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Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib

Authors' Affiliations: ¹ Beth Israel Deaconess Medical Center, ² Massachusetts General Hospital, and ³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; ⁴ Yonsei University College of Medicine, Seoul, Republic of Korea; ⁵ Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁶ Case Western Reserve University, Cleveland, Ohio

Requests for reprints: Daniel B. Costa, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215. Phone: 617-667-9138; Fax: 617-667-3299; E-mail: dbcosta{at}bidmc.harvard.edu.

Purpose: Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib.

Experimental Design: Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification.

Results: Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib.

Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.

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				E. Vasile, C. Tibaldi, and A. Falcone Is erlotinib really active after failure of gefitinib in advanced non-small-cell lung cancer patients? Ann. Onc., April 1, 2009; 20(4): 790 - 791. [Full Text] [PDF]