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

Abstract

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.

Keywords: Immune Checkpoint Inhibitor; Lung Cancer.

Figure 1. Forest plot of the association between CH and treatment response in anti-PD-L1 and comparator arms. OR>1 indicated CH was associated with increased odds of non-response, while OR<1 suggested that CH was associated with increased odds of response. Results from each trial were meta-analyzed using a random effect model. We also meta-analyzed the association between CH and response in a subgroup of DNMT3A-specific and TET2-specific CH. The top panel represented results from the anti-PD-L1 treated group, while the bottom panel displayed results from the control arms. FIR was a single-arm anti-PD-L1 trial and was not included in the control arm analysis. CH, clonal hematopoiesis; PD-L1, programmed cell death ligand-1.

Figure 2. Baseline circulatory inflammatory markers and CH. Wilcoxon’s rank-sum test was used to compare circulatory inflammatory blood cell counts by CH status. After Bonferroni multiple testing adjustment, two cell populations were statistically significantly different by CH status (p adjusted<0.05). Lower leukocyte (panel A) and lymphocyte absolute levels (panel B) were observed in CH carriers. CH, clonal hematopoiesis.