Background Established biomarkers of immune checkpoint inhibitor (ICI) response in metastatic non-small cell lung cancer (mNSCLC), such as PD-L1 and tumor mutational burden (TMB), do not identify all patients with durable response. While biomarkers spanning multiple data modalities have been proposed to address this unmet need, additional evidence is required for use in the clinic. Here, we performed a comparative study assessing the association between previously described biomarkers of ICI response and outcomes in a real-world mNSCLC cohort.

Methods Using the Tempus database, we analyzed de-identified records of non-squamous EGFR-negative and ALK fusion-negative mNSCLC patients treated with first-line ICI regimens and profiled with targeted-panel DNA-seq and whole-exome-capture RNA-seq. ICI-related biomarkers were calculated following published methods using the Tempus IO platform (table 1). Immune biomarkers included features describing tumor biology (including PD-L1 IHC, STK11 and KEAP1 mutations, APOBEC signature¹), HLA (HLA-LOH, HLA A*03 genotype), neoantigens (TMB, neoantigen burden), and RNA-based signatures of immune activity such as IFNγ tumor inflammation signature,² IMPRES,³ Cytotoxic score,⁴ NRS,⁵tertiary lymphoid structure (TLS),^{6 7} and others. Real-world time to progression (rwTTP) was defined as the interval from ICI start to the first progression event, censored on last known physician encounter. Cox proportional hazards (Cox PH) models were fitted to evaluate the relationship between each biomarker and rwTTP.