported in two patients (1.2%). At the time of data cutoff, nine patients remained on avelumab.
Pembrolizumab (Keytruda), an FDA-approved anti–PD-1 antibody for melanoma and NSCLC, was studied in a “basket” trial that included several types of advanced cancers that express PD-L1.2
Among 25 evaluable patients (from a cohort of 261 breast cancer patients) with estrogen receptor–positive/HER2-negative breast cancers that express PD-L1, the overall response rate was 12% (comprising only 3 partial responders), with another 4 patients (16%) having stable disease. Five patients (60%) progressed on pembrolizumab, and three (22%) were not evaluable at the time of presentation. The clinical benefit rate (response rate plus stable disease) was 20%. Responses were durable in this group, ranging from 8.7 weeks to more than 44 weeks.
Despite these results, lead author Hope Rugo, MD, of the University of California San Francisco, was encouraged. “Based on these data, we believe that further investigation of immune therapies in HER2-positive, estrogen receptor–negative breast cancer is warranted, particularly if combination therapies can expand the T-cell compartment,” she told listeners.
At the 2015 SABCS, Dr. Rugo presented preliminary efficacy results of 25 evaluable patients with estrogen receptor–positive/HER2-negative breast cancer in KEYNOTE-028. The total breast cancer cohort included 261 patients who were screened for PD-L1 expression; 48 had PD-L1–positive tumors, according to the assay used in this trial (which is different from the assay used in the JAVELIN and other trials of anti–PD-1 and anti–PD-L1 therapies). At the time of data cutoff, all three partial responders remained on therapy with pembrolizumab.
Dr. Rugo and other investigators in this field believe that standardization of PD-L1 assays is critical. Despite the lack of such standardization, some studies show responses in PD-L1–negative tumors, so the jury is out as to whether PD-L1 expression will select all patients who will respond to these therapies. As in the JAVELIN trial, patients enrolled in the KEYNOTE-028 trial were heavily pretreated with advanced disease.
No new safety signals related to treatment with checkpoint inhibitors were raised. Grade 3 or 4 adverse events were reported in 4 of 25 patients; 4 immune-related grade 3 events occurred, and there was 1 grade 4 event. No treatment-related deaths were reported at a median follow-up of 7.3 months. ■
Disclosure: The JAVELIN study was sponsored by Merck and Serono, and the KEYNOTE-028 study was funded by Merck. Dr. Dirix reported no potential conflicts of interest. Dr. Rugo disclosed research funding from Merck and Genentech to the University of California San Francisco.
1. Dirix LY, Takacs I, Nikolinakos P, et al: Avelumab (MSB0010718C), an anti–PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. 2015 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 9, 2015.
2. Rugo HS, Delord J-P, Im S-A, et al: Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive estrogen receptor–positive/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. 2015 San Antonio Breast Cancer Symposium. Abstract S5-07. Presented December 11, 2015.