Clinical course of patients (pts) with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKI).

Abstract

7520 Background: Pts with EGFR mutant lung cancer develop AR (i.e., progressive disease (PD) after initial sensitivity) on erlotinib or gefitinib after a median of 12 months. An acquired EGFR mutation (T790M) has been found in approximately half of tumors with AR, suggesting a change in tumor biology. EGFR mutant cell lines that acquire the T790M mutation have been found to demonstrate a more indolent growth pattern (Chmielecki and Pao, AACR, 2009). The clinical course of pts with AR has not been described. Methods: Pts fitting the consensus definition of AR (Jackman, et al., JCO, 2009) were enrolled in a rebiopsy/tissue analysis protocol. Medical records were reviewed. The first biopsy obtained after AR was tested for EGFR T790M mutation, using detection of EGFR sensitizing mutation as a control for specimen quality and clonal relatedness. Factors associated with survival after AR were explored using univariate logrank testing and Cox models. Results: 106 pts with AR and a documented EGFR sensitizing mutation were analyzed. Median time to PD on erlotinib (n = 76), gefitinib (n = 24), XL647 (n = 6) was 13 months. 100 pts had rebiopsy tissue available, which was adequate for analysis in 90%. T790M was detected in 59%. With 26 month median follow-up after AR, median survival from time of AR was 16 months and median survival from start of TKI was 38 months. EGFR TKI was maintained in 95% of pts in addition to subsequent therapies; 31% of pts received single-agent TKI for ≥ 6 months after PD. Factors associated with survival after AR were PD in an existing vs. new site of disease (HR 0.43, p < 0.01) and the presence vs. absence of T790M mutation (HR 0.55, p = 0.046). Factors not significantly associated with survival after AR included exon 19 vs. exon 21 EGFR mutation, female vs. male gender, and Asian vs. non-Asian race. Conclusions: (1) The median survival of lung cancer pts with sensitizing EGFR mutations who develop AR on EGFR TKI is 16 months following PD. (2) Detection of T790M in rebiopsy tissue is associated with better survival after AR. (3) A proportion of pts can continue on EGFR TKI alone for months after PD. Supported by R21 CA115051-01. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Boehringer Ingelheim, Genentech, MolecularMD, Pfizer, Roche