Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: Head and neck squamous cell carcinoma (HNSCC), in the locally advanced setting, relapses in more than 50% of cases after surgery and/or chemo-radiotherapy. Prognosis is then very poor with platinum-based chemotherapy yielding a median survival of 10 months and a 2-year survival rate of less than 20%. In recent years, immunotherapy, has changed treatment and prognosis of several tumor types. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for immunotherapy. This review describes the major therapeutic breakthrough worked by Immune Checkpoint Inhibitors (ICIs) blocking the PD-1/PD-L1 axis. These monoclonal antibodies have doubled the 2-year survival rate thanks to long lasting responses with a favorable toxicity profile. Further progress is expected with new immunotherapeutic agents having a different mechanism of action combined with anti-PD(L)1, chemotherapy or targeted therapies. ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median survival, and almost no effective treatment are available in second line. Immune checkpoint inhibitors (ICIs) have changed the prognosis of several metastatic solid tumors. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for ICIs treatments. First, a strong pembrolizumab efficacy signal was shown in the Keynote-012 Phase Ib study. Then, the phase III Checkmate-141 study validated the efficacy of nivolumab in platinum-resistant patients. Finally, the first line conquest is acquired since the final results of the keynote-048 phase III study that demonstrated the superiority of pembrolizumab versus EXTREME in CPS ≥ 1 patients, and with the addition of platinum and 5FU in all patients. However, the first line treatment landscape is not frozen. Two studies (Checkmate-651 and Kestrel) are investigating the efficacy of the combination of antibodies raised against CTLA-4 and PD-(L)1. Results are impatiently awaited. Further progress needs the use of new immunotherapeutic agents such as monalizumab or ICOS agonist rather in combination with an anti-PD(L)1. New associations of ICIs and chemotherapeutic or targeted therapeutic agents are also actively investigated. Finally, ICIs has to be studied in the locally advanced setting where there is a chance of cure. Several trials are testing the potential synergistic combination of ICIs with radiotherapy and platinum or cetuximab, or ICIs used in a neoadjuvant setting.