Epidermal Growth Factor Receptor Inhibitors in the Treatment of Head and Neck Cancer
Faculty Disclosure: Merrill S. Kies, MD
In this presentation by Dr. Kies there is discussion of C225 in the treatment of head and neck cancer which has not been approved by the FDA.
Presenter: Merrill S. Kies, MD
The treatment of patients with squamous cell cancer of the head and neck (SCCHN) is challenging both for the physician and the patient. About one-third of patients present with stage I/II disease, with cure rates as high as 70-90%, in contrast to the other two-thirds of patients who, despite multimodality therapy, still have 40-60% rate of local-regional recurrence, 10-20% rate of distant disease spread, and as much as 20-30% non-cancer-related mortality. Attempts to improve on these numbers have prompted numerous investigations, among the most active involving the arena of biologic agents, specifically manipulation of the epidermal growth factor receptor (EGFR).
EGFR is a 170,000 kD transmembrane glycoprotein found on epithelial cells. It consists of both an extracellular ligand-binding portion, an intracellular tyrosine kinase-linked signalling portion, and a connecting transmembrane domain. It is a member of the ErbB family, and is expressed in ~90% of SCCHN cases. Degree of EGFR expression has been directly correlated with worse prognosis in SCCHN patients (increased recurrence, advanced stage), and mRNA and protein expression of EGFR is increased in both dysplastic and "normal" tissues of SCCHN patients.
Monoclonal antibodies targeting EGFR and in various stages of development include: IMC-C225 (cetuximab), ABX-EGF, EMD 72000, RH3, and MDX-447. Related to EGFR blockade are the tyrosine kinase inhibitors, such as ZD1839 (gefitinib), OSI-774 and CI-1033. Although single-agent C225 has not been shown to have siginificant activity, marked suppression of tumor growth in SCC xenografts has been seen with the combination of C225 and radiation therapy (RT)(Huang and Harari, CCR 2000). Phase Ib data from MDACC of previously treated patients given C225 and high-dose cisplatin (100 mg/m2 q3wks) is showing promising response rates on preliminary analysis. Interestingly, the beneficial effects of C225 have been directly linked to the development of a characteristic skin rash. This correlation between response to C225 and development of the rash has been found not only in patients with SCCHN, but also those with colorectal and pancreatic cancers.At present, the following studies have been conducted:
- Phase II Barcelona: cisplatin + C225 in recurrent disease/ refractory patients with disease progression
- Phase II MDACC: same as above
- Phase II MSKCC: cisplatin + C225 + radiation therapy in locally advanced patients not previously treated
- Phase III ECOG 5397: cisplatin + C225 (n=60)vs. cisplatin + placebo (n=60) in recurrent disease (not necessarily refractory)
- Phase II U of Chicago: ZD1839 in recurrent disease
Of note, another phase II MDACC study of C225 with high dose cisplatin and concomitant boost RT was closed prematurely due to unacceptable adverse outcomes, including anaphylaxis (n=1), myocardial infarction (n=1) and 2 deaths (one of which was allegedly not tx-related). However, with median follow-up of 26 months, 16 of 21 patients had no evidence of disease and 2-yr progression-free survival was as high as 76%. Such promising results prompt the question of whether this approach might warrant a second look, and that perhaps the adverse outcomes were were by chance.
Results from the randomized ECOG trial show statistically significantly better response rate with the experimental arm, and a trend towards an overall survival benefit.
The Chicago data (Cohen et al. JCO 2003) with 52 patients receiving C225, 500 mg po qd, showed a median survival of 8.1 months. Also, the authors confirmed that C225-induced rash, as well as performance status, predicted for response to the agent.
Future studies in the pipeline include combinations of C225 with dose dense carboplatin/paclitaxel, as well as docetaxel. Finally, long-awaited results should be coming soon from a phase III trial of RT +/- C225 in intermediate stage patients, which will help to shed more light on this exciting new treatment strategy.