EGFR compound mutants and survival on erlotinib in non-small cell lung cancer (NSCLC) patients (p) in the EURTAC study.

Abstract

7522 Background: When EGFR compound mutants (exon 19 deletions or L858R plusT790M) are present at the time of clinical resistance to erlotinib, patients attain longer overall survival (OS) (Oxnard et al. CCR 2011). The H1975 cell line, harboring L858R plus T790M prior to treatment, is sensitive to gefitinib (Sordella et al. Science 2004; Faber et al. Cancer Discovery 2011), though the compound mutant may become dominant after multiple passages in vitro, leading to resistance (Pao et al. PLoS Med 2005). Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Progression-free survival (PFS) was 9.7 months (m) vs 5.2 m, respectively (P<0.0001). No differences in OS were observed.123 p with remaining available pre-treatment tumor tissue were re-analyzed for the concomitant presence of the T790M mutation with an allelic discrimination Taqman assay in the presence of a PNA clamp designed to inhibit the amplification of the exon 20 wild-type (wt) allele. This assay is capable of detecting the T790M allele at a ratio of 1:5000 wt alleles. Results: The T790M mutation was detected in 21/64 (32.8%) p in the erlotinib arm and 26/59 (44.1%) in the chemotherapy arm. PFS was 12.1 m for p with mutant T790M in the erlotinib arm, 8.8 m for p with wt T790M in the erlotinib arm, 6.3 m for p with mutant T790M in the chemotherapy arm, and 4.5 m for p with wt T790M in the chemotherapy arm (P<0.0001). OS was not reached for p with mutant T790M in the erlotinib arm, 16.1 m for p with wt T790M in the erlotinib arm, 22.6 m for p with mutant T790M in the chemotherapy arm, and 18.4 m for p with wt T790M in the chemotherapy arm (P=0.04). Conclusions: Our unexpected finding that p with EGFR compound mutants attain the maximum benefit from erlotinib suggests a need for more sensitive assays to detect EGFR compound mutants and for studies of inhibitors targeting the EGFR T790M mutation. Whole genome sequencing may provide greater understanding of the genetic factors involved in the differences in OS.