Germline HLA and KIR Variation and Disease Control After Immune Checkpoint Blockade in Non-Small Cell Lung Cancer: Exposure Definition Shapes the Signal

Immune checkpoint inhibitors (ICIs) benefit only a minority of patients with advanced non-small cell lung cancer (NSCLC). Whether germline human leukocyte antigen (HLA) or killer cell immunoglobulin-like receptor (KIR) variation identifies them is unclear, partly because studies define HLA exposures differently. We asked whether allele groups, supertypes and evolutionary divergence associate with disease control. In 122 ICI-treated patients, HLA and KIR typed from germline exomes were tested in 448 pre-specified exposure-endpoint combinations; the primary endpoint was progression or death at 3 months (99 evaluable patients; 31 events). No test survived correction across the screen (lowest n = 0.299). Nominally, HLA-A*02 carriers had higher odds of early failure (odds ratio 4.00, 95% CI 1.64 to 10.07), whereas none of the 12 HLA-B*14 carriers failed (0.07, 0.0006 to 0.58), yet the B27 supertype containing B*14 was null. In 297 public SU2C-MARK patients, B*14 was not supported; A*02 was inconclusive for time to event and not reproduced at a 90-day landmark. HLA-DQA1 divergence at 12 months was hypothesis-generating (within-family n = 0.004). Exome typing resolved HLA allele groups (99.1%) but not KIR (19.0% ambiguous). How an HLA exposure is defined determines whether a signal is visible; only large effects were detectable; replication is required.