Pharmacogenomics of Erlotinib

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Erlotinib (OSI-774, Tarceva) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) currently in clinical development for the treatment of cancer. Despite the significant knowledge with regards to the clinical pharmacology, toxicity, and activity or Erlotinib, the fundamental question regarding which factor (s) determine susceptibility to the drug remain poorly understood. The recent discovery that mutations in the EGFR kinase domain are associated with marked susceptibility to Gefitinib, a drug with similar mechanism of action as Erlotinib, explains why a set of patients with non small cell lung cancer respond very well to the drug. Factors that predict response in other diseases such as squamous cell carcinoma of the head and neck (SCCHN) in which no mutations have been found are not known. In studies conducted thus far, it has been observed that the development of cutaneous rash is associated with higher response rate and increased survival. A potential explanation for this association could be that genetic factors that are shared between normal and tumor tissues predispose such tissues to the toxic and antitumor effects of the drug, respectively. The EGFR has a highly polymorphic single segment CA dinucleotide repeat in the intron 1 of the gene that is know to regulate transcription of the gene. Preliminary studies conducted by our group suggest that this polymorphism is related to the activity of Erlotinib. This study will tesl the hypothesis that subjects with different number of CA repeats respond differently to Erlotinib. The specific aims are: 1) estimate the response rate, time to progression, and toxicity (skin rash) of Erlotinib in patients with SCCHN with different number of CA repeats in intron 1 of the EGFR gene and 2) compare the pharmacodynamic effects of Erlotinib in serial skin biopsies of these patients. We will conduct a prospective phase II clinical study in two groups of patients with SCCHN and short (16/16) or long (16/20 or 20/20) CA dinucleotide repeat will receive 150 mg/day of Erlotinib. The response rate, time to tumor progression, skin rash, inhibition of EGFR and upregulation of p27 in skin biopsies will be determined. Plasma levels of total and free Erlotinib will be measured to rule out pharmacological bases for the expected differences. This study will determine whether a genetic basis for the pharmacological effects of Erlotinib is likely.