Retrospective analysis of antitumor effects and biomarkers for nivolumab in NSCLC patients with EGFR mutations

PLoS One. 2019 Apr 12;14(4):e0215292. doi: 10.1371/journal.pone.0215292. eCollection 2019.

Abstract

Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / therapeutic use*
  • B7-H1 Antigen / antagonists & inhibitors
  • Biomarkers, Tumor / immunology
  • CD4 Lymphocyte Count
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • ErbB Receptors / genetics
  • Female
  • Forkhead Transcription Factors / metabolism
  • Genes, erbB-1
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology
  • Male
  • Middle Aged
  • Mutation
  • Nivolumab / therapeutic use*
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Retrospective Studies
  • Tumor Microenvironment / immunology

Substances

  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • EGFR protein, human
  • ErbB Receptors

Grants and funding

The authors received no specific funding for this work.