Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer. (June 2021) - Bourhis, Jean
Graphical abstract: Proposed complementary mechanisms of action of avelumab and cetuximab. Avelumab blocks the PD-1/PD-L1 interaction, thus preventing the inhibition of CD8+ T cells, while cetuximab inhibits EGFR-mediated tumor cell growth and induces immunogenic cell death. Avelumab counteracts the potential resistance mechanisms of cetuximab (T regulatory cell recruitment into the tumor microenvironment) and cetuximab-induced PD-L1 expression on tumor cells via IFNγ and JAK/STAT signaling. Highlights: Avelumab and cetuximab have complementary mechanisms of action. This combination may result in potential synergistic antitumor effects. Studies investigating this combination will help inform future treatment strategies. Abstract: Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.