Clinical Development of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma

Abstract

A better understanding of cancer biology has led to the development of molecular targeted therapy, which has dramatically improved the outcome of some cancer patients, especially when a biomarker of efficacy has been used for patients’ selection. In head and neck oncology, cetuximab that targets epidermal growth factor receptor is the only targeted therapy that demonstrated a survival benefit, both in the recurrent and in the locally advanced settings, yet without prior patients’ selection. We herein review the clinical development of targeted therapy in head and neck squamous cell carcinoma in light of the molecular landscape and give insights in on how innovative clinical trial designs may speed up biomarker discovery and deployment of new molecular targeted therapies. Given the recent approval of immune checkpoint inhibitors targeting programmed cell death-1 in head and neck squamous cell carcinoma, it remains to be determined how targeted therapy will be incorporated into a global drug development strategy that will inevitably incorporate immunotherapy.

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

“…Furthermore, CTX has shown limited efficacy in HNSCC with an overall response rate of 10%–20%, contrasting with the high rates of EGFR overexpression ( 51 , 72 ). This underlines the existence of resistance mechanisms, remaining unresolved, but for which several hypotheses have been proposed ( 48 , 56 , 64 , 67 , 73 – 81 ) ( 4 , 12 , 21 , 24 , 29 – 37 ). The different type of resistance mechanisms to CTX could be defined as follows: alterations of the EGFR-ligand binding, alterations of the EGFR downstream signaling effectors, parallel/bypass pathway activation, alterations of proteins involved in classic cancer pathways, EMT, epigenetic alterations and establishment of an immunosuppressive TME ( Figure 1 ).…”

“…Because EGFR is overexpressed in 80%–90% of HNSCC cases, tumors are often addicted to EGFR signaling for sustained survival and proliferation, and this overexpression is correlated with poor prognosis and treatment outcomes ( 53 – 55 ), therapies targeting EGFR have been widely evaluated for HNSCC ( 56 – 58 ): first, intravenous anti-EGFR antibodies that bind to the extracellular domain of the receptor causing its internalization to prevent its activation by other ligand–receptor interactions ( 59 ) while favoring antibody-dependent cell-mediated cytotoxicity (i.e., ADCC, which refers to the linking to innate and adaptive antitumor immune responses via NK cells and antigen-presenting cells that lead to EGFR-specific T cells) ( 60 – 63 ) and ii-oral EGFR tyrosine kinase inhibitors (TKI) binding to the intracellular domain of EGFR inhibiting its autophosphorylation (blocking of the ATP binding to the intracellular tyrosine kinase domain of EGFR) and downstream signaling ( 56 , 64 , 65 ).…”

“…Cetuximab (CTX), a monoclonal antibody targeting the EGFR extracellular domain, is to date the only targeted therapy that has demonstrated benefits in OS in combination with both radiotherapy for patients with locally advanced HNSCC ( 66 ) and chemotherapy (platinum, 5-FU, and CTX) as the first-line treatment of patients with recurrent and/or metastatic HNSCC ( 5 , 67 ). Of note, CTX has never proven to be effective postoperatively ( 56 , 58 , 68 ).…”

Predictive Value of EGFR-PI3K-AKT-mTOR-Pathway Inhibitor Biomarkers for Head and Neck Squamous Cell Carcinoma: A Systematic Review

“…The understanding of the molecular pathogenesis of HNSCC has improved considerably in the last decade, resulting in the development of several targeted therapies for HNSCC [ 7 ]. In particular, therapies targeting the epidermal growth factor receptor (EGFR) have been explored extensively.…”

Industry and MASCC—an opportunity not to be missed

“…Simultaneously, the limited success and toxicities of many cytotoxic treatment regimens necessitated the introduction of new approaches to cancer treatment which have largely been driven by advances in understanding of cancer biology. Cancer therapies have continuously evolved to include novel radiation delivery technologies, an expanding range of cytotoxic agents, and new targeted drugs and immunotherapies [1][2][3][4]. Though the benefits have been extensive, advances also add to the variety and complexity of treatment-associated complications [5,6].…”