Variation in Mechanisms of Acquired Resistance Among EGFR-Mutant NSCLC Patients With More Than 1 Postresistant Biopsy: Metastatic Non-Small Cell Lung Cancer

Abstract

Acquired resistance (AR) typically develops after 9-12 mo of EGFR TKI therapy among EGFR-mutant patients (pts). Repeat biopsies after the development of AR have become a standard of care, and are increasingly obtained more than once during postresistance treatment. Here we report a unique series of 57 EGFR mutants who had >1 postresistant biopsy that illustrates the heterogeneity of AR within individual pts. We analyzed prospective data from 136 EGFR mutants with advanced NSCLC who had ≥1 biopsy after AR developed on EGFR TKI therapy. All biopsies underwent multiplexed CLIA-certified SNaPshot genotyping. When possible, preresistant biopsies were also studied. Some pts consented to provide tissue for patient-derived cell-line (PDCL) establishment. Fifty-seven pts had >1 post-AR biopsy. We collected data on EGFR TKI therapy, mechanisms of AR observed over multiple biopsies, biopsy safety, and correlations between clinical and PDCL data. Among 57 pts with multiple post-AR biopsies, median age= 58 (range 39-88), 72% were female, 58% had EGFR exon 19 deletion and 37% had L858R. The median number of post-AR biopsies was 2 (range 2-5). While the original EGFR mutation was uniformly maintained, we observed variation in AR mechanisms among 25/57 pts, with changes in T790M status over time in 14 (25%) pts. Both gain and loss of T790M were observed on serial biopsies, without a clear correlation to the timing of EGFR TKI therapy or biopsy site. Changes in histology (8), development of EMT (1) and EGFR amp (1) were also seen. Thirty-two of 57 pts had no variations in detected mechanisms of AR on serial biopsies, including T790M (n=19), MET amp (2), both MET and EGFR amp (1), SCLC transformation (1), BRAF mutation (1), and no AR mechanism identified (8). Repeat biopsies were safe, with 2.2% biopsy-related complications and no serious complications. We observed frequent and unexpected changes in the mechanism of AR, particularly T790M status, in pts undergoing serial biopsies, suggesting heterogeneity of resistant clones in these pts. Among pts with T790M observed at any time in their disease, 40% gained or lost the mutation over time. Relationship of AR mechanisms to therapy at the time of biopsy, biopsy location, and correlations with PDCL data to understand their biologic implications will be presented. Our data suggest serial biopsies in EGFR pts are informative and safe, and may become increasingly important as T790M-specific TKIs become available.