Elsevier

Lung Cancer

Volume 125, November 2018, Pages 212-217
Lung Cancer

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

https://doi.org/10.1016/j.lungcan.2018.10.001Get rights and content

Highlights

  • Eighteen of 123 patients (14.6%) experienced anti-PD-1-related pneumonitis.

  • The median onset time of pneumonitis after starting anti-PD-1 was 60 days.

  • Pulmonary fibrosis was the only risk factor for anti-PD-1-related pneumonitis.

  • Other factors including emphysema did not increase the risk of pneumonitis.

Abstract

Objectives

Pneumonitis related to the use of anti-programmed death 1 (PD-1) antibodies is a common immune-related adverse event that can be life-threatening. However, the relationship between pulmonary fibrosis/emphysema and the incidence of anti-PD-1-related pneumonitis is unclear.

Materials and methods

We retrospectively reviewed data from 123 patients who were diagnosed with non-small-cell lung cancer and treated with anti-PD-1 antibodies (nivolumab or pembrolizumab) at the Aichi Cancer Center Hospital, Japan, between December 17, 2015, and November 30, 2017. Patients who previously received thoracic radiotherapy to the primary lesion, mediastinum, spinal, or rib metastases were excluded from the analysis. Fibrosis score (0–5) and emphysema score (0–4) on baseline chest computed tomography (CT) were determined by two diagnostic radiologists.

Results

Eighteen patients (14.6%) experienced anti-PD-1-related pneumonitis, of which four (3.3%) were grade ≥3. The median onset time of pneumonitis after starting anti-PD-1 therapy was 60 days (range, 6–634 days). According to the analysis of fibrosis score, pneumonitis occurred in 13 (35.1%) of the 37 patients with a fibrosis score ≥1 and in 5 (5.8%) of 86 patients with a fibrosis score of 0. Univariate and multivariate logistic regression analysis revealed that fibrosis score ≥1 was the only risk factor for anti-PD-1-related pneumonitis (p = 0.0008).

Conclusion

Our results indicate that pre-existing pulmonary fibrosis significantly increases the risk of anti-PD-1-related pneumonitis. Further studies are needed to identify predictive factors of anti-PD-1-related pneumonitis in patients with fibrotic changes on CT findings.

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.

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