Genome and transcriptome biomarkers of response to immune checkpoint inhibitors in advanced solid tumours.

Purpose Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of solid tumours with dramatic and durable responses seen across multiple tumour types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers. Experimental design We characterised fresh tumour biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pre-treated disease through the Personalized OncoGenomics (POG) program at BC Cancer using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow up data were collected retrospectively. Results We found that tumour mutation burden (TMB), independent of mismatch repair status, was the most predictive marker of time to progression (TTP, p=0.007), but immune related CD8+ T cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS) (p=0.0014 and 0.0012 respectively). While CD274 (PD-L1) gene expression is comparable to protein levels detected by immunohistochemistry (IHC), we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients (p=0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a non-small cell lung cancer (NSCLC) patient. Conclusions Interpreting the tumour-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumour type-specific testing.