Abstract CT158: Phase II study of monalizumab, a first-in-class NKG2A monoclonal antibody, in combination with cetuximab in previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Preliminary assessment of safety and efficacy
Authors: Cohen Roger , Fayette Jérôme , Posner Marshall , Lefebvre Gautier , Bauman Jessica , Salas Sébastien , Even Caroline , Seiwert Tanguy , Colevas Dimitrios , Jimeno Antonio , Saada Esma , Burtness Barbara , André Pascale , Paturel Carine , Bonnafous Cécile , Soulié Anne-Marie , Tirouvanziam-Martin Anne , Zerbib Robert , Boyer-Chammard Agnès 
Published: August 2018

Abstract
Background Monalizumab is an immune checkpoint inhibitor targeting NKG2A receptors expressed on subsets of tumor-infiltrating cytotoxic CD8 T cells and Natural Killer (NK) cells. NKG2A ligand is HLA-E, a non-classical HLA class I molecule often upregulated in cancer. Preclinical experiments have shown that blocking NKG2A binding to HLA-E may promote NK and T cell anti-tumor responses. NK cell stimulation with a checkpoint inhibitor might also enhance antibody dependent cellular cytotoxicity (ADCC) induced by cetuximab. Although approved in SCCHN after platinum-based therapy, cetuximab has limited activity in that setting (12% response rate).
Methods This is a multicenter non-randomized study (NCT02643550). After previous exploration of 5 dose levels of monalizumab (0.4, 1, 2, 4 or 10 mg/kg every 2 weeks) in combination with fixed doses of cetuximab (400 mg/m² load then 250 weekly) using a 3+3 design, the cohort expansion used monalizumab at the highest dose tested (10 mg/kg) and included a futility analysis after the first 11 patients (pts). The trial was open to pts ≥ 18 years old with SCCHN progressing after platinum-based therapy with no more than 2 previous lines, regardless of HLA-E or human papilloma virus status. The primary endpoint for anti-tumor activity was overall response rate per RECIST, assessed every 8 weeks. Pts were treated until disease progression or unacceptable toxicity.
Results As of 12/19/2017, 26 pts were enrolled in the expansion part, and 16 pts had a minimum of 16 weeks of follow-up to be evaluable for efficacy. The safety profile was as expected, similar to the single agent experience with either agent. The majority of adverse events (AE) were of Grade 1-2 severity, rapidly reversible and easily manageable, with 3 treatment-related grade 3-4 AE and 1 pt stopped monalizumab due to safety. Median age was 62 years (range: 34-77); 56 % were male; PS was 0 or 1; 4 were HPV+. All 16 pts had received prior platinum-based therapy, 8 prior immune therapy, 2 prior cetuximab with radiation. There were 6 pts with partial responses (PR) (4 confirmed; 2 not yet confirmed) of whom 2 were previously treated with immune therapy and 1 had disease deemed resistant to cetuximab. Median treatment duration for confirmed PR is 25+ weeks (16, 23+, 28+, 35+), 9 pts had stable disease (SD). The study was not stopped for futility and is planned to enroll up to 40 pts. Further follow-up is needed to evaluate duration of response, progression-free and overall survival.
Conclusion Preliminary data suggest promising antitumor activity of the combination of monalizumab and cetuximab compared to historical data with single agent cetuximab, with acceptable safety. These encouraging results will need to be confirmed on larger sample size with longer follow up.
Citation Format: Roger Cohen, Jérôme Fayette, Marshall Posner, Gautier Lefebvre, Jessica Bauman, Sébastien Salas, Caroline Even, Tanguy Seiwert, Dimitrios Colevas, Antonio Jimeno, Esma Saada, Barbara Burtness, Pascale André, Carine Paturel, Cécile Bonnafous, Anne-Marie Soulié, Anne Tirouvanziam-Martin, Robert Zerbib, Agnès Boyer-Chammard. Phase II study of monalizumab, a first-in-class NKG2A monoclonal antibody, in combination with cetuximab in previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Preliminary assessment of safety and efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT158.