Avelumab: clinical trial innovation and collaboration to advance anti-PD-L1 immunotherapy

Cancer development and progression are characterised by evasion of immune responses, including tumour escape mediated through immune checkpoint pathways [1–4]. Programmed death ligand-1 (PDL1) is a suppressive immune checkpoint ligand that binds two receptors expressed on T cells—programmed death-1 (PD-1) and B7.1 (CD80)—to inhibit T-cell activation, proliferation, and cytotoxicity [5–9]. PD-L1 expression can be upregulated on various immune cells, including antigen-presenting cells (APCs), as a physiological mechanism for regulating immune responses and suppressing T-cell activity [10]. A second checkpoint pathway ligand for PD-1, PD-L2, is expressed on various immune cells and may play a role in immune homeostasis [11, 12]. By overexpressing PD-L1, cancer cells exploit the PD-1/PD-L1 pathway to promote an immunosuppressive environment and allow tumour growth [5, 13]. Blocking PD-L1 inhibitory signals can restore T-cell antitumour activity and thus represents a key therapeutic strategy [13, 14]. Five checkpoint inhibitors are currently approved by the US Food and Drug Administration (FDA) for the treatment of cancer, including an anti-CTLA-4 antibody (ipilimumab), anti-PD-1 antibodies (pembrolizumab and nivolumab), and anti-PD-L1 antibodies (atezolizumab and avelumab). Avelumab (MSB0010718C) is a human immunoglobulin G1 (IgG1) anti-PD-L1 monoclonal antibody [15] with the potential to utilise both adaptive and innate immune mechanisms to destroy cancer cells [5, 15, 16]. Its ability to induce innate immune mechanisms against cancer cells, shown in preclinical studies [17], makes avelumab unique among anti-PD-L1 or anti-PD-1 antibodies approved or in advanced clinical development. Avelumab is being evaluated in the international JAVELIN clinical trial programme across more than 16 different tumour types, both as monotherapy and in combination [17]. This programme is sponsored by an alliance between two global companies, Merck KGaA, Darmstadt, Germany, and Pfizer, Inc., New York, NY. Evidence of promising antitumour activity and manageable adverse events has been demonstrated for multiple advanced malignancies [18–24], leading to accelerated approval of avelumab by the US FDA in March 2017 for the treatment of metastatic Merkel cell carcinoma [25]. Here, we provide an overview of avelumab’s development from discovery to registrational studies in multiple tumour types.