Gefitinib in Patients with Malignant Mesothelioma: A Phase II Study by the Cancer and Leukemia Group B

Abstract

Purpose: The Cancer and Leukemia Group B conducted a phase II study of gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously untreated malignant mesothelioma. Experimental Design: Eligible patients had unresectable pleural or peritoneal mesothelioma, measurable disease, no prior therapy, and performance status 0-1 by Cancer and Leukemia Group B criteria. Gefitinib (500 mg p.o.) was administered once a day for 21 days. Patients underwent restaging after every two cycles. Therapy was continued until disease progression or unacceptable toxicity. Results: The most common grade 3 toxicities were diarrhea (16%) and nausea (12%). Of 43 patients enrolled, 1 patient (2%) had a complete response, 1 patient (2%) had a partial response, 21 (49%) had stable disease lasting two to eight cycles, 15 (35%) had progressive disease, and 5 (12%) had early deaths. One-year survival was 32% [95% confidence interval (CI), 21-50%]. Median survival and failure-free survival were 6.8% (95% CI, 3.5-10.3) and 2.6 months (95% CI, 1.5-4.0), respectively. The 3-month failure-free survival was 40% (95% CI, 25-56%). EGFR expression score by immunohistochemistry done in 28 patients was categorized as low (EGFR 1+ or 2+) or high (EGFR 3+) expression: 97% had EGFR overexpression (2+ or 3+). The median and 3-month failure-free survival were 3.6 months and 40% for those patients with low EGFR expression compared with 8.1 and 40% for those with high EGFR expression. Conclusions: Although 97% of patients with mesothelioma had EGFR overexpression, gefitinib was not active in malignant mesothelioma. EGFR expression does not correlate with failure-free survival.

Novel systemic therapy against malignant pleural mesothelioma

“…In a phase II study, none of the 63 MPM patients responded to single agent erlotinib in the front line setting despite high expression of EGFR (103). In a phase II trial evaluating single-agent gefitinib in the front line setting, only 2 out of 43 patients responded to therapy and thus the investigators of this study concluded that gefitinib is not active in MPM (104). A clinical trial evaluating cetuximab in combination with pemetrexed and either cisplatin or carboplatin in the front line setting is ongoing (clinicaltrials.gov NCT00996567).…”

Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity

“…Despite the fact that greater than 75% of MM tumour samples overexpressed EGFR, clinical trials targeting EGFR in MM with tyrosine kinase inhibitors have yielded some objective responses, but not with the desired frequency (Govindan et al, 2005;Garland et al, 2007). This inconsistency of response is likely because of the fact that few MM tumours possess the activating EGFR mutations that correlate with tyrosine kinase inhibitor efficacy (Cortese et al, 2006).…”

“…Previous research has shown overexpression of epidermal growth factor receptor (EGFR) on most MM cell lines and clinical tumour samples (Cole et al, 2005;Govindan et al, 2005). Activation of EGFR promotes processes responsible for tumour growth and progression, including proliferation and maturation, angiogenesis, invasion, metastasis, and inhibition of apoptosis, making it a popular target for anti-cancer therapy (Yarden and Sliwkowski, 2001).…”

The Role of Inflammation in Development and Therapy of Malignant Mesothelioma

“…Novel therapies such as gene therapy, immunotherapy and targeted molecular therapy are under investigation through preclinical research and clinical trials (Takigawa et al, 2011;Vachani et al, 2011;Zauderer and Krug, 2012 (Govindan et al, 2005). Other tyrosine kinase inhibitors, such as imatinib and erlotinib, have been studied in phase II clinical trials and have produced negative results (Mathy et al, 2005;Garland et al, 2007).…”