Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck.
OBJECTIVE
The epidermal growth factor receptor (EGFR) is a mediator of squamous cell carcinoma of the head and neck (SCCHN) development. ZD1839 is an orally active, selective EGFR tyrosine kinase inhibitor. This phase II study sought to explore the activity, toxicity, and pharmacodynamics of ZD1839 in SCCHN.


METHODS
Patients with recurrent or metastatic SCCHN were enrolled through the University of Chicago Phase II Consortium. Patients were allowed no more than one prior therapy for recurrent or metastatic disease and were treated with single-agent ZD1839 500 mg/d. Patient tumor biopsies were obtained and stained immunohistochemically for EGFR, extracellular signal-regulated kinase 1 (ERK1), and phosphorylated ERK1 (p-ERK). Study end points included response rate, time to progression, median survival, and inhibition of p-ERK.


RESULTS
Fifty-two patients were enrolled (40 male and 12 female) with a median age of 59 years (range, 34 to 84 years). Fourteen patients received ZD1839 through a feeding tube. Half the cohort received ZD1839 as second-line therapy. Forty-seven patients were assessable for response, with an observed response rate of 10.6% and a disease control rate of 53%. Median time to progression and survival were 3.4 and 8.1 months, respectively. The only grade 3 toxicity encountered was diarrhea in three patients. Performance status and development of skin toxicity were found to be strong predictors of response, progression, and survival. Ten biopsy samples were assessable and revealed no significant change in EGFR or p-ERK expression with ZD1839 therapy.


CONCLUSIONS
ZD1839 has single-agent activity and is well tolerated in refractory SCCHN. In contrast to other reports, development of skin toxicity was a statistically significant predictor of response and improved outcome.
Cohen
Ezra E W
EE
Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637-1470, USA. ecohen@medicine.bsd.uchicago.edu
Rosen
Fred
F
Stadler
Walter M
WM
Recant
Wendy
W
Stenson
Kerstin
K
Huo
Dezheng
D
Vokes
Everett E
EE
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007087:Illinois; D007150:Immunohistochemistry; D007441:Intubation, Gastrointestinal; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib