BIOMARKER ANALYSES FROM A PHASE III, RANDOMIZED, OPEN-LABEL, FIRST-LINE STUDY OF GEFITINIB VS CARBOPLATIN/PACLITAXEL IN CLINICALLY SELECTED PATIENTS WITH ADVANCED NSCLC IN ASIA (IPASS)

Fukuoka M, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N, Watkins C, Duffield E, Armour A, Mok T; Kinki University School of Medicine, Osaka, Japan; Guangdong General Hospital , Guangzhou, China; Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand; National Taiwan University Hospital, Taipei, Taiwan; Chinese Academy of Medical Sciences, Beijing, China; National Cancer Centre Hospital East, Chiba, Japan; AstraZeneca, Macclesfield, United Kingdom; The Chinese University of Hong Kong, Hong Kong, China

Although platinum-based doublet chemotherapy (ie, cisplatin or carboplatin with paclitaxel, docetaxel, vinorelbine, or gemcitabine)¹ is the current standard of care for advanced non–small-cell lung cancer (NSCLC), recent findings indicate that first-line treatment with gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor,² may be efficacious in selected patients harboring somatic EGFR mutations. Indeed, one study involving patients with chemotherapy-naïve NSCLC with EGFR mutations demonstrated a 55% response rate to gefitinib,³ a considerable improvement over the 20% to 35% response rates traditionally seen with cytotoxic chemotherapy.^4-6 Importantly, gefitinib may not be significantly effective in all patients with NSCLC who have EGFR mutations; subset analyses of several clinical trials indicate that female gender, adenocarcinoma histology (particularly bronchioalveolar carcinoma), non-smoker status, Asian ethnicity, and good performance status are important factors associated with a positive response to this medication.^2,7

In one phase III, open-label, randomized comparison study, previously untreated East Asian patients with advanced (stage IIIB/IV) pulmonary adenocarcinoma were assigned to receive gefitinib (250 mg/day; n = 609) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg/mL/min) plus paclitaxel (200 mg/m² of body surface area; n = 608). Treatment continued until disease progression, development of unacceptable adverse effects, or completion of 6 chemotherapy cycles. The majority of study participants were female (79.3%), had never smoked (93.7%), and had a World Health Organization performance status of 0 or 1 (89.6%); baseline demographics were similar between groups. Investigators assessed progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), both in the overall population and in a subset of patients whose tumors expressed EGFR mutations, as determined by the amplification refractory mutation system.⁸

Among the overall population, PFS was longer in the gefitinib group than in the carboplatin/paclitaxel group (hazard ratio [HR] = 0.74; 95% confidence interval [CI], 0.65–0.85; P <.001); the ORR was also significantly higher among patients who received gefitinib than those who received carboplatin/paclitaxel (43% vs 32.2%; OR = 1.59; 95% CI, 1.25–2.01; P <.001). OS was similar between the 2 groups, but follow-up is ongoing. Of the 437 patients with evaluable EGFR mutation (M) data, 261 (59.7%) were positive for a mutation (M+). M+ patients had a significantly longer PFS (HR = 0.48; 95% CI, 0.36–0.64; P <.0001) and a significantly higher ORR (71.2% vs 47.3%; OR = 2.75; 95% CI, 1.65–4.6; P <.0001) with gefitinib than with carboplatin/paclitaxel; conversely M- patients had a significantly shorter PFS (HR = 2.85; 95% CI, 2.05–3.98; P <.0001) and a significantly lower ORR (1.1% vs 23.5%; OR = 0.04; 95% CI, 0.01–0.27; P = .0013) with gefitinib than with carboplatin/paclitaxel. An early analysis of OS favored gefitinib in M+ patients (HR = 0.78; 95% CI, 0.5–1.2) and carboplatin/paclitaxel in M- patients (HR = 1.38; 95% CI, 0.92–2.9), but differences were not statistically significant.^8,9

In a subsequent analysis, fluorescence in situ hybridization (FISH) was used to evaluate EGFR gene-copy number in 406 patients. Similar PFS and ORR results were observed by FISH status as by M status, given that many patients who were M+ were also FISH+, and vice versa. Specifically, FISH+ patients had a significantly longer PFS (HR = 0.66; 95% CI, 0.5–0.88; P = .005) and a higher ORR (58.9% vs 44.8%; OR = 1.79; 95%CI, 1.08–2.96; P = .0243) with gefitinib than with carboplatin/paclitaxel; conversely FISH- patients had a shorter PFS (HR = 1.24; 95% CI, 0.87–1.76; P = .2368) and a lower ORR (22.2% vs 26.3%%; OR = 0.8; 95% CI, 0.38–1.68; P = .558) with gefitinib than with carboplatin/paclitaxel. Finally, an immunohistochemistry analysis enabled investigators to assess EGFR protein expression (PE) in 365 patients. PFS results did not differ significantly between PE+ and PE- patients, whereas ORR results favored the use of gefitinib in both PE+ and PE- patients. Specifically, PE+ patients had a higher ORR (51.5% vs 41.8%; OR = 1.49; 95% CI, 0.92–2.42; P = .1093) with gefitinib than with carboplatin/paclitaxel, whereas PE- patients had a lower ORR (34% vs 26.1%; OR = 1.44; 95% CI, 0.6–3.47; P = .4146) with gefitinib than with carboplatin/paclitaxel.⁹ Investigators concluded that gefitinib may be superior to carboplatin/paclitaxel for the treatment of pulmonary adenocarcinoma among East Asian nonsmokers/former light smokers, and that the presence of EGFR tumor mutations is a strong predictor of gefitinib’s efficacy in this patient population.^8,9

This biomarker analysis of the IPASS (IRESSA Pan Asia Study) study helps to elucidate exactly which patient population may benefit from gefitinib therapy. Although results of the IPASS study revealed that gefitinib was superior to carboplatin/paclitaxel in the overall East Asian advanced NSCLC population, subsequent analysis demonstrated that these conclusions may be specific to those who are EGFR M+ and/or FISH+. These findings will significantly impact future therapeutic decisions for patients with NSCLC harboring EGFR mutations because these patients respond well to tyrosine kinase inhibitors such as gefitinib. Although the study focused on patients in whom gefitinib was previously shown to be effective (female, East Asian, and non-smokers with good performance statuses), what determined the effectiveness of this agent was whether a patient’s tumor had the EGFR mutation, not the phenotypic characteristics of the patient. Further evaluation needs to be done to assess the use of gefitinib in other patients with NSCLC who have EGFR mutations.

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