Trial Information

Phase II Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma With Evaluation of Neoadjuvant Biomarker Modulation With TARCEVA vs. TARCEVA Plus Sulindac

Head and neck squamous cell carcinoma (HNSCC) constitutes 3 percent of all malignancies and
is the sixth most common malignancy worldwide. There will be an estimated 38,000 new cases
and 11,000 deaths in the United States in 2004 and approximately 500,000 cases worldwide
yearly [1]. Squamous cell carcinoma accounts for at least 95 percent of all head and neck
cancers. Surgical treatment remains the standard of therapy for patients with resectable
HNSCC. For patients with high risk of local or distant relapse, radiation therapy (RT)
alone, or in combination with chemotherapy, is given after surgery to improve loco-regional
control and overall survival.

Neoadjuvant chemotherapy for patients with respectable HNSCC remains an experimental option
for these patients. A two-week delay in definitive surgical resection in patients with
operable HNSCC is not thought to impact the clinical outcome of these patients and in many
cases may be needed to complete all of the preoperative work-up. As a result, a study design
involving a two-week preoperative course of therapy in patients with operable HNSCC should
not be a concern.

EGFR as a therapeutic target in HNSCC

Epidermal growth factor receptor (EGFR) is a 170-Kda transmembrane protein that is thought
to be important in the proliferation and survival of cancer cells [2]. Overexpression of
EGFR has been found in several malignancies, including head and neck, lung, breast,
prostate, bladder, and pancreatic cancer [3-7]. In HNSCC, EGFR and its ligand TGF are
overexpressed in 80-90% of tumors compared to normal mucosa; [8] the coexpression of
receptor and ligand implicates an autocrine regulatory pathway in HNSCC carcinogenesis. The
clinical relevance of EGFR overexpression as an independent prognostic factor in HNSCC has
been well demonstrated. High tumor EGFR levels are correlated with advanced stage,[9]
increased tumor size, [9] decreased survival,[10-13] increased recurrence,[10] and decreased
sensitivity to radiation treatment [14]. A recent study suggests that high serum EGFR levels
may even correlate with higher head and neck tumor grade [15]. The overexpression of EGFR
and ligand in partially and fully transformed HNSCC tissue, its correlation with poor
clinical outcome, and the aberrant function of the EGFR network in HNSCC provide compelling
evidence of a relationship between EGFR and the development and progression of HNSCC, and
suggest a role for EGFR as a target for cancer therapy.

EGFR has been targeted at the extracellular domain by blocking ligand binding, at the
intracellular domain by inhibiting tyrosine kinase activity, and at the genetic level by
targeting production of the receptor itself. EGFR-specific monoclonal antibodies interfere
with ligand binding, while conjugation of an EGFR ligand or antibody to a bacterially
derived toxin enables the delivery of a cytotoxic agent to the cell surface. Many of the
EGFR-targeting agents are undergoing clinical evaluation in HNSCC. In general, clinical
responses in HNSCC patients with advanced disease have only been observed when these agents
have been combined with cytotoxic chemotherapy or radiation therapy. Clinical trials using
EGFR inhibitors as adjuvant therapy for HNSCC are currently underway.