Immune-Related Adverse Events (irAEs) Predict for Clinical Efficacy: Focusing on Organ-Specific irAEs and the Critical Role of Steroids
Authors: Xu Yang, Jianzhen Lin, Dongxu Wang, Li Zhang, Haitao Zhao
Journal: Journal of Thoracic Oncology (2019)

We were excited to read the commentary by Remon et al., which concerned the association between immune-related adverse events (irAEs) and outcome of taking immune checkpoint inhibitors (ICIs) in NSCLC.1Remon J. Reguart N. Auclin E. Besse B. Immune-related adverse events and outcomes in patients with advanced non-small cell lung cancer: a predictive marker of efficacy?.J Thorac Oncol. 2019; 14: 963-967Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar They gave us a comprehensive and timely review and addressed some important issues to allow us to better understand the relationship between irAEs and efficacy. We agree that irAEs may be predictors of the efficacy of ICIs, but we have two concerns about this commentary. As stated in by Remon et al.,1Remon J. Reguart N. Auclin E. Besse B. Immune-related adverse events and outcomes in patients with advanced non-small cell lung cancer: a predictive marker of efficacy?.J Thorac Oncol. 2019; 14: 963-967Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar not all irAEs are equal in terms of their ability to predict clinical benefit. Knowing which type of irAE contributes to clinical benefit is more important. In our opinion, organ-specific irAEs may be more meaningful, which is the first issue on which we want to focus. Skin irAEs (especially vitiligo) and endocrine irAEs (especially hypothyroidism) always indicate clinical benefit but do not always in hepatitis or gastrointestinal and lung irAEs.2Haratani K. Hayashi H. Chiba Y. et al.Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer.JAMA Oncol. 2018; 4: 374-378Crossref PubMed Scopus (584) Google Scholar, 3Berner F. Bomze D. Diem S. et al.Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2019.0402Google Scholar However, cardiac irAEs and neurologic irAEs also are high-grade and severe when they occur and always lead to worse outcomes. So we think that identifying organ-specific irAEs is very important to knowing the association between irAEs and efficacy of ICIs. The second issue on which we want to focus is the use of steroids to manage irAEs and the influence of clinical benefit. Remon et al.1Remon J. Reguart N. Auclin E. Besse B. Immune-related adverse events and outcomes in patients with advanced non-small cell lung cancer: a predictive marker of efficacy?.J Thorac Oncol. 2019; 14: 963-967Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar stated that steroids are not hampered by the positive association of irAEs and outcome of taking ICIs. Most irAEs are treated with steroids when necessary. It is true that we use steroids appropriately to reduce autoimmune inflammatory reactions and to prevent development of higher-grade irAEs. Reducing the dose of steroids and stopping steroids appropriately could avoid the negative impact of steroids. As we all know, however, corticosteroids may suppress the immune system and increase the chance of infections and other adverse effects, especially with their long-term use. Moreover, corticosteroids may also increase the progression and spread of cancer. What is more, recent studies have emphasized that early use of steroids can damage their clinical benefit. Studies found that when corticosteroids were used at baseline (≥10 mg of prednisone equivalent) or in the early period of treatment (during the first 30 days), patients with NSCLC had significantly poorer overall survival.4Arbour K.C. Mezquita L. Long N. et al.Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer.J Clin Oncol. 2018; 36: 2872-2878Crossref PubMed Scopus (549) Google Scholar, 5Scott S.C. Pennell N.A. Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab.J Thorac Oncol. 2018; 13: 1771-1775Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Using alternatives to steroids (such as antihistamines) may also be an effective treatment in for low-grade skin irAEs. Using steroids appropriately according to the guideline for irAEs in a multidisciplinary approach is recommended. With regard to organ-specific irAEs, especially skin and endocrine system irAEs, better management of irAEs could maximize therapeutic efficacy. On the other hand, in cases involving patients who obtain a greater benefit from use of ICIs, irAEs also need to be monitored closely. Caution is required when using steroids in the early period of treatment. In the future, a better understanding of the pathophysiologic mechanism of irAEs and investigation of who will experience development of irAEs will help to prevent irAEs in the early stage of treatment and sustain the immunotherapy to maximize therapeutic efficacy. In Response to the Letter by Dr. Yang et al, Immune-Related Adverse Events (irAEs) Predict for Clinical Efficacy: Forcing on Organ-Specific irAEs and the Critical Role of SteroidsJournal of Thoracic OncologyVol. 14Issue 11PreviewWe thank Yang et al.1 for reporting their concerns about the potential correlation between immune-related adverse events (ir-AEs) and outcome in patients with NSCLC. We would like to take this opportunity to clarify the following points. Full-Text PDF Open Archive