Abstract 5666: Safety of the first-in-class anti-NKG2A monoclonal antibody monalizumab in combination with cetuximab: a phase Ib/II study in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)
Authors: Cohen Roger B. , Salas Sébastien , Even Caroline , Kotecki Nuria , Jimeno Antonio , Soulié Anne-Marie , Tirouvanziam-Martin Anne , Zerbib Robert , André Pascale , Boyer-Chammard Agnès , Fayette Jérôme 
Published: July 2017

Abstract
Background:
Monalizumab (IPH2201) is a first-in-class immune checkpoint inhibitor targeting CD94-NKG2A receptors expressed on tumor infiltrating cytotoxic CD8 T lymphocytes and NK cells. HLA-E, the ligand of this inhibitory checkpoint receptor is up-regulated in SCCHN, protecting cancer from killing by CD94-NKG2A+ cells. Monalizumab blocks binding of CD94-NKG2A to HLA-E, reducing inhibitory signaling and thereby enhancing NK and T cell anti-tumor responses. Cetuximab is an anti-EGFR monoclonal antibody blocking oncogenic signaling and inducing Fcγ receptor-mediated antibody dependent cellular cytotoxicity (ADCC). In vitro cetuximab-mediated ADCC is inhibited by HLA-E expression on target cells and this inhibition can be circumvented with CD94-NKG2A blockade. Combination of monalizumab and cetuximab might provide greater antitumor activity than either drug alone.
Methods:
A multicenter, non-randomized dose-escalation and expansion study is evaluating monalizumab plus cetuximab in patients with R/M SCCHN (NCT02643550). Patients ≥ 18 years who progressed after platinum-based chemotherapy (regardless of the number of previous lines of treatment) were enrolled, without regard to HLA-E or human papilloma virus status. Using a 3+3 design, 5 dose levels of monalizumab (0.4, 1, 2, 4 or 10 mg/kg every 2 weeks) were explored with fixed doses of cetuximab (400 mg/m² load followed by 250 mg/m² weekly). Patients were treated until disease progression or unacceptable toxicity. The primary objective was to evaluate safety and Dose Limiting Toxicity (DLT). The secondary objectives were to estimate the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D), and to determine the pharmacokinetics, pharmacodynamics and immunogenicity of the combination.
Results:
Enrolment began in December, 2015. As of October 11, 2016, 13 patients with R/M SCCHN were enrolled at dose levels 0.4, 1, 2 and 4 mg/kg. Median age was 60 years (range: 40-74); 92% were male; PS was 0 or 1; all patients had received prior systemic therapy (1 prior line in 1 patient and &gt; 2
lines in 12 patients) for R/M SCCHN including platinum based chemotherapy (100% of the patients) and cetuximab (85%). There were no DLTs, infusion related reactions, immune related disorders or deaths related to treatment. No discontinuation attributable to treatment-related adverse events and no treatment-related grade 3 and 4 adverse events were reported, except fatigue (grade 3) in one patient. Updated data including pharmacodynamics and pharmacokinetics on the full dose escalation part will be presented.
Conclusion:
Monalizumab + cetuximab were well tolerated with no additional safety concerns compared to monalizumab or cetuximab alone. The dose-expansion phase of the study will be initiated in the near future.
Citation Format: Roger B. Cohen, Sébastien Salas, Caroline Even, Nuria Kotecki, Antonio Jimeno, Anne-Marie Soulié, Anne Tirouvanziam-Martin, Robert Zerbib, Pascale André, Agnès Boyer-Chammard, Jérôme Fayette. Safety of the first-in-class anti-NKG2A monoclonal antibody monalizumab in combination with cetuximab: a phase Ib/II study in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5666. doi:10.1158/1538-7445.AM2017-5666