Pre-existing pulmonary fibrosis is a risk factor for anti-PD-1-related pneumonitis in patients with non-small cell lung cancer: A retrospective analysis
Introduction
Chemotherapy-related pneumonitis is a relatively common adverse event that can be life-threatening, especially in patients with lower levels of lung function. Although interstitial lung disease (ILD) is associated with a high incidence of lung cancer [[1], [2], [3]], it is also a substantial risk factor for pneumonitis during cytotoxic chemotherapy, molecular-targeted therapy, and radiotherapy [[4], [5], [6], [7], [8]].
Nivolumab, a fully human IgG4 monoclonal antibody, and pembrolizumab, a humanized IgG4 monoclonal antibody, both target the programmed death 1 (PD-1) receptor expressed on activated T cells, B cells, and myeloid cells. Nivolumab or pembrolizumab anti-PD-1 antibodies bind and block the interaction between PD-1 and its ligands programmed death-ligand 1 (PD-L1) and PD-L2, thereby resulting in the activation of T cells and cell-mediated immune responses [9,10]. Nivolumab and pembrolizumab improved overall survival in a second-line setting compared with docetaxel for patients with advanced non-small-cell lung cancer (NSCLC) [[11], [12], [13]], and pembrolizumab demonstrated longer progression-free survival and overall survival compared with standard platinum-doublet chemotherapy in patients with PD-L1 high expression (at least 50%) chemotherapy-naïve advanced NSCLC [14].
In phase III clinical trials of anti-PD-1 antibodies for advanced NSCLC, there was less toxicity associated with anti-PD-1 antibodies compared with standard chemotherapy. However, some patients treated with anti-PD-1 antibodies develop severe, potentially life-threatening immune-related adverse events (irAE), including pneumonitis. The incidence of pneumonitis in NSCLC patients treated with anti-PD-1-antibody monotherapy has been reported as 3–5% [[11], [12], [13], [14]]. However, patients with ILD are typically excluded from clinical trials; thus, it remains unclear whether the presence of fibrosis and/or emphysema is associated with the development of anti-PD-1-related pneumonitis. The aim of this study was to explore the association between pulmonary fibrosis/emphysema on chest computed tomography (CT) and pneumonitis in patients with NSCLC treated with anti-PD-1 antibodies.
Section snippets
Patients
We reviewed consecutive data for all patients with histologically or cytologically confirmed NSCLC who received anti-PD-1-antibodies (nivolumab or pembrolizumab) as routine treatment at the Aichi Cancer Center Hospital between December 17, 2015, and November 30, 2017. Patients who underwent chest CT in the 6 months before anti-PD-1 therapy and who did not receive chemotherapy between the last chest CT and beginning of anti-PD-1 therapy were included in this analysis. Patients who received
Patient characteristics
Patient characteristics are listed in Table 1. The median age was 68 years (range, 37–87 years), 35 were female (28.5%), and 95 (77.2%) patients had smoking history. Eighty-one patients (65.9%) had adenocarcinoma, 27 patients (22.0%) had squamous cell carcinoma, and 15 (12.2%) were classed as “others.” The majority of patients had stage IV disease (73.2%, n = 90) and an Eastern Cooperative Oncology Group performance status of 0 (35.0%, n = 43) or 1 (52.8%, n = 65). Eighty-nine (72.4%) and 34
Discussion
Pre-existing ILD is considered a significant risk factor for developing drug-related pneumonitis. Previous studies indicated that patients who have lung cancer with pulmonary fibrosis or interstitial pneumonia are at high risk of developing pneumonitis or exacerbation after cytotoxic chemotherapy and molecular-targeted therapy [[4], [5], [6], [7]]. However, whether the risk of pneumonitis is associated with PD-1/PD-L1 blockade therapy for NSCLC patients with ILD is unclear. Patients with ILD
Conclusions
Our study showed that pulmonary fibrosis was a risk factor for anti-PD-1-related pneumonitis in patients with NSCLC and that even mild pulmonary fibrosis might increase the risk of anti-PD-1-related pneumonitis. Further studies are required, however, to explore the predictive factors of anti-PD-1-related pneumonitis in patients with both NSCLC and ILD.
Conflict of interest
Dr. Hida has obtained research grants from Ono Pharmaceutical, Novartis Pharma, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Pfizer, Bristol-Meyers Squibb, Clovis Oncology, Eisai, Takeda Bio, Sumitomo Dainippon Pharma, Abbvie, Merck Serono, MSD, Kyowa Hakko Kirin, Daiichi Sankyo, and Astellas, and has received personal fees from Ono Pharmaceutical, Novartis Pharma, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Nippon
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgment
We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
References (37)
- et al.
Combined analysis of V20, VS5, pulmonary fibrosis score on baseline computed tomography, and patient age improves prediction of severe radiation pneumonitis after concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer
J. Thorac. Oncol.
(2014) - et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Lancet
(2016) - et al.
CT assessment of subtypes of pulmonary emphysema in smokers
Chest
(2001) - et al.
Pulmonary resection for lung cancer in patients with idiopathic interstitial pneumonia
Ann. Thorac. Surg.
(2015) - et al.
A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia
Lung Cancer
(2017) - et al.
Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer
Lung Cancer
(2017) - et al.
Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab
Lung Cancer
(2018) - et al.
Clinical significance of PD-L1 protein expression in surgically resected primary lung adenocarcinoma
J. Thorac. Oncol.
(2016) - et al.
Genomic landscape of non-small cell lung cancer in smokers and never-smokers
Cell
(2012) - et al.
Atezolizumab in Japanese patients with previously treated advanced non-small-cell lung cancer: a subgroup analysis of the phase 3 OAK study
Clin. Lung Cancer
(2018)
Does interstitial lung disease predispose to lung cancer?
Curr. Opin. Pulm. Med.
The epidemiology of interstitial lung disease and its association with lung cancer
Br. J. Cancer
Prevalence of lung cancer in patients with interstitial lung disease is higher than in those with chronic obstructive pulmonary disease
Medicine (Baltim.)
Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study
Am. J. Respir. Crit. Care Med.
Interstitial shadow on chest CT is associated with the onset of interstitial lung disease caused by chemotherapeutic drugs
Jpn. J. Clin. Oncol.
Clinical characteristics of acute respiratory deterioration in pulmonary fibrosis associated with lung cancer following anti-cancer therapy
Respirology
Exacerbation of idiopathic interstitial pneumonias associated with lung cancer therapy
Intern. Med.
Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs
Int. Immunol.
Cited by (113)
Japanese guidelines for the treatment of idiopathic pulmonary fibrosis 2023:Revised edition
2024, Respiratory InvestigationCancers pulmonaires associés à une pathologie interstitielle pulmonaire fibrosante
2023, Revue des Maladies Respiratoires Actualites