The 1-year survival rate was 47% in the cetuximab group versus 42% in the chemotherapy-alone group. The group receiving cetuximab also had a significantly better response rate (36% vs 29%, p = .012). Number of pre specified subgroup analyses for potential survival benefit were also conducted. While the subgroup of white patients had improved OS with cetuximab (10.5 vs 9.1 months; p = .003). Asian patients in the cetuximab group had worse

survival HTS assay (17.6 vs 20.4 months), suggesting that cetuximab is not effective in this subgroup of patients (who are more likely to harbor EGFR mutations). In patients with squamous-cell tumors, OS was numerically better with cetuximab (10.2 vs 8.9 months; p = .0567); this was also true in patients Selleck BMN 673 with adenocarcinoma (12.0 vs 10.3 months; p = .0673). In a preplanned analysis, the development of early acne-like rash was associated with significant outcome (median OS: 15 months vs 8.8. months, HR 0.63, 95% CI: 0.52–0.77, p < 0.0001) [29]. Data from FLEX indicated that cetuximab does not appear to benefit patients who have K-Ras mutations. Unlike colon cancer, K-Ras testing does not help identify patients who are most likely to benefit from treatment with cetuximab [30]. In IDEAL 1 study, 210 pretreated

patients were randomized to receive gefitinib at 250 or 500 mg/day. The overall RR (ORR) was 18.4% and 19% and overall survival (OS) was 7.6 months and 8.0 months for the lower dose and the higher dose groups, respectively. In IDEAL 2 study, 216 patients who had relapsed after platinum and docetaxel regimens were randomized to receive gefitinib 250 or 500 mg/day. Efficacy results were similar between the dosing groups; the ORR was 12% and the 1-year survival rate was 25%. In both studies, grade 3–4 adverse events (AEs) such as acne form rash and diarrhea were more frequent with the higher dose [31]. Based on the results of IDEAL 2, gefitinib

received accelerated FDA approval as a third-line therapy for NSCLC. However, the 500-mg gefitinib dose was more CYTH4 toxic as it induced more acne-like rash and diarrhea. Diarrhea was noted in 57% of patients receiving 250 mg and 75% in those receiving 500 mg. Skin toxicity (rash, acne, dry skin, pruritus) was observed in 62% and 75%, respectively. Grade 3/4 toxicities were unusual, but more frequent in the 500-mg dosing. Dose reductions as a result of toxicity were also more frequent in the higher dose [32]. The subsequent phase 3 ISEL (Iressa Survival Evaluation in Lung cancer) trial found that gefitinib did not offer a significant OS benefit compared with placebo (5.6 vs 5.1 months, respectively; p = .087), which led to withdrawal of its FDA approval [33]. The reasons of lack of efficacy are not clear but it can be related to the use of lower dose that are less than the maximum tolerated dose and the inclusion of primary refractory cancers.