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Background Although treatment options and survival of HER2+ metastatic breast cancer (MBC) patients have greatly improved, the majority of MBC-patients still die of this disease. The relatively high levels of TILs observed in this BC subtype provide a rationale for immunomodulatory strategies, however, PD1-blockade has only shown modest response rates in this setting. While PD-1 blockade mainly acts on T cells, monalizumab targets the inhibitory immune checkpoint NKG2A which interacts with HLA-E on tumor cells, thereby unleashing NK- as well as CD8 T cells. We hypothesize that monalizumab can promote antibody-dependent cell-mediated cytotoxicity (ADCC) which is critical for trastuzumab efficacy. Clinical activity was shown in patients with head and neck cancer when monalizumab was combined with cetuximab (anti-EGFR). Here, we present the first results of the MIMOSA-trial investigating the efficacy of the novel combination monalizumab and trastuzumab in patients with HER2+ MBC. Methods In the phase II MIMOSA-trial (NTC04307329), HER2+ MBC patients were treated biweekly with 4mg/kg trastuzumab and 750mg monalizumab. Key eligibility criteria were progressive disease despite anti-HER2 therapy, had received a minimum of one and a maximum of three lines of palliative chemotherapy, had measurable disease according to RECIST1.1, and a serum LDH-level below 500U/L. Primary endpoint was objective response rate according to RECIST1.1. Secondary endpoints included clinical benefit rate (complete response CR, partial response PR or stable disease SD for at least 6 months) according to RECIST1.1, progression-free survival, overall survival and safety. Dose-limiting toxicities were continuously monitored throughout the trial and evaluated using a pre-defined Pocock-type boundary rule. Following a Simon’s two-stage design, 11 patients were included in stage I of the trial. If two or more responders were observed, further exploration is warranted in stage II. Results Between January 2021 and April 2022, eleven women of which ten are currently evaluable were enrolled in the trial. Patients received a median of two lines of prior treatment for MBC, of which 6 out of 11 patients were treated with trastuzumab emtansine (T-DM1). The majority of patients had hormone receptor positive BC (72% of the patients) and had low levels of tumor-infiltrating lymphocytes (TILs) with a median of 1% (ranging from 1% to 20%). Patients received a median of four cycles of trastuzumab and monalizumab. Treatment was well tolerated with no dose-limiting toxicities. No objective responses were observed in the first ten out of eleven evaluable patients. Therefore, MIMOSA stage I did not meet its primary endpoint, leading to discontinuation of the trial. Conclusions The novel combination of trastuzumab and monalizumab did not induce objective responses in heavily pre-treated HER2+ MBC patients. Citation Format: Veerle Geurts, Leonie Voorwerk, Karolina Sikorska, Roberto Salgado, Koen van de Vijver, Marloes van Dongen, Inge Kemper, Ingrid A. Mandjes, Martine Heuver-mes, John Haanen, Gabe S. Sonke, Hugo Horlings, Marleen Kok. Unleashing NK- and CD8 T cells by combining monalizumab (anti-NKG2A) and trastuzumab for metastatic HER2+ breast cancer: first results MIMOSA trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-01.

New assays are developed regularly to improve health care for patients. It is important to ensure that assays are performed correctly. Therefore, it is advised to participate in training and proficiency (competence assessment) programs. Tumor infiltrating lymphocytes (TILs) might improve the estimates of response to therapy and prognosis. Herewith, we propose a new training and proficiency program in which each pathologist can train and test themselves regarding TILs (and PDL1) scoring.