Targeting the human epidermal growth factor receptor-2 (HER2) is the cornerstone of the treatment of HER2+ breast cancer patients. The mechanism of action of trastuzumab is partly based on lysis of tumor cells via antibody dependent cellular cytotoxicity (ADCC), which among others involves NK cells. However, NK cell and CD8+ T-cell activity is inhibited by binding of the inhibitory receptor NKG2A to HLA-E. HLA-E expression is upregulated upon tumor cells and preserved throughout disease progression. Monalizumab is an antibody targeting the NKG2A receptor, thereby blocking NKG2A-HLA-E interaction. Monalizumab has shown clinical activity in head and neck cancer when combined with cetuximab (anti-EGFR). We hypothesize that monalizumab improves trastuzumab-mediated ADCC and thereby helps to overcome trastuzumab-resistance and can promote anti-tumor immunity by unleashing NK cells and CD8+ T cells in HER2+ breast cancer. The MIMOSA-trial (NCT04307329) is an explorative phase II trial in which patients will be treated biweekly with trastuzumab and monalizumab. Clinical efficacy will be assessed separately in patients with high stromal tumor-infiltrating lymphocytes (sTILs) (≥ 5%) and in patients with low sTILs (< 5%) using a Simon's-two stage design. In stage I, eleven patients will be accrued per cohort. If two or more responders are observed, another eight patients will be accrued. Inclusion criteria comprise histologically confirmed HER2+ breast cancer on a metastatic lesion, progression during previous trastuzumab or TDM-1 therapy, administration of at least one and maximum of three lines of palliative chemotherapy, a metastatic lesion accessible for biopsy and LDH <500 U/l. Primary endpoint is the objective response rate according to RECIST1.1. Secondary endpoints include to evaluate clinical benefit and progression-free survival according to RECIST1.1, overall survival and safety. Before and on-treatment blood and biopsies will be used for translational research to explore treatment-induced intra-tumoral and systemic changes with a focus on NK-cells and CD8+ T-cells. The MIMOSA-trial is currently open for enrollment at the Netherlands Cancer Institute. NCT04307329. Netherlands Cancer Institute. AstraZeneca.
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