{
  "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 (pBonferroni=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.",
  "authors": [
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Vylyny Chat"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Kipper Fletez-Brant"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Minu Srivastava"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Barzin Nabet"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Ira Mellman"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Mark I McCarthy"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Christian Hammer"
    }
  ],
  "title": "Clonal hematopoiesis is associated with reduced response to atezolizumab in non-small cell lung cancer",
  "uid": "a803a9eb-d3ce-5fc4-bb13-4b61920f15ce"
}