Impact of the Treatment Line on the Risks and Benefits of Immune Checkpoint Inhibitors in Patients with Non-Small Cell Lung Cancer and Interstitial Lung Disease

We have read with great interest the systematic review and meta-analysis by Zhang et al1Zhang M Fan Y Nie L et al.Clinical outcomes of immune checkpoint inhibitor therapy in patients with advanced non-small cell lung cancer and preexisting interstitial lung diseases: a systematic review and meta-analysis.Chest. 2022; 161: 1675-1686Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar in CHEST (June 2022) that described the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD). The authors interpreted that ICIs have favorable efficacy in NSCLC with preexisting ILD and that checkpoint inhibitor pneumonitis (CIP) is often mild and manageable. Although we congratulate Zhang et al1Zhang M Fan Y Nie L et al.Clinical outcomes of immune checkpoint inhibitor therapy in patients with advanced non-small cell lung cancer and preexisting interstitial lung diseases: a systematic review and meta-analysis.Chest. 2022; 161: 1675-1686Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar for their work, some issues regarding the present study need to be addressed. First, the pooled objective response rate (ORR) was 34% (95% CI, 20%-47%), which may be a higher rate than in previously reported phase 3 trials with ICI monotherapy. However, we should focus mostly on the treatment line (first, ≥ second, and mixed); hence, we added a novel study that met the author’s inclusion criteria and performed a subgroup analysis (Fig 1).2Nishiyama N. Honda T. Sema M. et al.The utility of ground-glass attenuation score for anticancer treatment-related acute exacerbation of interstitial lung disease among lung cancer patients with interstitial lung disease.Int J Clin Oncol. 2020; 25: 282-291Crossref Scopus (8) Google Scholar As a result, the treatment line may explain the heterogeneity between the studies, because the subgroup interactions were statistically significant (P = .012). The pooled ORR was 25% (95% CI, 11%-39%) in the ≥ second-line treatment, which was equivalent to that of real-world data with the various ICIs in pretreated patients with NSCLC.3Pasello G. Pavan A. Attili I. et al.Real world data in the era of immune checkpoint inhibitors (ICIs): increasing evidence and future applications in lung cancer.Cancer Treat Rev. 2020; 87: 102031Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Second, the pooled grade 3 or higher CIP rate was 15% (95% CI, 9%-22%). We integrated and analyzed eight studies, including two novel studies,4Nakanishi Y. Masuda T. Yamaguchi K. et al.Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer.Respir Investig. 2019; 57: 451-459Crossref PubMed Scopus (41) Google Scholar that showed 14% (95% CI, 9%-19%) and reproduced the author’s results. A subgroup analysis was performed for the treatment line as with the ORR; however, the treatment line could not explain the heterogeneity between the studies (P = .44). In addition, we demonstrated that the pooled grade 3 or higher CIP rates were 15%, 21%, and 12% in the first, ≥ second, and mixed lines, respectively (Fig 1). The largest real-world data with ICI monotherapies revealed a grade 3 or higher CIP rate in the first and ≥ second lines, which were 4.7% and 4.3%, respectively.5Tamiya M. Tamiya A. Hosoya K. et al.Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).Invest New Drugs. 2019; 37: 1266-1273Crossref Scopus (23) Google Scholar In the ≥ second-line treatment, grade 3 or higher CIP may be approximately five times more likely to develop in patients with preexisting ILD than in those without. Therefore, CIP can no longer be described as often mild. We emphasize the importance of treatment lines when ICI monotherapy is used in patients with NSCLC with preexisting ILD. Considering the incidence of severe and fatal CIP, the risks of ICI monotherapy may outweigh its benefits, especially in second- or later-line treatment. Financial/nonfinancial disclosures: None declared. Clinical Outcomes of Immune Checkpoint Inhibitor Therapy in Patients With Advanced Non-small Cell Lung Cancer and Preexisting Interstitial Lung Diseases: A Systematic Review and Meta-analysisCHESTVol. 161Issue 6PreviewProgrammed cell death protein 1/programmed cell death ligand 1 inhibitors had favorable efficacy in NSCLC with preexisting ILD. CIP is frequent in patients with preexisting ILD who receive ICI therapy but is often mild and easily manageable. Clinicians should be cautious when using ICIs in patients with preexisting ILD. Full-Text PDF