Context-dependent value of HLA class I diversity in advanced non-small cell lung cancer treated with immune...

Immune checkpoint inhibitors (ICI), alone or in combination with chemotherapy, are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) without actionable oncogenic drivers. Programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) are routinely used biomarkers, yet both show limited predictive accuracy at the individual level, particularly in the context of chemo-immunotherapy. HLA class I diversity has been proposed as a biomarker of response to ICI monotherapy, although its role in first-line chemo-immunotherapy remains unclear.

We performed a retrospective validation and exploratory study including patients with stage IV NSCLC treated with ICI monotherapy or platinum-based chemo-immunotherapy in the first-line setting. Tumors were profiled using a single clinically-validated targeted sequencing assay (TruSight Oncology 500), allowing simultaneous assessment of TMB and HLA class I diversity. Furthermore, tumors had a complete clinical annotation, including the level of PD-L1 expression. Associations with objective response rate (ORR) and progression-free survival (PFS) were evaluated.

PD-L1 expression and TMB showed limited discriminative performance for ORR, particularly in chemo-immunotherapy-treated patients. Composite HLA class I diversity did not predict ORR or PFS. A triple-negative biomarker profile identified a subgroup with reduced likelihood of response, although statistical significance was not reached. Exploratory analyses suggested that locus-specific HLA-B diversity, when combined with TMB, was associated with numerically longer PFS, whereas HLA-A, HLA-C, and composite HLA metrics showed no consistent association.

In advanced NSCLC treated predominantly with first line chemo-immunotherapy, composite HLA class I diversity does not improve outcome prediction beyond established biomarkers. Locus-specific HLA metrics, particularly HLA-B, may warrant further investigation.