While other next-generation TKIs are also in clinical trials and have been reviewed elsewhere,61,62 one frontrunner is afatinib (BIBW2992), an irreversible ErbB family inhibitor that has been shown to suppress the kinase activity of wild-type and activated EGFR, including erlotinib-resistant isoforms. nine patients who responded to gefitinib, while these mutations were absent in all of the seven patients with no response.13 Their colleagues at the Ximelagatran Dana-Farber Cancer Institute also found mutations in gefitinib responders and no mutations in nonresponders.14 In adenocarcinoma tumor samples from never smokers, a Memorial Sloan-Kettering group similarly identified mutations that were associated with sensitivity to gefitinib and erlotinib.15 These mutations activate the EGFR signaling pathway that promotes survival, and commonly include exon 19 deletions or the L858R point mutation on exon 21. It is thought that lung adenocarcinomas that have these driver mutations are oncogene-addicted to the EGFR pathway; hence their sensitivity to EGFR tyrosine kinase inhibition.14,16C18 A meta-analysis showed that activating mutations were associated with a 67% response rate, time to progression of 11.8 months, and OS of 23.9 months.19 EGFR TKIs in the first-line setting Studies have identified mutations to be present in about 15% of NSCLC in the Western population and approximately 50% in the Asian population.20C23 The two most common mutations, accounting for 90%, are exon 19 deletions (50%) and L858R point mutations (40%), with a variety of other mutations such as exon 20 insertions, G719X, L861Q, and de novo T790M comprising the remainder.20 Other characteristics associated with the presence of mutations. Among those with activating mutations, PFS was longer in the gefitinib group (hazard ratio for progression, 0.48; 95% confidence interval, 0.36C0.64; < 0.001). Among those with wild-type < 0.001). OS, however, was not statistically different between gefitinib and chemotherapy.22,23 Another phase III study examining the role of EGFR TKIs as first-line therapy is the First-SIGNAL trial, in which 313 Korean never smokers with advanced lung adenocarcinoma were randomized to gefitinib or cisplatin and gemcitabine. Similar to the IPASS study, PFS was superior for gefitinib, but OS was comparable in both groups. PFS was 16.7% at 1 year in the gefitinib group, compared to 2.8% Ximelagatran at 1 year for the chemotherapy group. The median OS of the gefitinib group was 22.3 months versus 22.9 months for the chemotherapy group. However, about 75% of patients around the chemotherapy arm eventually crossed over to gefitinib, diluting any difference in OS between the two groups.29 In the US, the phase II CALGB 30406 study randomized 181 never smokers or former light smokers or patients with = 0.1988). The difference in OS was not statistically significant in the two arms: 24.6 months for erlotinib monotherapy versus 19. 8 months for erlotinib plus chemotherapy. Not surprisingly, the subgroup of patients with activating mutations experienced the greatest benefit from treatment in both arms. In the erlotinib monotherapy group, OS was 31.3 months for mutant compared to 18.1 months for wild-type versus 14.4 months for wild-type However, within the mutations and compared EGFR TKIs with chemotherapy. The West Japan Thoracic Oncology Group 3405 trial randomized 177 treatment-naive patients with stage IIIB or IV mutations. 34 The recently reported OS was comparable in both arms.35 The benefit of TKIs as first-line therapy in mutations and who experienced never received chemotherapy for metastatic disease were randomized to either erlotinib or a platinum-based doublet. The chemotherapy regimens were a platinum agent Rabbit Polyclonal to Musculin (cisplatin or carboplatin) plus a second drug (docetaxel or gemcitabine). The median PFS was 9.7 months in the erlotinib group versus 5.2 months in the chemotherapy group.36,37 Median OS did not differ significantly between the two groups: 19.3 months for erlotinib and 19.5 months for chemotherapy. These pivotal trials examining erlotinib or gefitinib as first-line therapy are summarized in Table 1. As a result of these studies of TKIs in the first-line setting for NSCLC patients with mutations, the European Medicines Agency has expanded the label of erlotinib to include first-line therapy for patients with advanced mutation. Table 1 Selected phase III and randomized phase II studies including EGFR tyrosine kinase inhibitors as first-line treatment in Ximelagatran advanced pulmonary adenocarcinoma mutationsmutations= 0.10921.6 vs 21.9; HR = 1.00 (95% CI: 0.76C1.33); = 0.99011.2 vs 12.7; HR = 1.18 (95% CI: 0.86C1.63); = 0.3095.7 vs 5.8; HR = 0.74 (95% CI: 0.65C0.85)HR = 0.48 (95% CI: 0.36C0.64)HR = 2.85 (95% CI: 2.05C3.98)First-SIGNAL29Asian never smokersGefitinib vs cisplatin/gemcitabine22.3 vs 22.9; HR = 0.932 (95% CI: 0.716C1.213); = 0.60427.2 vs 25.6; HR = 1.043 (95% CI: 0.498C2.182)18.4 vs 21.9; HR = 1.000 (95% CI 0.523C1.911)5.8 vs 6.4; HR = 1.198 (95% CI: 0.944C1.520); = Ximelagatran 0.1388.0 vs 6.3; HR = 0.544 (95% CI: 0.269C1.100); = 0.0862.1 vs 6.4; HR = 1.419.