Genetic Variants In Angiogenesis Pathway Associated With Clinical Outcome In Nsclc Patients (Pts) Treated With Bevacizumab In Combination With Carboplatin And Paclitaxel: Subset Pharmacogenetic Analysis Of Ecog 4599

8032 Background: E4599 was a randomized phase III study which demonstrated a survival advantage in advanced NSCLC pts treated with bevacizumab (bev) + carboplatin/paclitaxel (BPC) versus carboplatin/paclitaxel alone (PC). Recent studies have shown certain germline polymorphisms (SNPs) are associated with clinical outcome in advanced breast cancer pts treated with paclitaxel plus bev and in advanced colorectal cancer pts treated with first line 5-FU or capecitabine in combination with oxaliplatin and bev. A study also found 2 SNPs in WNK1 gene were associated with bev-induced hypertension. We tested the hypothesis that SNPs involved in angiogenesis pathway (VEGF, EGF, EGFR, IL-8, KDR, ICAM1, FGFR4), DNA repair pathway (ERCC1, XPD, XRCC1, GSTP1) and WNK1 may predict clinical outcome in a subset of pts enrolled on E4599. Methods: Of 878 pts enrolled, samples from 146 pts were available for the current pharmacogenetic study and only 133 of the samples (67 PC, 66 BPC) came from eligible pts. PCR-RFLP assays were performed on genomic DNA extracted from sera of pts. The Kaplan-Meier method was used to estimate time-to-event distributions. Multivariable Cox models adjusted for gender, PS, stage, adrenal, liver and bone mets were separately fitted for each SNP to obtain estimates of hazard ratios. Results: Median OS for the 133 patients was 10.3 mos (8.2–15.6) for PC and 13.0 mos (10.2–16.6) for BPC. Median PFS was 4.6 mos (3.6–5.6) for PC & 6.5 mos (5.4–8.3) for BPC. Pts with mutant homozygote CC genotype for ICAM1 T469C had significantly higher tumor response rate (39%) than heterozygote CT (13%) and homozygote TT (20%) genotype (Fisher's test, p=0.04). Tests for whether treatment effect differs by genotype via interaction terms in the Cox models were statistically significant (p<0.05) for VEGF G-634C, ICAM1 T469C and WNK1-rs11064560 for OS, and for ICAM1 T469C, EGF A-61G and CXCR2 C785T for PFS. Conclusions: Although exploratory, our preliminary results suggest germline SNPs in angiogenesis pathway may predict response, PFS and OS in NSCLC pts treated with BPC. Prospective trials based on these correlative studies are warranted. [Table: see text]