Phase II Study of Gefitinib in Patients with Relapsed or Persistent Ovarian or Primary Peritoneal Carcinoma and Evaluation of Epidermal Growth Factor Receptor Mutations and Immunohistochemical Expression: A Gynecologic Oncology Group Study

Abstract

Purpose: This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR). Experimental Design: Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib. Results: Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free >6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation. Conclusions: Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.

A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers

“…A parallel translational component to this international study will evaluate the possibility that patients most likely to derive benefit from erlotinib can be predicted by molecular tumour analysis. This phenomenon, in a similar manner to that seen in NSCLC, has been observed in a blinded molecular analysis of a Gynecologic Oncology Group (GOG) phase II trial in ovarian cancer with another EGFR inhibitor, gefitinib (Schilder et al, 2005). Results of the EORTC erlotinib trial are expected in 2009.…”

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

“…44,45). Mutations in the tyrosine kinase domain of EGFR have been found in 8% of non -small cell lung cancers (46, 47) and 3.5% of invasive ovarian cancers (48). Similar mutations have been found in ERBB2 in 1.6% to 4% of non -small cell lung cancers (49,50) and a small number of ovarian tumors (50-52), including 2 of 21 serous LMP tumors (52).…”

Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling

“…Finally, for EGFR mutations, drug responses are evident in cell lines from NSCLC (5%), esophageal (14%), and gastric (4%) cancers. Notably, dramatic responses to gefitinib or erlotinib have been reported outside of NSCLC, including a patient with head and neck cancer harboring a HER2 mutation (19) and two patients with EGFR-mutant ovarian cancer (20). Recognition that drug sensitizing mutations are distributed at low frequency across different types of cancer suggests that a primary genotype-based diagnostic strategy aimed at identifying these rare cases may have significant impact in the treatment of diverse human cancers.…”