EGFR and ABCG2 polymorphisms as prognostic and predictive markers in the NCIC CTG BR.21 trial of single-agent erlotinib in advanced non-small cell lung cancer (NSCLC).

Abstract

7538 Background: EGFR and ABCG2 polymorphisms have been evaluated in small nonrandomized studies of EGFR tyrosine kinase inhibitors as markers of clinical outcome. BR.21 is a double-blind, placebo controlled trial of erlotinib as second/third line treatment in Stage IIIB/IV NSCLC. Methods: Normal tissue (± tumor) DNA was extracted from 242 paraffin tissues of 731 enrolled patients. Genotyping involved sequencing (EGFR -216 G>T [EGFR 216], EGFR -191 C>A [EGFR 191]), microsatellite length analysis (EGFR intron 1 CA dinucleotide repeat [CADR]) and allelic discrimination (ABCG2 421 C>A [ABCG2]). Cox proportional hazard and logistic regression models compared genotypes to overall survival (OS), progression-free survival (PFS), and skin toxicity (presence/absence). Results: In a 30 patient subset, genotyping concordance rates were > 93% between normal and corresponding tumor tissue DNA. Subgroups of genotyped and non-genotyped patients had similar OS/PFS and benefited similarly from study treatment. Genotyping technical success rates exceeded 92%. In the prognostic evaluation of patients on placebo (n = 86), carrying at least one short CADR allele (< 16 repeats) was associated with longer PFS compared with carrying all long (adjusted hazard ratio [aHR] 0.6, 95% confidence interval [CI] 0.3-1.0). In the predictive evaluation, no interaction was demonstrated between treatment arm and CADR (interaction p = 0.76). For OS, the heterozygous variant of EGFR 191 was predictive of lack of benefit from study treatment (HR 1.97, 95% CI 0.6-6.5) in univariate, but not multivariate analyses; EGFR 191 was not predictive of PFS or skin toxicity. EGFR 216 and ABCG2 421 polymorphisms were neither prognostic nor predictive of survival/skin toxicity outcomes. Conclusions: Carrying shorter alleles of the EGFR CADR polymorphism is associated with longer PFS, but is not predictive of survival benefit from erlotinib treatment or skin toxicity. EGFR and ABCG2 polymorphisms do not appear to aid in the selection of EGFR TKI therapy in advanced NSCLC patients who have failed platinum-based therapy. Supported by CCS, OICR research grants, Alan Brown and CCO Chairs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Boehringer Ingelheim, Roche