New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN)

Abstract

Despite recent advances in radiotherapy and chemotherapy, survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained poor. The focus of SCCHN therapy has more recently shifted to the molecular level, particularly the epidermal growth factor receptor (EGFR/ErbB) pathway. Several agents that target the EGFR pathway, including monoclonal antibodies and tyrosine kinase inhibitors, are under investigation for SCCHN. Searches of PubMed and results of key oncology congresses were performed to identify relevant articles and abstracts. The EGFR-targeted monoclonal antibody cetuximab is approved for the treatment of locally advanced SCCHN in combination with radiotherapy, for first-line treatment of recurrent or metastatic SCCHN in combination with platinum-based chemotherapy and 5-fluorouracil, and for recurrent or metastatic SCCHN following progression with platinum-based chemotherapy. Other investigational EGFR-targeted monoclonal antibodies (e.g., panitumumab, nimotuzumab, zalutumumab) are in clinical development for SCCHN. Inhibition of the tyrosine kinase domain of EGFR has also been explored as a therapeutic approach in SCCHN using small-molecule reversible inhibitors, such as gefitinib and erlotinib. However, a key challenge in SCCHN is the development of resistance, and strategies are being pursued to delay or overcome resistance to EGFR-targeted agents. These strategies include development of agents that inhibit multiple ErbB receptors simultaneously (e.g., lapatinib) or that bind multiple ErbB family receptors irreversibly (e.g., afatinib, PF-00299804) and investigation of combinations of agents that target multiple pathways implicated in the pathogenesis of SCCHN. Ongoing large clinical trials are evaluating these emerging agents and combinations for the treatment of SCCHN.

Fig. 1

Epidermal growth factor receptor and ErbB family downstream signaling pathways potentially involved in squamous cell carcinomas of the head and neck. Downstream pathways activated by dimerization and activation of the ErbB family. Adapted with permission from Venook et al. [5]. ©2005 John Wiley & Sons, Inc. Akt v-akt murine thymoma viral oncogene homolog, serine-threonine kinase 1, Bad Bcl-2 antagonist of cell death, Bcl B-cell lymphoma, CdK cyclin dependent kinase, EGFR epidermal growth factor receptor, ELK-1 Ets like gene 1, ErbB erythroblastic leukemia viral oncogene homolog, ERK extracellular signal-regulated kinase, Fos protooncogene c-fos, GRB2 growth factor receptor-bound protein 2, HIF-1α hypoxia inducible factor-1α, JAK Janus kinase, MEK mitogen-activated protein kinase kinase, mTOR mammalian target of rapamycin, NF-κB nuclear factor-κB, PI3K phosphatidylinositol-3-kinase, Raf v-raf 1 murine leukemia viral oncogene homolog 1, Ras retrovirus-associated DNA sequences, SoS son of sevenless, STAT signal transducers and activators of transcription, VEGF vascular endothelial growth factor

Fig. 2

Survival estimates from key trials of chemotherapy in patients with SCCHN. Kaplan–Meier estimates of overall survival in patients with metastatic/recurrent SCCHN treated with (a) methotrexate versus cisplatin/5-fluorouracil versus carboplatin/5-fluorouracil (Southwest Oncology Group) [32]; b cetuximab plus 5-fluorouracil/platinum-based chemotherapy versus 5-fluorouracil/platinum-based chemotherapy alone (NCT00122460) [22]. a Reprinted with permission [32] ©1992 American Society of Clinical Oncology. All rights reserved. b Reprinted with permission [22] ©2008 Massachusetts Medical Society. SCCHN squamous cell carcinoma of the head and neck, 5-FU 5-fluorouracil