Abstract
PurposeAgents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC.MethodsIn a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx).ResultsA total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2–50 weeks and followed for 6–15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1− tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%).ConclusionAvelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.
Highlights
Despite advances in the treatment of breast cancer and an encouraging 5-year overall survival rate of approximately 90% in the United States, up to 30% of patients with an early-stage diagnosis eventually progress to incurable metastatic disease, and 6% of patients have metastatic disease at diagnosis [1, 2]
Treatment of metastatic breast cancer (MBC) is based on molecular subtype and may include chemotherapy, human epidermal growth factor receptor 2 (HER2)-directed agents, and endocrine-based therapies or agents targeted to mechanistic target of rapamycin or CDK4/6 for those tumors overexpressing estrogen receptor (ER) and/or progesterone receptor (PR) [3]
PD-L1 expression may serve as a marker of immune activity, and local immunosuppression of tumor-infiltrating lymphocytes (TILs) via the PD-L1/programmed death receptor 1 (PD-1) pathway may be an important means of tumor immune evasion [8, 14]
Summary
Despite advances in the treatment of breast cancer and an encouraging 5-year overall survival rate of approximately 90% in the United States, up to 30% of patients with an early-stage diagnosis eventually progress to incurable metastatic disease, and 6% of patients have metastatic disease at diagnosis [1, 2]. 15–20% of patients have breast cancers lacking expression of ER, PR, or HER2, which are termed triple-negative breast cancer (TNBC). For these patients, standard treatment is cytotoxic chemotherapy, which is limited by poor tolerability and short duration of response [4,5,6]. Inhibition of the PD-L1/PD-1 axis with monoclonal antibodies may be one means of restoring immune surveillance and cell-mediated antitumor activity, and studies of anti-PD-L1/PD-1 agents have shown durable antitumor responses in patients with various advanced cancers [7, 16]. Early-phase studies have suggested that these agents may have clinical activity in breast cancer, in the TNBC subtype [17,18,19]
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