Clonal hematopoiesis is associated with reduced response to atezolizumab in non-small cell lung cancer

Background The acquisition of somatic mutations associated with the expansion of certain hematopoietic stem cells is known as clonal hematopoiesis (CH). Despite evidence of CH association with age-related pro-inflammatory diseases, little is known about its role in the response to antitumor immune modulatory therapies such as immune-checkpoint inhibition (ICI). In this report, we characterize the effect of CH on ICI objective response in non-small cell lung cancer (NSCLC). Methods We performed baseline blood-derived whole-exome sequencing of 1,281 patients with NSCLC from five anti-programmed death ligand-1 (PD-L1) trials (FIR, POPLAR, IMpower110, IMpower150, and IMpower131). Multivariable logistic regression adjusting for age, sex, and smoking history was used to model the odds of being a non-responder in each trial, and random effects meta-analyses were performed in anti-PD-L1 and comparator arms. Results CH carriage, defined as the presence of CH with variant allele fraction≥2%, was associated with adverse objective response across the anti-PD-L1 treatment arms (OR=1.69 (95% CI 1.08 to 2.63); p=0.02). No association was observed in the comparator arms (OR=0.61 (95% CI 0.31 to 1.21); p=0.16). CH carriers had lower absolute leukocyte counts (p Bonferroni =0.01), driven by reduced lymphocytes (p Bonferroni =0.004). Conclusions In this report, we provide evidence of the adverse impact of CH on ICI treatment objective response in NSCLC, highlighting CH as a potential predictive biomarker for patient stratification in ICI. Further experimental validation is needed to better understand the mechanism of action behind this reduction in ICI efficacy.