Beyond EGFR targeting in SCCHN: Angiogenesis, PI3K, and other molecular targets

Abstract

Although the molecular landscape of squamous cell carcinoma of the head and neck (SCCHN) has been largely deciphered, only one targeted therapy has been approved to date without any molecular selection, namely cetuximab. Cetuximab is a monoclonal antibody targeting EGFR. It has been shown to improve overall survival in the locally advanced setting in combination with radiotherapy and the recurrent and/or metastatic setting in combination with a platinum compound and 5FU. Beside EGFR targeting agents, antiangiogenic agents have been shown to produce antitumor activity but were associated with substantial toxicity. Buparlisib that targets PI3K was also shown to improve survival in combination with paclitaxel in an unselected patient population. Several other targeted therapies have been developed in SCCHN, most of time in all comers, potentially explaining the limited efficacy reported with them. The recent emergence of clinical trials of targeted therapies in enriched patient populations and precision medicine trials such as umbrella trials might boost the clinical development of targeted therapy in SCCHN. KEY CONCEPTS 1) EGFR is the only clinically validated target beside PD-1 in SCCHN. 2) Antiangiogenic agents have been shown to produce antitumor activity in SCCHN but are associated with substantial toxicity. 3) Buparlisib has been the only drug targeting the PI3K/AKT/mTOR pathway to show a survival improvement in SCCHN. 4) There is an urgent need to develop targeted therapies in enriched patient populations in SCCHN.