Association Between Pretreatment Chest Imaging and Immune Checkpoint Inhibitor Pneumonitis Among Patients With Lung Cancer

Authors:
Alexander Wong Department of Internal Medicine, The Ohio State Wexner Medical Center, Columbus, Ohio

Search for other papers by Alexander Wong in
Current site
Google Scholar
PubMed Close
 MD
,
Maria Riley Department of Internal Medicine, The Ohio State Wexner Medical Center, Columbus, Ohio

Search for other papers by Maria Riley in
Current site
Google Scholar
PubMed Close
 BA
,
Songzhu Zhao Center for Biostatistics, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Songzhu Zhao in
Current site
Google Scholar
PubMed Close
 MS
,
Jessica Zimmer Department of Internal Medicine, The Ohio State Wexner Medical Center, Columbus, Ohio

Search for other papers by Jessica Zimmer in
Current site
Google Scholar
PubMed Close
 BS, BA
,
Matthew Viveiros Department of Internal Medicine, The Ohio State Wexner Medical Center, Columbus, Ohio

Search for other papers by Matthew Viveiros in
Current site
Google Scholar
PubMed Close
 BA
,
Jing Gennie Wang Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio

Search for other papers by Jing Gennie Wang in
Current site
Google Scholar
PubMed Close
 MD
,
Vincent Esguerra Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio

Search for other papers by Vincent Esguerra in
Current site
Google Scholar
PubMed Close
 MD
,
Mingjia Li Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Mingjia Li in
Current site
Google Scholar
PubMed Close
 MD
,
Gabrielle Lopez Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Gabrielle Lopez in
Current site
Google Scholar
PubMed Close
 BSc
,
Kari Kendra Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Kari Kendra in
Current site
Google Scholar
PubMed Close
 MD, PhD
,
David P. Carbone Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by David P. Carbone in
Current site
Google Scholar
PubMed Close
 MD, PhD
,
Kai He Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Kai He in
Current site
Google Scholar
PubMed Close
 MD, PhD
,
Asrar Alahmadi Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Asrar Alahmadi in
Current site
Google Scholar
PubMed Close
 MD
,
Jacob Kaufman Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Jacob Kaufman in
Current site
Google Scholar
PubMed Close
 MD, PhD
,
Regan M. Memmott Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Regan M. Memmott in
Current site
Google Scholar
PubMed Close
 MD, PhD
,
Peter G. Shields Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Peter G. Shields in
Current site
Google Scholar
PubMed Close
 MD
,
Jeremy Brownstein Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Jeremy Brownstein in
Current site
Google Scholar
PubMed Close
 MD
,
Karl Haglund Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Karl Haglund in
Current site
Google Scholar
PubMed Close
 MD, PhD
,
Meng Welliver Division of Medical Oncology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota

Search for other papers by Meng Welliver in
Current site
Google Scholar
PubMed Close
 MD, PhD
,
Gregory A. Otterson Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Gregory A. Otterson in
Current site
Google Scholar
PubMed Close
 MD
,
Carolyn J. Presley Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Carolyn J. Presley in
Current site
Google Scholar
PubMed Close
 MD, MHS
,
Lai Wei Center for Biostatistics, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Lai Wei in
Current site
Google Scholar
PubMed Close
 PhD
,
Dwight H. Owen Division of Medical Oncology, Department of Internal Medicine, The Ohio State University – James Comprehensive Cancer Center, Columbus, Ohio

Search for other papers by Dwight H. Owen in
Current site
Google Scholar
PubMed Close
 MD
, and
Kevin Ho Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio

Search for other papers by Kevin Ho in
Current site
Google Scholar
PubMed Close
 MD
Volume/Issue:
Volume 21: Issue 11
Online Publication Date:
Nov 2023
DOI:
https://doi.org/10.6004/jnccn.2023.7059
Restricted access

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Submitted May 21, 2023; final revision received July 17, 2023; accepted for publication July 18, 2023.

Author contributions: Study design: Wong, Owen, Ho. Data acquisition: Wong, Riley, Zimmer, Viveiros, Li, Lopez, Kendra, Carbone, He, Alahmadi, Kaufman, Memmott, Shields, Brownstein, Haglund, Welliver, Otterson, Presley, Owen, Ho. Database management: Kendra, Carbone, He, Alahmadi, Kaufman, Memmott, Shields, Brownstein, Haglund, Welliver, Otterson, Presley, Owen. Statistical analysis: Zhao, Wei. Imaging review: Wang, Esguerra, Ho. Manuscript preparation: Wong, Riley, Zhao, Wei, Owen, Ho.

Disclosures: Dr. Kendra has disclosed receiving grant/research support from Bristol Myers Squibb, Checkmate Pharmaceuticals, GSK, Immunocore, Medpace, Merck, Novartis, and Varian Medical Systems. Dr. Brownstein has disclosed receiving honoraria from AstraZeneca and DAVA Oncology; and receiving grant/research support from Varian Medical Systems. Dr. Otterson has disclosed serving as a data safety monitoring board for BeiGene and Novocure; and receiving grant/research support from Bristol Meyers Squibb, Genentech, Merck, Dizal, AbbVie, Apollomics, and Nuvalent. Dr. Presley has disclosed receiving grant/research support from Jazz Pharmaceuticals. Dr. Owen has disclosed receiving grant/research from Bristol Myers Squibb, Genentech, Pfizer, Palobiofarma, AbbVie, Merck, Elevation Oncology, and Onc.AI; and serving as a principal investigator for Genentech, Palobiofarma, Bristol Myers Squibb, Merck, Pfizer, and Onc.AI. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Kevin Ho, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, 241 West 11th Avenue, Suite 5000, Columbus, OH 43201. Email: kevin.ho@osumc.edu

Supplementary Materials

    • Supplemental Materials (PDF 456 KB)
  • Collapse
  • Expand
Print ISSN:
1540-1405
Online ISSN:
1540-1413
Publisher:
National Comprehensive Cancer Network
Cover Journal of the National Comprehensive Cancer Network
  • 1.

    Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun 2020;11:3801.

  • 2.

    Onoi K, Chihara Y, Uchino J, et al. Immune checkpoint inhibitors for lung cancer treatment: a review. J Clin Med 2020;9:1362.

  • 3.

    Yang S, Yu KH, Palmer N, et al. Autoimmune effects of lung cancer immunotherapy revealed by data-driven analysis on a nationwide cohort. Clin Pharmacol Ther 2020;107:388–396.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Boland P, Pavlick AC, Weber J, et al. Immunotherapy to treat malignancy in patients with pre-existing autoimmunity. J Immunother Cancer 2020;8:e000356.

  • 5.

    Marrone KA, Naidoo J, Brahmer JR. Immunotherapy for lung cancer: no longer an abstract concept. Semin Respir Crit Care Med 2016;37:771–782.

  • 6.

    Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor–related pneumonitis in patients with advanced cancer. JAMA Oncol 2016;2:1607–1616.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Wu J, Hong D, Zhang X, et al. PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis. Sci Rep 2017;7:44173.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Yamaguchi T, Shimizu J, Hasegawa T, et al. 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. Lung Cancer 2018;125:212–217.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol 2018;13:1930–1939.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Zhai X, Zhang J, Tian Y, et al. The mechanism and risk factors for immune checkpoint inhibitor pneumonitis in non-small cell lung cancer patients. Cancer Biol Med 2020;17:599–611.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Tiu BC, Zubiri L, Iheke J, et al. Real-world incidence and impact of pneumonitis in patients with lung cancer treated with immune checkpoint inhibitors: a multi-institutional cohort study. J Immunother Cancer 2022;10:e004670.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Khunger M, Rakshit S, Pasupuleti V, et al. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials. Chest 2017;152:271–281.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:1919–1929.

  • 14.

    Shimoji K, Masuda T, Yamaguchi K, et al. Association of preexisting interstitial lung abnormalities with immune checkpoint inhibitor-induced interstitial lung disease among patients with nonlung cancers. JAMA Netw Open 2020;3:e2022906.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Kanai O, Kim YH, Demura Y, et al. Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting interstitial lung disease. Thorac Cancer 2018;9:847–855.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Suzuki Y, Karayama M, Uto T, et al. Assessment of immune-related interstitial lung disease in patients with NSCLC treated with immune checkpoint inhibitors: a multicenter prospective study. J Thorac Oncol 2020;15:1317–1327.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Li F, Zhou Z, Wu A, et al. Preexisting radiological interstitial lung abnormalities are a risk factor for severe radiation pneumonitis in patients with small-cell lung cancer after thoracic radiation therapy. Radiat Oncol 2018;13:82.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Ozawa Y, Abe T, Omae M, et al. Impact of preexisting interstitial lung disease on acute, extensive radiation pneumonitis: retrospective analysis of patients with lung cancer. PLoS One 2015;10:e0140437.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Wong A, Riley M, Zhao S, et al. Association between pre-treatment chest imaging and pulmonary function abnormalities and immune checkpoint inhibitor pneumonitis. Cancer Immunol Immunother 2023;72:1727–1735.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–381.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform 2019;95:103208.

  • 22.

    Li M, Spakowicz D, Zhao S, et al. Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer. Cancer Immunol Immunother 2020;69:2403–2408.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Shankar B, Zhang J, Naqash AR, et al. Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol 2020;6:1952–1956.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Nishino M, Brais LK, Brooks NV, et al. Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach. Eur J Cancer 2016;53:163–170.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Graham BL, Steenbruggen I, Miller MR, et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med 2019;200:e70–88.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Sterk PJ. Let’s not forget: the GOLD criteria for COPD are based on post-bronchodilator FEV1. Eur Respir J 2004;23:497–498.

  • 27.

    Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 2008;177:1348–1357.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Adegunsoye A, Vij R, Noth I. Integrating genomics into management of fibrotic interstitial lung disease. Chest 2019;155:1026–1040.

  • 29.

    Owen DH, Wei L, Bertino EM, et al. Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer. Clin Lung Cancer 2018;19:e893–900.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    von Reibnitz D, Chaft JE, Wu AJ, et al. Safety of combining thoracic radiation therapy with concurrent versus sequential immune checkpoint inhibition. Adv Radiat Oncol 2018;3:391–398.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Barrón F, Sánchez R, Arroyo-Hernández M, et al. Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non-small cell lung cancer patients previously treated with radiotherapy. Front Oncol 2020;10:570233.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Cui P, Liu Z, Wang G, et al. Risk factors for pneumonitis in patients treated with anti-programmed death-1 therapy: a case-control study. Cancer Med 2018;7:4115–4120.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Desai O, Winkler J, Minasyan M, et al. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis. Front Med (Lausanne) 2018;5:43.

  • 34.

    Heukels P, Moor CC, von der Thüsen JH, et al. Inflammation and immunity in IPF pathogenesis and treatment. Respir Med 2019;147:79–91.

  • 35.

    Suresh K, Naidoo J, Zhong Q, et al. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J Clin Invest 2019;129:4305–4315.

  • 36.

    Krombach J, Hennel R, Brix N, et al. Priming anti-tumor immunity by radiotherapy: dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells. OncoImmunology 2018;8:e1523097.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Hsiehchen D, Naqash AR, Espinoza M, et al. Association between immune-related adverse event timing and treatment outcomes. Oncoimmunology 2022;11:2017162.

  • 38.

    Sears CR, Peikert T, Possick JD, et al. Knowledge gaps and research priorities in immune checkpoint inhibitor-related pneumonitis. An official American Thoracic Society research statement. Am J Respir Crit Care Med 2019;200:e31–43.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Atchley WT, Alvarez C, Saxena-Beem S, et al. Immune checkpoint inhibitor-related pneumonitis in lung cancer: real-world incidence, risk factors, and management practices across six health care centers in North Carolina. Chest 2021;160:731–742.

    • PubMed
    • Search Google Scholar
    • Export Citation
Copyright:
Copyright © 2023 by the National Comprehensive Cancer Network 2023
Article Category:
Research Article
Received:
21 May 2023
Accepted:
18 Jul 2023
Print Publication Date:
01 Nov 2023
Online Publication Date:
Nov 2023
Keywords:
Immune Checkpoint Inhibitor Pneumonitis; Lung cancer; Imaging Abnormalities; Chest Radiation; Pulmonary Function Tests

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 5540 5540 106
PDF Downloads 2083 2083 58
EPUB Downloads 0 0 0