Predictive factors for outcome in a phase II study of gefitinib in second-line treatment of advanced esophageal cancer patients.
OBJECTIVE
The efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib was assessed in a phase II study in patients with advanced esophageal cancer. Several biologic features were investigated as potential markers of gefitinib activity.


METHODS
Patients with advanced esophageal cancer, who had failed one line of prior chemotherapy, were administered gefitinib 500 mg/d. Response was evaluated every 8 weeks. Tumor material obtained before gefitinib treatment was investigated for gene mutations in EGFR, k-ras, and PIK3CA; protein expression levels of EGFR, p-Akt, and p-Erk; and EGFR gene amplification.


RESULTS
Of the 36 enrolled patients, one (2.8%) achieved a partial response, 10 (27.8%) had stable disease, 17 (47.2%) experienced progression on treatment, and eight (22.2%) were not assessable for response. The progression-free survival time was 59 days, and the median overall survival time was 164 days. Although EGFR or PIK3CA mutations were absent, k-ras mutations were found in two patients with progressive disease. High EGFR gene copy number was identified in two patients experiencing partial response or progressive disease. A higher disease control rate (response plus stable disease) was observed in females (P = .038) and in patients with squamous cell carcinoma (SCC; P = .013) or high EGFR expression (P = .002).


CONCLUSIONS
Gefitinib has a modest activity in second-line treatment of advanced esophageal cancer. However, the patient outcome was significantly better in female patients and in patients demonstrating high EGFR expression or SCC histology. The selection of esophageal cancer patients for future studies with EGFR-TKIs based on the level of EGFR expression in their tumors or SCC histology should be considered.
Janmaat
Maarten L
ML
Department of Medical Oncology, Vreije Universiteit Medical Center, Amsterdam, The Netherlands.
Gallegos-Ruiz
Mariëlle I
MI
Rodriguez
José A
JA
Meijer
Gerrit A
GA
Vervenne
Walter L
WL
Richel
Dick J
DJ
Van Groeningen
Cees
C
Giaccone
Giuseppe
G
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D018628:Gene Dosage; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011799:Quinazolines; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib