e sequencing was not performed. In addition, 81% of patients were previously treated with erlotinib or gefitinib for 24 weeks, with 45% having responded (PR or CR) to prior treatment. Primary analysis revealed median OS times of 10.8 months for afatinib plus BSC and 12.0 months for placebo plus BSC (HR, 1.08; 95% CI, 0.86 –1.35). Despite the lack of OS benefit, afatinib provided significantly better results in the secondary endpoints of PFS time (3.3 months versus 1.1 months; HR, 0.38; p  .0001), disease control rate (DCR) at 8 weeks (58% versus 19%; p  .0001), and objective RR (7.4% versus 0.5% by independent analysis; p .01) than with placebo [77]. Afatinib has also been evaluated as first-line and secondline therapy in patients who have not received a first-generation EGFR TKI. LUX-Lung 2 is a single-arm, multicenter, phase II trial evaluating the efficacy of afatinib (50 mg/day or 40 mg/day) in patients with stage Cediranib

IIIB/IV mutant EGFR adenocarcinoma and no prior EGFR-targeted therapy. Of 129 patients who received treatment (first line, n 61; second line, n 68), 54 had L858R EGFR mutations, 52 had exon 19 deletions in EGFR, and 23 had other EGFR mutations [79]. By investigator assessment, the objective RR, DCR, median PFS interval, and median OS time were 60%, 86%, 14 months, and 24 months, respectively, for all patients [73]. The objective RR, DCR, and median PFS were 59%, 83%, and 16.1 months, respectively, for patients with L858R mutations and 69%, 93%, and 13.7 months, respectively, for patients with exon 19 deletions. Additional trials of afatinib in NSCLC are ongoing and summarized Expectations have been high for irreversible HER family inhibitors in the treatment of NSCLC, and results are awaited from ongoing large randomized clinical trials evaluating these agents in NSCLC, particularly in clinically and/or molecularly selected populations. The optimal role of irreversibleHERinhibitors in the treatment of Cediranib AZD2171

NSCLC has yet to be determined; however, their potential potency in the first-line setting and ability to bind covalently to block the ATP-binding site of mutant EGFR could potentially improve upon outcomes seen with gefitinib and erlotinib. This may be true particularly for specific activating mutations. In NSCLCs with the most common EGFR activators, exon 19 deletions and L858R mutations (85% of known mutations), outcomes are better after reversible TKI treatment for patients with exon 19 mutations than for patients with L858R mutations perhaps because of less effective inhibition of the L858R mutant. In vitro, PF00299804 was more effective at inhibiting exon 19 deletions and L858R compared with gefitinib [64]. Similar activity has also been observed with afatinib compared with gefitinib against exon 19 mutations [82]. Therefore, potent irreversible inhibitors may improve outcomes and delay the onset of resistance than with reversible TKIs, particularly for patients with L858R-mutant NSCLCs.

Randomized trials of first-line irreversible inhibitors versus erlotinib or gefitinib in Cediranib VEGFR inhibitor prospectively identified mutantEGFRNSCLCs are required to explore this concept. Anongoing trial (ClinicalTrials.gov identifier, NCT00769067) of PF00299804 versus erlotinib in patients previously treated with chemotherapy may answer these questions in part, although that trial does not include prospective identification of EGFR mutations. Results of irreversible inhibitors in erlotinib- or gefitinibresistant, mutant EGFR NSCLCs have been disappointing to date and suggest that the ability of irreversible inhibitors to overcome acquired resistance may have limitations that were not predicted in preclinical studies. This may be a result of an inability to attain the drug concentrations in humans that were effective in preclinical studies. In the case of neratinib, grade 3 diarrhea in half of the patients necessitated a dose reduction in the three-arm phase II trial. Although not measured, it was proposed that dose reduction of neratini