15 General introduction Targeted therapy and immunotherapy Besides the classical treatment modalities mentioned above, there is an interest to implement targeted therapies (e.g. cetuximab , a monoclonal antibody (moAb) directed against the epidermal growth factor receptor (EGFR, also known as HER1) (53)) and immune checkpoint inhibitors (e.g. pembrolizumab (a moAb directed against PD-1) (54)), nivolumab (a moAb directed against PD-1 (55)), and ipilimumab (a moAb directed against CTLA-4 (56)) in the management of recurrent and/or metastatic (52), as well as locally advanced OSCC (57, 58). The use of targeted therapy and immunotherapy in the treatment of recurrent and/or metastatic disease Historically, the choice of systemic therapies in the treatment of recurrent and/or metastatic disease was not based on improved overall survival and/or quality of life. This changed in 2008, after publication of the results of the phase III randomized EXTREME trial, showing improved survival after addition of cetuximab, to the traditional cytotoxic doublet platinum/5-fluorouacil while maintaining quality of life in the first line setting for recurrent and/or metastatic disease. As a result, adding cetuximab became standard first-line palliative treatment for patients that are fit enough to withstand this treatment regimen (52, 59, 60). This changed with the advent of the immune checkpoint inhibitors nivolumab and pembrolizumab that showed unprecedented results in the second line (CheckMate 141, KEYNOTE-040) and first line (KEYNOTE-048) treatment or recurrent and/or metastatic disease with objective response rates of 13 to 17% and two-year overall survival rates of 17 to 27% (55, 61-63). Specifically, the KEYNOTE-048 trial illustrated the superiority of pembrolizumab alone or pembrolizumab with platinum and 5-FU compared to cetuximab with platinum and 5-FU in the first line setting, with median overall survival of 11.6 versus 10.7 months (not significant) and median overall survival of 13.0 versus 10.7 months (p=0.0034) respectively (61). This survival benefit increases with PD-L1 combined positive score, defined as ‘the number of PD-L1-positive cells (tumor cells, lymphocytes, and macrophages divided by the total number of tumor cellsx100)’ (61). Based on the results observed in this trial for the entire sample population, pembrolizumab plus chemotherapy is nowadays the preferred first-line treatment for patients with recurrent and metastatic disease with a high disease burden. Pembrolizumab alone is used for patients with small tumors and high PD-L1 expression (9, 60). Patients that are not eligible for first-line immunotherapy, due to e.g. high-comorbidity, should receive cetuximab according to the EXTREME protocol (9, 60). 1
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