Association of IL8 polymorphisms with overall survival in patients with renal cell carcinoma in COMPARZ (pazopanib versus sunitinib phase III study)

4519 Background: Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced renal cell carcinoma (RCC). COMPARZ, a phase III randomized clinical trial comparing pazopanib vs sunitinib for RCC, demonstrated similar efficacies for the two therapies but safety profiles differed. Our genetic analyses of previous pazopanib clinical trials found that IL8 polymorphisms may be associated with progression-free survival (PFS) and overall survival (OS). We attempted to validate these associations in the COMPARZ study. Methods: Of the 1110 participants in COMPARZ, 724 (65%) provided consent and DNA for pharmacogenetic analyses (pazopanib, N = 371; sunitinib, N = 353).Associations of IL8 polymorphisms (rs1126647 and rs4073) with PFS and OS were tested using the Cox proportional hazards model with baseline factors as covariates in a combined analysis of all patients and also separately in pazopanib-treated and sunitinib-treated patients. One-tailed P values were calculated for effects in the same direction as previously observed. Results: For PFS there was no significant association in the combined analysis or in pazopanib-treated patients, but there was a significant association in sunitinib-treated patients (P = 0.017). For OS there were significant associations in the combined analysis (P = 0.010) and in sunitinib-treated patients (P = 0.0043) but not in pazopanib-treated patients (P = 0.30). Hazard ratios (HRs) for genetic effects were not significantly different between sunitinib- and pazopanib-treated patients (two-tailed P = 0.23 for genotype-by-treatment interaction). Kaplan-Meier plots suggested a recessive genetic model in the combined data set, with median OS (95% CI) 23.7 months (15.4–29.1) for rs1126647 TT genotype compared to 35.5 months (30.8–∞) for AA or AT genotypes (HR = 1.66, P = 0.0007). Similar associations were seen for rs4073. Conclusions: Germline variants in IL8 are associated with survival outcome in patients with RCC who have received angiogenesis inhibitors. These findings may provide additional scientific insights in making treatment decisions and developing alternative therapies.