Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors

Dan Zhao, Isa Mambetsariev, Haiqing Li, Chen Chen, Jeremy Fricke, Patricia Fann, Prakash Kulkarni, Yan Xing, Peter P. Lee, Andrea Bild, Erminia Massarelli, Marianna Koczywas, Karen Reckamp, Ravi Salgia

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Objectives: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients. Materials and methods: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis. Results: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06−0.59; P < 0.01), EGFR (HR 7.38; 95% CI, 1.15–47.42; P < 0.05), and TET2 (HR 0.15; 95% CI, 0.03−0.90; P < 0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P < 0.05). Conclusions: We described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC.

Original languageEnglish (US)
Pages (from-to)174-181
Number of pages8
JournalLung Cancer
Volume146
DOIs
StatePublished - Aug 2020

Keywords

  • FANCA
  • Immune checkpoint inhibitors
  • Immunotherapy
  • Lung cancer
  • Molecular
  • Next-generation sequencing (NGS)
  • PD-L1
  • TET2
  • TMB

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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