Schilder RJ, Sill MW, Chen X, Darcy KM, Decesare SL, Lewandowski G, Lee RB, Arciero CA, Wu H, Godwin AKPhase 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. Clin Cancer Res 11: 5539-5548

ArticleinClinical Cancer Research 11(15):5539-48 · September 2005with4 Reads
DOI: 10.1158/1078-0432.CCR-05-0462 · Source: PubMed
Abstract
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). 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. 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. 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.
    • "Tyrosine kinase inhibitors such as erlonitib and gefitinib have been successfully directed against the EGFR (Sirotnak et al., 2000; Sirotnak, 2003). Phase 2 clinical trials with gefinitib in patients with advanced recurrent ovarian carcinomas showed very little activity, although the drug was well tolerated (Schilder et al., 2005). Phase 3 trials with erlonitib, however did not show any significant improvement in activity (Vergote et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Ovarian cancer is the most lethal gynaecological cancer. About 90% of ovarian cancers are epithelial, (ovarian carcinomas) thought to arise from the ovarian surface epithelium. Diagnosed usually at clinically advanced stages, many patients show poor response to chemotherapy, with resistance and recurrent disease being prevalent. The cell origin and the mechanism of neoplastic transformation of this malignancy are poorly understood. Apoptosis is crucial in normal ovarian development and function; and gonadotropins play a significant role in modulating the expression of several pro-apoptotic and pro-survival genes and other molecules in the ovary. Targeted therapeutic strategies using small molecule protein kinase inhibitors and monoclonal antibodies have been explored in the management of ovarian carcinomas. These molecules, used in combination with chemotherapy, have shown better prognosis in ovarian cancer. With several ongoing clinical trials using kinase inhibitors and the ideal targets being sought after, significant improvements of patients suffering with ovarian carcinomas are expected in the near future. This manuscript aims to review ovarian apoptotic mechanisms and the therapeutic progress in the use of small molecule kinase inhibitors and monoclonal antibodies as targets for inducing apoptosis in ovarian cancer.
    Full-text · Article · Mar 2015 · International Journal of Molecular Sciences
    • "Tyrosine kinase inhibitors such as erlonitib and gefitinib have been successfully directed against the EGFR (Sirotnak et al., 2000; Sirotnak, 2003). Phase 2 clinical trials with gefinitib in patients with advanced recurrent ovarian carcinomas showed very little activity, although the drug was well tolerated (Schilder et al., 2005). Phase 3 trials with erlonitib, however did not show any significant improvement in activity (Vergote et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Ovarian cancer is the deadliest cancer among women. About 90% of ovarian cancers are epithelial, (ovarian carcinomas) thought to arise from the ovarian surface epithelium. Diagnosed usually at clinically advanced stages, many patients show poor response to chemotherapy, with resistance and recurrent disease being prevalent. The cell origin and the mechanism of neoplastic transformation of this malignancy are poorly understood. Apoptosis is crucial in normal ovarian development and function; and gonadotropins play a significant role in modulating the expression of several pro-apoptotic and pro-survival genes and other molecules in the ovary. Targeted therapeutic strategies using small molecule protein kinase inhibitors and monoclonal antibodies have been explored in the management of ovarian carcinomas. These molecules, used in combination with chemotherapy, have shown better prognosis in ovarian cancer. With several ongoing clinical trials using kinase inhibitors and the ideal targets being sought after, significant improvements of patients suffering with ovarian carcinomas are expected in the near future. This manuscript aims to review ovarian apoptotic mechanisms and the therapeutic progress in the use of small molecule kinase inhibitors and monoclonal antibodies as targets for inducing apoptosis in ovarian cancer.
    Full-text · Article · Mar 2015
    • "In several phase I-II-studies of ovarian cancer the tyrosine kinase inhibitor Erlotinib (Tarceva ® ) did not effectively contribute to a therapeutic improvement neither as a single agent nor combined with chemotherapy or with the anti-VEGF-antibody Bevacizumab9101112. Single TKI-inhibition with Gefitinib (Iressa ® ) reached only limited responses [13,14]. Preclinical data revealed that Gefitinib could potentiate cytostatic antitumoural effects [15], which might be also of clinical benefit [16]. "
    [Show abstract] [Hide abstract] ABSTRACT: The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine kinase inhibitors (TKI) and cytolytic NK cells was tested against different ovarian cancer cell lines and primary tumour cells cultured from patient ascites. We found that selected ovarian cancer cells were susceptible to cetuximab and anti-EGFR-TKI-treatment, while the majority of cell lines were resistant to single or combination treatment with both substances. In addition, most ovarian cancer cells displayed low susceptibility to natural cytotoxicity of unstimulated NK cells. Notably, NK cytotoxicity against resistant ovarian cancer cells could be effectively enhanced by addition of Cetuximab mediating antibody-dependent cellular cytotoxicity (ADCC). Neither natural cytotoxicity nor ADCC of NK cells were negatively affected by the presence of TKIs. ADCC could be further increased when NK cells were pre-stimulated with monocytes and the immunostimulatory mycobacterial protein PstS-1. Our data suggest that targeted antibody therapy could be beneficial even against resistant tumour cells by augmenting supplementary cytolytic NK functions. Future studies should evaluate the combination of targeted therapy and immunotherapeutic approaches in patients with advanced ovarian cancer being resistant to standard treatment.
    Full-text · Article · Dec 2012
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