Skip to main content

Association of immune-related pneumonitis with the presence of preexisting interstitial lung disease in patients with non-small lung cancer receiving anti-programmed cell death 1 antibody

Cancer Immunology, Immunotherapy volume 69, pages 15–22 (2020)Cite this article

Abstract

The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3–2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2–14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

CI:

Confidence interval

CT:

Computed tomography

CTCAE:

Common Terminology Criteria for Adverse Events

DAD:

Diffuse alveolar damage

HP:

Hypersensitivity pneumonitis

HR:

Hazard ratio

ICIs:

Immune checkpoint inhibitors

ILD:

Interstitial lung disease

irAEs:

Immune-related adverse events

NSCLC:

Non-small cell lung cancer

OP:

Organizing pneumonia-like

PD-1:

Programmed cell death 1

PD-L1:

Programmed death ligand 1

References

  1. King TE Jr (2005) Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med 172:268–279. https://doi.org/10.1164/rccm.200503-483OE

    Article  PubMed  Google Scholar 

  2. Le Jeune I, Gribbin J, West J, Smith C, Cullinan P, Hubbard R (2007) The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med 101:2534–2540. https://doi.org/10.1016/j.rmed.2007.07.012

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hubbard R, Venn A, Lewis S, Britton J (2000) Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med 161:5–8. https://doi.org/10.1164/ajrccm.161.1.9906062

    CAS  Article  PubMed  Google Scholar 

  4. Omori T, Tajiri M, Baba T et al (2015) Pulmonary resection for lung cancer in patients with idiopathic interstitial pneumonia. Ann Thorac Surg 100:954–960. https://doi.org/10.1016/j.athoracsur.2015.03.094

    Article  PubMed  Google Scholar 

  5. Fujimoto D, Kato R, Morimoto T et al (2016) Characteristics and prognostic impact of pneumonitis during systemic anti-cancer therapy in patients with advanced non-small-cell lung cancer. PLoS ONE 11:e0168465. https://doi.org/10.1371/journal.pone.0168465

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Kenmotsu H, Naito T, Kimura M et al (2011) The risk of cytotoxic chemotherapy-related exacerbation of interstitial lung disease with lung cancer. J Thorac Oncol 6:1242–1246. https://doi.org/10.1097/JTO.0b013e318216ee6b

    Article  PubMed  Google Scholar 

  7. Enomoto Y, Inui N, Kato T, Baba T, Karayama M, Nakamura Y, Ogura T, Suda T (2016) Low forced vital capacity predicts cytotoxic chemotherapy-associated acute exacerbation of interstitial lung disease in patients with lung cancer. Lung Cancer 96:63–67. https://doi.org/10.1016/j.lungcan.2016.03.017

    Article  PubMed  Google Scholar 

  8. Inoue A, Saijo Y, Maemondo M et al (2003) Severe acute interstitial pneumonia and gefitinib. Lancet 361:137–139. https://doi.org/10.1016/s0140-6736(03)12190-3

    Article  PubMed  Google Scholar 

  9. Sakai F, Noma S, Kurihara Y, Yamada H, Azuma A, Kudoh S, Ichikawa Y (2005) Leflunomide-related lung injury in patients with rheumatoid arthritis: imaging features. Mod Rheumatol 15:173–179. https://doi.org/10.1007/s10165-005-0387-9

    Article  PubMed  Google Scholar 

  10. Fujimoto D, Morimoto T, Ito J et al (2017) A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia. Lung Cancer 111:1–5. https://doi.org/10.1016/j.lungcan.2017.06.008

    Article  PubMed  Google Scholar 

  11. Michot JM, Bigenwald C, Champiat S et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148. https://doi.org/10.1016/j.ejca.2015.11.016

    CAS  Article  Google Scholar 

  12. Weber JS, Hodi FS, Wolchok JD et al (2017) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785–792. https://doi.org/10.1200/JCO.2015.66.1389

    CAS  Article  Google Scholar 

  13. Nishino M, Ramaiya NH, Awad MM et al (2016) PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 22:6051–6060. https://doi.org/10.1158/1078-0432.CCR-16-1320

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Naidoo J, Wang X, Woo KM et al (2016) Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. https://doi.org/10.1200/JCO.2016.68.2005

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gettinger SN, Horn L, Gandhi L et al (2015) Overall Survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 33:2004–2012. https://doi.org/10.1200/JCO.2014.58.3708

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028. https://doi.org/10.1056/NEJMoa1501824

    Article  PubMed  PubMed Central  Google Scholar 

  17. Leffler DA, Lamont JT (2015) Clostridium difficile infection. N Engl J Med 373:287–288. https://doi.org/10.1056/NEJMc1506004

    Article  PubMed  Google Scholar 

  18. Nishino M, Chambers ES, Chong CR et al (2016) Anti-PD-1 inhibitor-related pneumonitis in non-small cell lung cancer. Cancer Immunol Res 4:289–293. https://doi.org/10.1158/2326-6066.CIR-15-0267

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Shibaki R, Murakami S, Matsumoto Y et al (2019) Tumor expression and usefulness as a biomarker of programmed death ligand 1 in advanced non-small cell lung cancer patients with preexisting interstitial lung disease. Med Oncol 36:49. https://doi.org/10.1007/s12032-019-1274-0

    Article  PubMed  Google Scholar 

  20. Raghu G, Remy-Jardin M, Myers JL et al (2018) Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 198:e44–e68. https://doi.org/10.1164/rccm.201807-1255ST

    Article  PubMed  Google Scholar 

  21. Kubo K, Azuma A, Kanazawa M et al (2013) Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig 51:260–277. https://doi.org/10.1016/j.resinv.2013.09.001

    Article  PubMed  Google Scholar 

  22. Ando M, Okamoto I, Yamamoto N, Takeda K, Tamura K, Seto T, Ariyoshi Y, Fukuoka M (2006) Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 24:2549–2556. https://doi.org/10.1200/JCO.2005.04.9866

    CAS  Article  PubMed  Google Scholar 

  23. Mizushima Y, Kobayashi M (1995) Clinical characteristics of synchronous multiple lung cancer associated with idiopathic pulmonary fibrosis. A review of Japanese cases. Chest 108:1272–1277

    CAS  Article  Google Scholar 

  24. Suresh K, Voong KR, Shankar B et al (2018) Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol 13:1930–1939. https://doi.org/10.1016/j.jtho.2018.08.2035

    Article  PubMed  Google Scholar 

  25. Kudoh S, Kato H, Nishiwaki Y et al (2008) Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 177:1348–1357. https://doi.org/10.1164/rccm.200710-1501OC

    Article  Google Scholar 

  26. Kenmotsu H, Sakai F, Kato T et al (2017) Nivolumab-induced interstitial lung disease (ILD) in Japanese patients with non-small cell lung cancer: a study on risk factors using interim results of post-marketing all-case surveillance. J Clin Oncol 35:9078. https://doi.org/10.1200/JCO.2017.35.15_suppl.9078

    Article  Google Scholar 

  27. Kanai O, Kim YH, Demura Y et al (2018) Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting interstitial lung disease. Thorac Cancer 9:847–855. https://doi.org/10.1111/1759-7714.12759

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135. https://doi.org/10.1056/NEJMoa1504627

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Cho JY, Kim J, Lee JS et al (2018) Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer 125:150–156. https://doi.org/10.1016/j.lungcan.2018.09.015

    Article  PubMed  Google Scholar 

  31. Cooper JA Jr, White DA, Matthay RA (1986) Drug-induced pulmonary disease. Part 1: cytotoxic drugs. Am Rev Respir Dis 133:321–340. https://doi.org/10.1164/arrd.1986.133.2.321

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Mr. Takeharu Yamanaka for statistical support.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Ryota Shibaki, Shuji Murakami, Yuji Matsumoto, Tatsuya Yoshida, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Yutaka Fujiwara, Noboru Yamamoto & Yuichiro Ohe

  2. Department of Pulmonary Medicine and Oncology, Wakayama Medical University, Wakayama, Japan

    Ryota Shibaki & Nobuyuki Yamamoto

  3. Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan

    Masahiko Kusumoto

Authors
  1. Ryota Shibaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuji Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuji Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatsuya Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasushi Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shintaro Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hidehito Horinouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yutaka Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nobuyuki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masahiko Kusumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Noboru Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yuichiro Ohe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RS: collection of clinical data, data quality control, statistical data analysis, interpretation of results, and writing of the manuscript; SM: interpretation of results, and participating in writing the manuscript; YM, TY, YG, SK, HH, YF, Nobuyuki Y, Noboru Y, and YO: manuscript writing and editing; MK: collection of clinical data, and interpretation of results. All authors have approved the manuscript’s final version.

Corresponding author

Correspondence to Shuji Murakami.

Ethics declarations

Conflict of interest

Shuji Murakami has served on speakers’ bureaus for Taiho Pharmaceutical, Ono Pharmaceutical. Yasushi Goto has had consulting/advisory roles for Taiho Pharmaceutical; served on speakers’ bureaus for Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Merck Sharp and Dohme (MSD); and received research funding from Taiho Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. Shintaro Kanda has received research funding from Ono Pharmaceutical; and received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb. Hidehito Horinouchi has received research funding from MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical. Yutaka Fujiwara has received research funding from MSD; and served on speakers’ bureaus for MSD, Taiho Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. Nobuyuki Yamamoto has had consulting/advisory roles for Taiho Pharmaceutical; served on speakers’ bureaus for Ono Pharmaceutical, Bristol-Myers Squibb, MSD; and received honoraria from Ono Pharmaceutical, and MSD. Noboru Yamamoto has received research funding from Taiho Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical; and served on speakers’ bureaus for Bristol-Myers Squibb, Ono Pharmaceutical. Yuichiro Ohe has received research funding from Taiho Pharmaceutical, MSD; and received honoraria from Taiho Pharmaceutical, MSD. All remaining authors have declared no conflicts of interest.

Ethical approval

This study was approved by the Institutional Review Board of the National Cancer Center Hospital, Tokyo, Japan (study approval no. 2015-355) and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was not obtained from each patient, because this retrospective analysis of existing data did not require any interaction with patients and did not intervene in their treatment.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 168 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shibaki, R., Murakami, S., Matsumoto, Y. et al. Association of immune-related pneumonitis with the presence of preexisting interstitial lung disease in patients with non-small lung cancer receiving anti-programmed cell death 1 antibody. Cancer Immunol Immunother 69, 15–22 (2020). https://doi.org/10.1007/s00262-019-02431-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-019-02431-8

Keywords

  • Non-small cell lung cancer
  • Immune checkpoint inhibitor
  • Pneumonitis
  • Interstitial lung disease
  • Anti-PD-1 antibody
  • Immune-related adverse event