Predictive value of EGFR and KRAS mutations detected in plasma from non-small cell lung cancer (NSCLC) patients treated with docetaxel and intermittent erlotinib

Abstract

8062 Background: Activating epidermal growth factor receptor (EGFR) mutations in NSCLC are associated with enhanced response to EGFR tyrosine kinase inhibitors; whereas KRAS mutations are associated with poor response. Determining the presence of EGFR/KRAS mutations in tumor DNA shed into plasma could have considerable clinical utility. We used an allele-specific PCR assay to detect EGFR & KRAS mutations in plasma DNA from NSCLC patients (pts) treated with docetaxel and intermittent erlotinib (Davies, ASCO 2007). Methods: Plasma from 49 NSCLC pts on this phase I/II trial was obtained. Mutations were detected using an allele-specific, real-time PCR assay with Scorpion primers (DxS, UK). This assay detects mutations comprising as little as 0.1% of total DNA (Holland ASCO 2007). Statistics: Cox Proportional Hazard Model; 2-sided Fisher’s Exact Test. Results: EGFR mutations (exons 19, 21 and/or 20) were detected in 12/49 pts. KRAS mutations were detected in 2/49. Pts were dichotomized into two groups: those with activating mutations (exon 19del or exon 21 L858R) and those with wt EGFR or harboring a T790M resistance mutation. The 7 pts with activating mutations had significantly improved progression-free survival (PFS), with a median of 11.8 months vs. 4.2 months for all others. A non-significant trend was observed for overall survival (OS) with a median of 40.2 months vs. 25.5 months (p=.12; HR 0.38 [95%CI: 0.11–1.31]), respectively. A significant relationship was also observed between EGFR mutational status and best response (45 evaluable): for pts with favorable mutations, 6 had PR/CR vs. 1 with SD; for all others, 8 had PR vs. 30 with SD/PD (p=0.0021). Both CR pts had exon 19 deletions, and all 13 PD pts were EGFR wt. Two pts with mutant KRAS rapidly progressed after 35 and 48 days, with survival of 103 and 48 days. Conclusions: 1) Allele-specific Scorpion technology can detect EGFR/KRAS mutations in shed tumor DNA in plasma. 2) OS was enhanced in this study (>2 year median); pts with activating EGFR mutations had a non-significant trend towards improved survival. 3) The presence of activating EGFR mutations (absent a T790M) significantly correlated with a favorable PFS and response rate in advanced NSCLC pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OSI Oncology Genentech™ BioOncology