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Comprehensive Genomic Analysis of Non-Small Cell Lung Cancer for Predicting Treatment Response to Immunotherapy
40 Pages Posted: 17 Jun 2019
More...Abstract
Background: Few patients with advanced non-small cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs), and the underlying mechanisms mediating the response to ICIs remains unclear.
Methods: We performed whole-exome sequencing (WES) on 198 advanced NSCLC tumors sampled prior to immunotherapy. Detailed clinical annotation and treatment response were collected on these patients. PD-L1 staining was performed in 144 patients. Additionally, TMB was modified (we further called corrected TMB) by considering loss of heterozygosity of human leukocyte antigen to characterize the associations between altered tumor antigen presentations and clinical response to ICIs.
Findings: Corrected TMB was more predictive of improved progression-free survival (PFS) compared to conventional TMB (corrected TMB high versus low, PFS log-rank P = 0.005; TMB high versus low, PFS log-rank P = 0.020). Homology-dependent recombination (HR) deficiency was identified in 37 patients (18.7%) and was associated with longer PFS (hazard ratio 0.65, 95% CI, 0.42-1.00, P = 0.049). TP53 and EGFR alterations were significant prognostic factors in never-smokers administered ICIs (log-rank P = 0.008 for EGFR mutation; log-rank P =0.026, for TP53 mutation). The relationship of TMB and PD-L1 was further studied and we observed that PD-L1 was significantly associated with response to ICIs in TMB low group of patients.
Interpretation: Our results suggest that integrated analysis of genomic features can reconcile the observed disparity in relationships between predictive biomarkers and ICI responses.
Funding Statement: Post-Genome Technology Development Program (South Korean Ministry of Trade, Industry and Energy), and National Research Foundation of Korea Grant.
Declaration of Interests: JS Ahn reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from Boehringer Ingelheim, personal fees from BMSOno, personal fees from MSD, personal fees from Janssen, personal fees from Samsung Bioepis, outside the submitted work. S-H Lee reports grants and personal fees from MSD, personal fees from Novartis, personal fees from AstraZeneca, personal fees from BMS, personal fees from Roche, outside the submitted work. K Park reports personal fees from Astellas, Astra Zeneca, AMGEN, Boehringer Ingelheim, Clovis, Eli lilly, Hanmi, KHK, Merck, MSD, Novartis, ONO, Roche, BluePrint, outside the submitted work.
Ethics Approval Statement: This study was approved by either the Samsung Medical Center Institutional Review Board/Privacy Board (approval number: 2018-03-130 and 2013-10-112) or Institutional Review Board of Seoul National University Hospital Board (approval number: 1805-109-947). All participating patients provided written informed consent before enrollment.
Keywords: Non-small cell lung cancer; tumor mutation burden, immunotherapy, Homologous recombination deficiency, STING pathway
Suggested Citation: Suggested Citation