In 00, gefitinib was approved in Europe for all lines of therapy in patients with locally advanced or metastatic NSCLC with an EGFR-activating mutation . Two Japanese phase III trials published in 00 confirmed the activity of gefitinib in chemotherapy-naive patients with advanced NSCLC harboring an EGFR mutation , 0. In the first trial (West Japan Thoracic Oncology Group 0) , gefitinib resulted in a longer PFS duration (. months versus . months; HR, 0.; % CI, 0.–0.0; p  .000) and a higher objective RR (.% versus .%; p  .000) than with cisplatin plus docetaxel; OS data were not available at the time of this review. Similarly, in a second trial conducted by the North- East Japan Study Group 0, gefitinib was associated with a longer PFS time (0. months versus . months; HR, 0.0; % CI, 0.– 0.; p  .00) and a higher RR (.% versus 0.%; p  .00) than with carboplatin plus paclitaxel. However, the OS time was not significantly different between the two arms (. months, versus 0. months with gefitini tovok

This lack of a significant OS difference was also reported in the IPASS trial—the OS times were similar for gefitinib and chemotherapy in the overall population (HR, 0.0; % CI, 0.–.0; p  .0), in the subgroup of patients with EGFR mutations (HR, .00; % CI, 0. –.; p  .0), and in the subgroup of patients without EGFR mutations (HR, .; % CI, 0.–.; p  .0) The similarity in OS times for gefitinib- and chemotherapy- treated patients with mutant EGFR tumors is likely a result of crossover and the effectiveness of EGFR inhibitors whether given in the first- or second-line setting . Interestingly, a subgroup analysis of never-smokers from the TRIBUTE trial demonstrated that the survival duration of patients randomized to erlotinib plus carboplatin and paclitaxel was . months, compared with 0. months for those randomized to placebo plus chemotherapy (HR, 0.; % CI, 0.–0.), suggesting that, in the absence of crossover, EGFR inhibition would likely produce superior outcomes in patients with mutant EGFR tumors The most prevalent determinant of de novo resistance to EGFR TKIs is the presence of a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, associated primarily with NSCLC patients having a history of smoking tovok EGFR inhibitor

Most studies have found that EGFR-activating mutations and KRAS mutations, found in approximately one third of NSCLCs of adenocarcinoma histology , are mutually exclusive. Retrospective analyses suggest that KRAS mutations may be associated with poorer survival with erlotinib in patients with NSCLC , . However, in a retrospective analysis of the BR. trial, correlation of KRAS status with erlotinib treatment outcome did not reach statistical significance (p.0), and the RR was % (one of 0) among patients with KRAS mutations (RR among patients with wild-type KRAS, 0%) . Even among tumors tovok 439081-18-2 with activated EGFR, a subset of mutations, such as exon 0 insertions, is inherently resistant to erlotinib or gefitinib .

For those cases in which primary resistance is not the obstacle to EGFR TKI benefit, acquired resistance becomes the challenge. Despite initial response to EGFR TKIs, patients with mutant EGFR NSCLC experience disease progression within  months of treatment . The most common mechanism of acquired resistance is the emergence of a secondary mutation in exon 0, T0M, within the catalytic cleft of EGFR, detectable in approximately 0% of NSCLCs that become resistant to first-generation EGFR TKIs . Interestingly, although the T0M mutation is associated with acquired resistance, it has also been detected in circulating tumor cells from TKI treatment–naive patients . In addition, the T0M mutation was identified in the germline of a family predisposed to NSCLC, indicating an additional role in NSCLC susceptibility