Man scripClick here to access/download;Manuscript;2020.08.12_Manuscript_DIVA_TrAuthor's role and participation on the manuscript 38 All authors have participated to the conception and design, acquisition of data, or analysis and interpretation of data; All authors have participated to the drafting the article or revising it critically for important 41 intellectual content; 42 All authors have approved the final version to be published; 43 All authors have participated to the agreement to be accountable for all aspects of the work in 44 ensuring that questions related to the accuracy or integrity of any part of the work are 45 appropriately investigated and resolved 46 47 Approval and confirming statements 48 This study was approved by Institutional review board and performed in accordance with the 49 Helsinki declaration. Collection of data and analysis were in accordance with guidelines of 50 the French National Committee for the Protection of Personal Data (Commission Nationale 51 Informatique et Libertés, CNIL, declaration number 2218907v0). 52

Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.