EGFR in head and neck squamous cell carcinoma: exploring possibilities of novel drug combinations

Abstract

The standard care for head and neck squamous cell carcinoma (HNSCC) patients involving postoperative radiation therapy (RT) with concurrent cisplatin-based chemotherapy remains the same to this day since it's conceptualization in the 1960s (1). Though this treatment plan does improve locoregional control and disease-free survival in head and neck cancer patients, rates for overall 5-year survival is unimpressive in advanced HNSCC, ranging from 30% to 60%. The human epidermal growth factor receptor (EGFR), also known as ErbB-1 or HER1, is a member of the ErbB receptor family. It is an extensively studied oncogenic gene influencing gene expression, proliferation, angiogenesis, apoptosis inhibition, cell motility, metastasis, adhesion, and angiogenesis. As one of the top targets of precision therapy, especially due to high levels of mutations found in lung cancer, it was natural to assume that head and neck cancer patients may benefit from EGFR-targeted therapies. This is due to the fact that EGFR is overexpressed in over 90% of head and neck tumors (2) and the association translates to shorter survival for patients (3-5). HNSCCs have significantly increased EGFR expression, high frequency of EGFR amplification, and low rates of single nucleotide variations (SNV)/indels (6). In 2006, Cetuximab (Erbitux), a monoclonal antibody (mAb) targeting the extracellular domain of EGFR, was approved for head and neck cancer for either local/regional advanced squamous cell carcinoma in combination with RT, or as a monotherapy for recurrent or metastatic squamous cell carcinoma progressing after platinum-based therapy. Then in November 2011, the FDA approved Cetuximab for late-stage head and neck cancer in combination with chemotherapy (recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with Fluorouracil). However, it became clear later that the response rate for Cetuximab was less than 20% in HNSCC patients, despite high amplification of EGFR and independent of human papillomavirus (HPV) status. The addition of Cetuximab to platinum-based chemoradiation (CRT) did not lead to an improved outcome (7) and Cetuximab with RT yielded inferior overall survival in comparison with cisplatin for the nonoperative management of stage III to IVb HNSCC (8). Additionally, for patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus Cetuximab showed lower overall survival and progression-free survival compared with radiotherapy plus cisplatin (9). Yet, these results coincide with recent findings that the addition of Cetuximab to either carboplatin/paclitaxel chemotherapy or high-dose radiotherapy treatment provided no survival benefit for nonresectable stage III non-small cell lung cancer (NSCLC), a cancer subtype that displays high EGFR expression and mutation rates (10). Another arm of targeting EGFR, besides monoclonal antibodies, involves tyrosine kinase inhibitors (TKI) that Editorial