The patients had received one or two neuronal signaling previous chemotherapy regimens and were not selected according to EGFR expression. There was no difference between the two doses in terms of RR, symptoms improvement, median PFS and median OS. However, the toxicity profile was better with the low dose and gefitinib at 250 mg/day was recommended for previously treated NSCLC patients. The IDEAL 2 study had been similarly designed but was conducted in the USA and included patients previously treated with at least two lines of chemotherapy. Both gefitinib doses were similar in terms of the objective RR and symptoms improvement. Based on these results, gefitinib was approved as single agent treatment of patients with locally advanced or metastatic NSCLC, after failure of both platinum based and docetaxel chemotherapy. However, a subsequent phase III trial assigned 1,692 previously treated patients to receive gefitinib at 250 mg/day or placebo alongside BSC. It did not reveal any statistically significant difference in OS. Although this study did not TCR pathway meet its primary endpoint, it suggested that never smokers and patients of Asian origin had survival benefit.
Following this study, in June 2005, the FDA jak stat restricted use of gefitinib to patients who were already participating in running clinical trials and to those continuing to benefit from treatment. While gefitinib was not a treatment option for the vast majority of patients in U.S.A, it was approved in other countries and trials investigating its activity continued. A large open label phase III trial compared the efficacy of docetaxel to that of gefitinib in patients whose disease progressed after platinum based chemotherapy. The primary endpoint was the non inferiority of gefitinib as compared to docetaxel in terms of OS, whereas the co primary endpoint was the superiority of gefitinib in patients with high EGFR gene copy number. Never smokers and patients of Asian origin represent 20% of the enrolled population. Adenocarcinoma was the most frequent histological type, approximately 55% in both arms. Median OS was similar in the two FK-506 treatment arms, demonstrating that gefitinib was not inferior to docetaxel. Superiority of gefitinib in patients with high EGFR gene copy number was not proven.
In a preplanned subset analysis in patients who were never smokers, of Asian descent and of adenocarcinoma histology, no statistically significant and clinically relevant difference in QoL was observed. The overall rate of adverse effects was lower in the gefitinib arm. One more study compared gefitinib 250 mg/day to triweekly docetaxel at 75 mg/m2 as second line treatment. This study enrolled 161 patients and the primary objective was PFS. The latter was longer for gefitinib and overall RR was better. Gefitinibwas well tolerated and had similar QoL improvement rates as docetaxel, suggesting that gefitinib is a valid option as second line therapy. New Targeted Therapies Newer targeted agents that are being examined in the prolong thirdline setting are presented in Table I. The monoclonal chimeric antibody against EGFR, cetuximab, which has not yet received approval in combination with cisplatin/vinorelbine for first line treatment of NSCLC, has already been evaluated in patients with recurrent or progressive.