Lack of efficacy of erlotinib in most EGFR mutated non-small cell lung cancers (NSCLCs) with acquired resistance to gefitinib

Abstract

8105 Background: The majority of NSCLC patients (pts) with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib, however acquired resistance to this tyrosine kinase inhibitor (TKI) ensues. The secondary resistant T790M mutation has been identified in 50% of progressing pts. The amplification of the MET oncogene occurs in 20% of TKI-resistant pts and sometimes concomitantly with T790M. Very few other secondary mutations (D761Y, L747S) exist. Our goal was to determine the effects of erlotinib 150mg/d in EGFR mutated pts who became resistant to gefitinib 250mg/d, since the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Methods: We followed radiographic responses of 18 EGFR mutated pts from 4 academic medical centers that were given gefitinib and subsequently erlotinib. All pts, but one, had either exon 19 deletion or L858R mutations. 4 pts had tumor re-sampling after becoming resistant to TKI therapy. Results: Most pts achieved a response to gefitinib monotherapy (14/18, 77.7%) and median time to progression (TTP) was 11 months (95%CI, 4–16.5). After the tumors became gefitinib-resistant, most of the pts exposed to erlotinib had progressive radiographic disease (14/18, 77.7%) and median TTP was 2 months (95%CI, 2–3.8). The 3 pts with exon 19 deletions that acquired the T790M gefitinib-resistant mutation progressed on erlotinib. Only 1 gefitinib-resistant pt achieved a radiographic partial response and this patient had acquired L858R-L747S EGFR, which in vitro is sensitive to serum levels of erlotinib 150mg/d. Conclusions: In EGFR mutated tumors that become resistant to gefitinib, a switch to another reversible EGFR TKI given at higher biological doses - erlotinib - does not lead to responses in most pts. These findings were expected since the two most common mechanisms of gefitinib resistance (T790M and MET amplification) in vitro lead to high-grade resistance to clinically achievable doses of gefitinib and erlotinib. A gefitinib to erlotinib switch may only be beneficial in the rare EGFR mutated pt who acquires atypical “partial” resistance secondary EGFR mutations. Continued clinical development of novel EGFR and MET inhibitors for pts with EGFR mutated TKI resistant tumors is warranted. No significant financial relationships to disclose.