Impact of KIR/KIR Ligand Genotype for Neuroblastoma Patients in a Phase III COG Immunotherapy Trial.

e14014 Background: High-risk neuroblastoma (NBL) patients (pts) enrolled in a COG phase III clinical trial (ANBL0032) were randomized to isotretinoin (RA) alone or RA + immunotherapy (IM): dinutuximab (anti-GD2 mAb) + IL2 + GMCSF (Yu et al., NEJM363:1324, 2010). Dinutuximab acts via antibody-dependent cell-mediated cytotoxicity by innate immune cells, including NK cells. NK cells express Killer Immunoglobulin-like Receptors (KIRs) that bind KIR-Ligands (KIR-Ls), MHC Class I molecules. Prior studies suggest that KIR/KIR-L status impacts outcome for pts with NBL. We investigated whether KIR/KIR-L genotype was associated with event-free survival (EFS) and overall survival (OS) in this trial. Methods: Of the 226 pts randomized, 174 pts had DNA allowing evaluation of genotype correlations with outcome (IM: n=88; RA: n=86; >5yr follow-up if no event). For the inhibitory KIRs, we assessed the impact of all KIR-Ls present vs. missing at least one KIR-L (KIR-L missing) on outcome. Cox regression models and log-rank tests were used to evaluate EFS/OS with genotypes. Results: In contrast to prior reports, outcome for IM pts was not associated with KIR-L present vs. KIR-L missing genotypes (EFS p=0.35; OS p=0.33; Table). Interestingly, we found that IM therapy benefited those pts with KIR-L present as opposed to those with KIR-L missing (OS: p=0.01 vs. p=0.77; Table). Conclusions: IM (vs. RA) treatment resulted in improved outcome (Yu et al., 2010), but IM can have toxic side effects. Our data suggest that KIR/KIR-L genotype could be used prospectively to identify pts most likely to benefit from this therapy. We are continuing to evaluate KIR/KIR-L genotypes in this study to determine if there are certain genotypes that are likely to respond to IM (eg. KIR-L present, Table), and identify KIR/KIR-L genotypes that might benefit from alternate treatment regimens (eg. KIR-L Missing, Table). Clinical trial information: NCT00026312.Treatment EFS OS KIR-L present KIR-L missing Genotype p-value KIR-L present KIR-L missing Genotype p-value RA 5 yr % 39 48 0.24 42 66 0.06 [95% CI] [22-55] [34-61] [24-58] [52-78] Events/n 19/31 27/55 18/31 21/55 RA + IM 5 yr % 72 52 0.35 80 71 0.33 [95% CI] [50-86] [39-64] [58-91] [59-81] Events/n 9/25 30/63 7/25 25/63 Treatment p-value 0.03 0.54 0.01 0.77