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Annals of Oncology Advance Access published online on February 21, 2007
Annals of Oncology, doi:10.1093/annonc/mdl495
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© 2007 European Society for Medical Oncology

Assessment of erlotinib pharmacodynamics in tumors and skin of patients with head and neck cancer

E Calvo1, SN Malik2, LL Siu3, GM Baillargeon2, J Irish3, SF Chin3, P Santabarbara4, JI Kreisberg2, EK Rowinsky1,2,*,{dagger} and M Hidalgo1,2,{dagger}

1 Cancer Therapy and Research Center, The Institute for Drug Development, San Antonio, TX, USA
2 University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
3 Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
4 OSI Pharmaceuticals Inc., 41 Pinelawn Road, Melville, NY 11747, USA

* Correspondence to: Dr E. K. Rowinsky, ImClone Systems, 33 ImClone Drive, Branchburg, NJ 08876, USA. Tel: +1-908-203-6912; Fax: +1-908-231-9885; E-mail: eric.rowinsky{at}imclone.com

Background: The purpose of the study was to evaluate the effects of erlotinib on epidermal growth factor receptor (EGFR)-related signaling elements in tumor and skin from patients with advanced squamous cell carcinoma of the head and neck (HNSCC) and seek relationships between relevant clinical, biological, and pharmacokinetic parameters.

Patients and methods: Immunostaining for EGFR, p-EGFR, p-ERK, p-Akt, and p27 were analyzed semiquantitatively in serial tumor and skin samples from participating patients. Steady-state trough concentrations of erlotinib and its metabolite OSI-420 were also determined.

Results: Of 25 patients enrolled, 20 (80%) paired pre- and posttreatment skin biopsies and seven (28%) paired tumor biopsies were evaluable for at least one immunohistochemical parameter. The severity of skin toxicity related to time to progression (TTP) (P = 0.048) and overall survival (P < 0.001). Css,min values for erlotinib and OSI-420 also related to TTP (P = 0.042 and 0.036, respectively). Erlotinib treatment was associated with decreased p-EGFR expression in 66% of evaluable tumor samples, which seemed related to increased TTP and survival, and p27 was up-regulated in 59% of evaluable skin biopsy samples following treatment.

Conclusions: The feasibility of obtaining serial evaluable biopsies of HNSCC was suboptimal. Nevertheless, erlotinib inhibited p-EGFR in HNSCC tumors, which appeared associated to clinical benefit, and induced p27 in biopsies of normal skin.

EGFR, erlotinib, head and neck cancer, pharmacodynamics, translational

{dagger} Both authors contributed equally as senior authors.

Received for publication August 10, 2006. Revision received December 7, 2006. Accepted for publication December 14, 2006.


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