Abstract
Abstract Immune checkpoint blockade (ICB) with ipilimumab and nivolumab is a front- line standard of care in patients with mesothelioma. However, only a minority of patients respond. The tyrosine receptor kinase AXL is a putative ICB resistance factor. We evaluated AXL and programmed death 1 (PD1) inhibition (AXL-PD1) with bemcentinib and pembrolizumab respectively, in a phase IIA clinical trial in patients with ICB naïve-relapsed mesothelioma (MIST3, NCT03654833 ). The study met its primary endpoint with a 12-week disease control rate of 46.2%, 90% confidence interval 29.2-63.8%. Grade 3 or greater adverse events occurred in 53.9% of patients. Multiomic analyses identified tumour-intrinsic and tumour extrinsic features linked to response to AXL-PD1 inhibition. Responders exhibited greater NF2 loss, heightened immune response signalling, and epithelial mesenchymal transition, which was lower in biopsies obtained at the time of acquired drug resistance. Neutrophil- related transcriptional programmes were associated with response to AXL-PD1 inhibition. Neutrophil regulating erythroblast transformation specific (ETS) transcription factors SPI1, ETS2, FLI1 were differentially activated in responding tumours. Gut microbiota rheostat differed between responders and non-responders and positively correlated with neutrophil- associated transcription program, IRF3 and TLR2. In summary, our findings support a hypothesis linking gut microbiota composition, neutrophil- associated tumour biology and response to AXL-PD1 inhibition in mesothelioma.