Skip to main content
2023 IKCS: North America Main banner
Icon Legend
This session is not in your schedule.
This session is in your schedule. Click again to remove it.
Back

Treatment Toxicities and Symptom Management

44: Germline investigations into treatment-related adverse events (TRAEs) from checkpoint inhibitors (CPI) in patients treated on CheckMate-214 (CM214) and CheckMate-025 (CM025).

Background: CPI therapy is given at the risk of immune-induced TRAEs. Host features affecting antigen presentation are candidate determinants of their pathogenesis, and reports have linked Human Leukocyte Antigen (HLA) variations to TRAEs. We used two large cohorts to investigate class-1 HLA variants and HLA-I evolutionary divergence (HED) in this context.

Methods: We utilized data from 234 patients receiving ipilimumab/nivolumab (I/N) on CM214 and 119 patients receiving nivolumab (N) on CM025. Based on allelic variants for HLA-A and B patients were categorized into 12 established HLA "Super-Types" (ST), sets of HLA variants with largely overlapping peptide binding specificity. Associations between ST grouping and time-to-grade 2+ TRAEs (TTRAE) were assessed with using Cox proportional hazard regression. ST frequencies were compared in outliers with multi-organ irAEs vs patients without TRAEs despite extended treatment exposure using Fisher’s exact test. Mean HED scores (HED A, B, C) were correlated with TTRAE via Wilcoxon rank sum test.

Results: : For I/N-treated patients on CM214, the HLA-B07 ST had protective association for TTrAE (HR= 0.69, 95% CI: 0.52,0.90; p= 0.007), while B62 associated adversely (HR=1.66, 95% CI: 1.19, 2.33; p=0.003). Frequency of these variants differed in outliers vs. controls without reaching statistical significance (table).
TTRAE association for B07 and B62 was not confirmed for N-treated patients on CM025 (table), nor was there association for any other ST in this cohort. Mean HED scores did not associate with TTrAE in either dataset (table).

Conclusions: Distinct HLA variants appeared to affect risk of TRAE in I/N-treated patients, but these associations were not seen with N monotherapy. These results highlight the potential of characterizing germline features to predict immune related toxicity upfront and deserves further study.