Date Published: April 12, 2019
Publisher: Public Library of Science
Author(s): Miyuki Sato, Satoshi Watanabe, Hiroshi Tanaka, Koichiro Nozaki, Masashi Arita, Miho Takahashi, Satoshi Shoji, Kosuke Ichikawa, Rie Kondo, Nobumasa Aoki, Masachika Hayashi, Yasuyoshi Ohshima, Toshiyuki Koya, Riuko Ohashi, Yoichi Ajioka, Toshiaki Kikuchi, Hiroyoshi Nishikawa.
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.
Lung cancer is the most common cause of cancer death worldwide [1, 2], and non-small-cell lung cancer (NSCLC) accounts for the most cases. Immunotherapy for NSCLCs has recently evolved into a new stage of a novel modality with immune-checkpoint inhibitors (ICIs) . For example, anti-programmed-cell death-1 (PD-1) and anti-PD-ligand (L) 1 antibodies have demonstrated promising and durable responses across a broad range of solid tumors, including NSCLCs .
Previous clinical trials have suggested that PD-1/PD-L1 blockade therapies are less effective for patients with EGFR mutations than for patients with wild-type EGFR [5, 21, 29, 30]. Meta-analysis of randomized trials comparing anti-PD-1/PD-L1 inhibitors with docetaxel revealed that patients with EGFR mutations did not benefit from PD-1/PD-L1 blockade therapies in terms of OS, and PFS was even worse . Thus, predictive biomarkers are required to improve the outcomes of PD-1/PD-L1 blockade therapies in EGFR-mutated NSCLC patients. The expression of PD-L1 in the tumor microenvironment is the most commonly investigated biomarker for anti-PD-1/PD-L1 treatments. The association of clinical benefits with PD-L1 expression has been demonstrated in PD-1/PD-L1 blockade therapies . However, it is controversial whether PD-L1 expression is also useful to predict the antitumor effects of PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. In a prospective phase II trial, pembrolizumab, which is an anti-PD-1 antibody, failed to show clinical benefits in PD-L1 positive EGFR-mutated NSCLC patients, even in those with a high expression of PD-L1 . In the current study, 4 out of 9 patients were PD-L1 positive, and a correlation between PD-L1 expression and clinical efficacy was not observed (Table 3 and Fig 3). Further, there was no statistical difference of PFS with nivolumab between patients with PD-L1 tumor proportion score of 50% or greater and patients with PD-L1 tumor proportion score of less than 50% (data not shown). Tumor cells express PD-L1 in response to inflammatory cytokines, such as IFN-γ, to escape from attack by effector T cells. Recent studies reported that PD-L1 expression is induced by signaling through EGFR [34, 35]. This finding may be the reason why PD-L1 expression is not a reliable predictive biomarker in patients with EGFR mutations.