A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

Abstract

BACKGROUNDThe primary objective of this study was to evaluate the biochemical effects of gefitinib on its target signal‐transduction pathways in patients with recurrent epithelial ovarian cancer (EOC). The secondary objectives included assessing clinical activity and toxicity and determining the association between biochemical and clinical outcomes.METHODSTwenty‐four heavily pretreated patients with EOC who had good end‐organ function and performance status and who had measurable disease received gefitinib 500 mg daily. Prospectively planned core‐needle tumor biopsies were obtained before treatment and after 4 weeks. Protein expression of total and phosphorylated (p) epidermal growth factor receptor (EGFR), protein kinase B (AKT), and extracellular regulated kinase (ERK) was quantified in microdissected tumor cells using tissue lysate array proteomics.RESULTSAll tumor samples had detectable levels of EGFR and p‐EGFR. A decrease in the quantity of both EGFR and p‐EGFR was observed with gefitinib therapy in >50% of patients. This was not associated with clinical benefit, nor were responses observed. However, trends for increased gastrointestinal and skin toxicity were observed with greater phosphorylation or quantities of EGFR, ERK, and AKT in tumor samples (P ≤ .05). Gefitinib had limited clinical activity as monotherapy despite documented target inhibition.CONCLUSIONSThe results from this study demonstrated that gefitinib inhibited the phosphorylation of EGFR in EOC tumor cells, providing proof of target in a clinical setting. Combinatorial therapy with molecular therapeutics against complementary targets may prove successful. Cancer 2007. Published 2007 by the American Cancer Society.

A prospective analysis of imatinib‐induced c‐kit modulation in ovarian cancer

“…A similar finding was observed in our Phase II study of single-agent gefitinib in ovarian cancer. 49 Our findings validate in vitro studies from Matei et al, who demonstrated that AKT activation typically occurs after therapy with imatinib mesylate. 34 The power of our findings, however, rests in the ability to demonstrate this impact on molecular signaling in a prospective fashion in patient tumor samples.…”

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

“…Small molecule tyrosine kinase inhibitors (TKI) targeting EGFR activity have been investigated in several trials specifically focused on ovarian cancer (Table 4). Single agent TKI did not show any substantial clinical benefit (0-9% for gefitinib (Posadas et al 2007, Schilder et al 2005, 0% for CI-1033 an irreversible EGFR inhibitor (Campos et al 2005)). TKIs combined with cytotoxic chemotherapy, anti-angiogenic therapy, or hormonal therapy have also shown limited clinical efficacy and in some cases excessive toxicity (Campos et al 2010, Chambers et al 2010, Nimeiri et al 2008, Vasey et al 2008.…”

Emerging molecular-targeted therapies—the challenging case of endometrial cancer

“…The other enrolled 24 patients and no clinical responses were observed [25] . There are currently no ongoing trials.…”

“…There were 2 Phase II trials evaluating the efficacy of gefitinib in recurrent metastatic endometrial cancer, however, they showed that it lacked sufficient efficacy to warrant further evaluation [24,25] . One of the trials enrolled 29 patients, of which one had a complete response, however, it was not associated with an ErbB mutation [24] .…”