Combined Survival Analysis of Prospective Clinical Trials of Gefitinib for Non–Small Cell Lung Cancer with EGFR Mutations

Abstract

Purpose: Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non^small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation^positive non^small cell lung cancer. Experimental Design: We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non^small cell lung cancer with EGFR mutations in Japan. We did a combined analysis based on individual patient data from the identified trials. Results: Seven eligible trials were identified for a total of 148 non^small cell lung cancer patients with EGFR mutations. The overall response rate to gefitinib was 76.4% [95% confidence interval (95% CI), 69.5-83.2]. The median progression-free survival and overall survival were 9.7 months (95% CI, 8.2-11.1) and 24.3 months (95% CI, 19.8-28.2), respectively. Good performance status and chemotherapy-naI« ve status were significantly associated with a longer progression-free survival or overall survival. Of the 148 patients, 87 received gefitinib as a first-line therapy, whereas 61received systemic chemotherapy before gefitinib treatment. The median progression-free survival after the start of first-line therapy was significantly longer in the gefitinib-first group than in the chemotherapy-first group (10.7 versus 6.0 months; P < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (27.7 versus 25.7 months; P = 0.782). Conclusions: Gefitinib monotherapy confers substantial clinical benefit in terms of progressionfree survival and overall survival in non^small cell lung cancer patients with EGFR mutations. Randomized trials comparing chemotherapy with gefitinib as a first-line treatment are warranted in such patients.Non-small cell lung cancer is the leading cause of death related to cancer worldwide (1). Cytotoxic chemotherapy remains the mainstay of treatment for patients with metastatic non -small cell lung cancer on the basis of the associated moderate improvement in survival and quality of life (2 -4). The poor outlook even for patients with advanced non -small cell lung cancer who receive such chemotherapy has prompted a search for new therapeutic approaches.The epidermal growth factor receptor (EGFR) is frequently overexpressed in non -small cell lung cancer and has been implicated in the pathogenesis of this disease (5, 6). Given the biological importance of EGFR signaling in non -small cell lung cancer, EGFR-specific tyrosine kinase inhibitors, including gefitinib and erlotinib, have been extensively studied in patients with this condition (7 -10). We and others have shown that a clinical response to these agents is more common in women than in men, in Japanese than in individuals from Europe or the United States, in patients with adenocarcinoma than in those with other histologic subtypes of cancer, and in individuals who have never

Prospective Study of Gefitinib Readministration After Chemotherapy in Patients With Advanced Non–Small-Cell Lung Cancer Who Previously Responded to Gefitinib

“…The extremely high response rate for gefitinib is associated with the presence of active EGFR mutations in tumor cells, such as in -frame deletions in exon 19 or point mutations in exon 21 ( e.g., L858R). [1][2][3][4][5][6][7] Two phase III trials comparing chemotherapy to gefitinib in a first -line setting demonstrated that gefitinib could produce improved progression-free survival (PFS) compared to chemotherapy in patients harboring EGFR -activating mutations. 6,7 EGFR-TKI in the second line after chemotherapy showed similar activity as the first line in sensitive patients with EGFR mutations.…”

Management of EGFR-Mutant Non-Small Cell Lung Cancer: Focus on Gefitinib

“…Recent trials clearly show that gefitinib induces a greater tumor response in patients with activating EGFR mutations. 18,19,21,29,30 However, a subset analysis of the results of the INTEREST study showed that the survival benefit of gefitinib is not limited to certain subgroups. 78 Similar findings were obtained in a randomized phase III study that compared another EGFR tyrosine kinase inhibitor, erlotinib, with placebo in patients with recurrent NSCLC (BR.21 study).…”

“…[18][19][20] Following this discovery, several prospective phase II studies demonstrated a high response rate to gefitinib of approximately 60%-80% in patients with EGFR mutations. [21][22][23][24][25][26][27][28][29][30] Moreover, a recent phase III trial that evaluated gefitinib monotherapy as first-line treatment in comparison with one of the standard platinum-based chemotherapies, paclitaxel and carboplatin (IRESSA Pan-ASia Study; IPASS), showed superior progression-free survival, a higher objective response rate, better tolerability, and a significant quality of life benefit in the gefinitib group. 31 Subset analyses suggested that EGFR mutations were both a predictive factor and prognostic factor in NSCLC patients treated with gefitinib.…”

“…The results of I-CAMP suggested that gefitinib produces longer progression-free survival in a first-line setting than in a second-line or subsequent treatment setting. 21 These findings should be validated, and the role of gefitinib as first-line chemotherapy in patients with EGFR mutations should be clarified by two ongoing randomized phase III trials comparing gefitinib with standard chemotherapy (Table 4).…”

Significance, Mechanisms, and Progress of Anticancer Drugs Targeting HGF-Met

“…Recent phase III clinical trials demonstrated that patients with EGFR mutant NSCLC had superior outcomes with gefitinib treatment, compared with standard first-line cytotoxic chemotherapy (Maemondo et al, 2010;Mitsudomi et al, 2010). However, almost without exception, the patients developed acquired resistance to EGFR tyrosine kinase inhibitors within several years (Morita et al, 2009). Furthermore, 20-25% of the patients with EGFR-activating mutations showed intrinsic resistance to EGFR tyrosine kinase inhibitors.…”