Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Abstract

Immune checkpoint inhibitors (ICIs) have been a major breakthrough for the treatment landscape and prognosis of patients with NSCLC. Treatment of patients with advanced NSCLC with ICIs has reached landmark 3-year overall survival (OS) rates of 26.4% and 19.0% among treatment-naive and previously treated patients, respectively,1Leighl N.B. Hellmann M.D. Hu R. Carcereny E. Ahn M.J. et al.Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study.Lancet Respir Med. 2019; 7: 347-357Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and approximately 8% of these patients are going to be long-term survivors with progression-free survival (PFS) lasting more than 18 months.2Rizvi H. Plodkowski A. Tenet M. HalpennyD Long N. et al.Clinical and molecular features predicting long-term response to anti-PD(L)1 based therapy in patients with NSCLC [abstract].J Clin Oncol. 2018; 36: 9022Crossref Google Scholar Programmed death ligand-1 (PD-L1) expression is currently accepted as a key indicator to identify which patients are likely to respond to ICIs,3Khunger M. Hernandez A.V. Pasupuleti V. et al.Programmed cell death 1 (PD-1) ligand (PD-L1) expression in solid tumors as a predictive biomarker of benefit from PD-1/PD-L1 axis inhibitors: a systematic review and meta-analysis.JCO Precis Oncol. 2017; 1: 1-15PubMed Google Scholar and several other biomarkers such as tumor mutation burden (TMB) are also beginning to emerge as potentially helpful surrogates for patient selection.4Rizvi H. Sanchez-Vega F. La K. et al.Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.J Clin Oncol. 2018; 36: 633-641Crossref PubMed Scopus (830) Google Scholar ICIs came with the emergence of a unique set of adverse events, the so-called immune-related adverse events (irAEs).5Judd J. Zibelman M. Handorf E. et al.Immune-related adverse events as a biomarker in non-melanoma patients treated with programmed cell death 1 inhibitors.Oncologist. 2017; 22: 1232-1237Crossref PubMed Scopus (95) Google Scholar A recent systematic review including more than 5000 patients with advanced NSCLC treated with ICIs has reported a global incidence of irAEs of 16% (3% grade ≥3) and 11% (5% grade ≥3) for anti–programmed cell death 1 (PD-1) and anti–PD-L1 agents, respectively,6Pillai R.N. Behera M. Owonikoko T.K. et al.Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: a systematic analysis of the literature.Cancer. 2018; 124: 271-277Crossref PubMed Scopus (209) Google Scholar an incidence that is remarkably increased to as high as 23% to 28% (9%–11% grade ≥3) when ICIs are combined with chemotherapy.7Gandhi L. Rodríguez-Abreu D. Gadgeel S. et al.Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.N Engl J Med. 2018; 378: 2078-2092Crossref PubMed Scopus (3588) Google Scholar, 8Paz-Ares L. Luft A. Tafreshi A. et al.Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab for patients with metastatic squamous non-small cell lung cancer (NSCLC) [abstract].J Clin Oncol. 2018; 36: 105Crossref Google Scholar On the plus side though, there are mounting data suggesting that irAEs might also serve as surrogate indicators of a better ICI efficacy in patients with advanced solid tumors treated with ICIs. This is the case with melanoma, in which better outcome has been significantly correlated with the incidence of irAEs,9Freeman-Keller M. Kim Y. Cronin H. Richards A. Gibney G. Weber J.S. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes.Clin Cancer Res. 2016; 22: 886-894Crossref PubMed Scopus (564) Google Scholar mainly among those patients who experience development of vitiligo and rash,9Freeman-Keller M. Kim Y. Cronin H. Richards A. Gibney G. Weber J.S. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes.Clin Cancer Res. 2016; 22: 886-894Crossref PubMed Scopus (564) Google Scholar, 10Teulings H.-E. Limpens J. Jansen S.N. et al.Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.J Clin Oncol. 2015; 33: 773-781Crossref PubMed Scopus (406) Google Scholar, 11Hua C. Boussemart L. Mateus C. et al.Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab.JAMA Dermatol. 2016; 152: 45-51Crossref PubMed Scopus (457) Google Scholar although this survival advantage eventually disappeared when patients experienced development of other irAEs such as colitis, endocrinopathies, or pneumonitis. Likewise, recent evidence also points to the potential association of irAEs and efficacy in advanced NSCLC treated with ICIs in second-line therapy or beyond (Table 1 and Fig. 1).12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google Scholar, 13Moor R. Roberts K.E. Mason R. et al.Immune-related adverse events and nivolumab outcome in non-small cell lung cancer patients: a multi-institutional, retrospective cohort study [abstract].J Clin Oncol. 2018; 36: 9067Google Scholar, 14Toi Y. Sugawara S. Kawashima Y. et al.Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab.Oncologist. 2018; 23: 1358-1365https://doi.org/10.1634/theoncologist.2017-0384Crossref PubMed Scopus (153) Google Scholar, 15Haratani 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 (595) Google Scholar, 16Teraoka S. Fujimoto D. Morimoto T. et al.Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017; 12: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 17Sato K. Akamatsu H. Murakami E. et al.Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.Lung Cancer. 2018; 115: 71-74Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar, 19von Pawel J. Syrigos K. Mazieres J. et al.Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK.Ann Oncol. 2017; 28 (mdx380.017–mdx380.017)Google Scholar, 20Kfoury M. Voisin A.L. Nejean M. et al.Association between immune related adverse events and efficacy in patients treated with anti-PD(L)1.Ann Oncol. 2018; 29: viii400-viii441Google Scholar, 21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google Scholar, 22Shafqat H. Gourdin T. Sion A. Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy.Semin Oncol. 2018; 45: 156-163Crossref PubMed Scopus (45) Google Scholar A high number of irAEs, specifically, having two or more irAEs,12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google Scholar, 18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar and having certain specific types of immune-related toxicities such as skin irAEs (scaly plaques and pruritus)23Hasan Ali O. Diem S. Markert E. et al.Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.Oncoimmunology. 2016; 5e1231292Crossref PubMed Scopus (92) Google Scholar or immune-related thyroiditis (especially in patients with antithyroid antibodies)18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar, 24Osorio J.C. Ni A. Chaft J.E. et al.Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.Ann Oncol. 2017; 28: 583-589Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar have also been proposed as potential predictive indicators of better outcomes in NSCLC. In contrast, development of pneumonitis worsens survival in patients with NSCLC who are receiving an ICI,25Suresh K. Psoter K.J. Voong K.R. et al.Impact of checkpoint inhibitor pneumonitis on survival in NSCLC patients receiving immune checkpoint immunotherapy.J Thorac Oncol. 2019; 14: 494-502Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar whereas the onset of diarrhea and increased liver enzyme levels does not seem to be correlated with the efficacy,16Teraoka S. Fujimoto D. Morimoto T. et al.Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017; 12: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar suggesting that not all irAEs are equal in terms of improving cancer outcomes with ICIs. Neither the mechanisms underlying the association of irAEs with outcome nor which patients are at risk for autoimmune toxicities completely understood as yet.26Khan S. Khan S.A. Luo X. et al.Immune dysregulation in cancer patients developing immune-related adverse events.Br J Cancer. 2019; 120: 63-68Crossref PubMed Scopus (84) Google Scholar Recently, it has been postulated that detection of preexisting autoimmune markers (such as rheumatoid factor, antinuclear antibodies, or antthyroid antibodies) in patients with NSCLC treated with ICIs (58% of whole population) correlated with increased risk of onset of irAEs (60% vs. 32%, p=0.002 compared with those patients without preexisting antibodies) and might be a surrogate for improved response rate and PFS, as well as for the development of some irAEs such as skin reactions and thyroid dysfunction (baseline rheumatoid factor and antithyroid antibodies, respectively).21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google Scholar This is also the case in SCLC, in which the association of baseline autoimmunity with outcome and toxicity has already been reported.27Hardy-Werbin M. Arpí O. Taus A. et al.Assessment of neuronal autoantibodies in patients with small cell lung cancer treated with chemotherapy with or without ipilimumab.Oncoimmunology. 2018; 7e1395125Google Scholar The potential association of irAEs and outcome in patients with NSCLC and identification of patients with the greatest likelihood of development of irAEs are of transcendental importance and deserve closer consideration.Table 1Outcome of Patients with Advanced NSCLC Treated with Immune Checkpoint Inhibitors as Second-Line Treatment or Beyond according to Onset or No Onset of irAEs of Any GradeStudyICInGrade ≥ 3 irAEs, %RR, %PFS, moOS, moCycles, nirAEsNo irAEsirAE’sNo irAEsirAEsNo irAEsirAEsNo irAEsRicciuti et al.12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google ScholarNivolumab1957.643.510.05.72.017.84.0132.5Moor et al.13Moor R. Roberts K.E. Mason R. et al.Immune-related adverse events and nivolumab outcome in non-small cell lung cancer patients: a multi-institutional, retrospective cohort study [abstract].J Clin Oncol. 2018; 36: 9067Google ScholarNivolumab19613.2NRNR5.92.523.86.4NRNRToi et al.14Toi Y. Sugawara S. Kawashima Y. et al.Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab.Oncologist. 2018; 23: 1358-1365https://doi.org/10.1634/theoncologist.2017-0384Crossref PubMed Scopus (153) Google ScholarNivolumab70NR5712123.6NRNR127ap = 0.001.Haratani et al.15Haratani 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 (595) Google ScholarNivolumab134952289.24.8Not R11.1NRNRTeraoka et al.16Teraoka S. Fujimoto D. Morimoto T. et al.Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017; 12: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar,bProspective.Nivolumab43037176.41.5NRNRNRNRSato et al.17Sato K. Akamatsu H. Murakami E. et al.Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.Lung Cancer. 2018; 115: 71-74Abstract Full Text Full Text PDF PubMed Scopus (259) Google ScholarNivolumab38NR647.4Not R1.6NRNRNRNRLisberg et al.cPatients enrolled on the KEYNOTE001 trial at a single center.Pembrolizumab973.139.58.98.2216.44.8NRdIn the KEYNOTE-001 trial, 71% of patients experienced a treatment-related AE compared with 40% in this cohort; this could be related to longer time on trial (median PFS in the overall trial versus in the University of California Los Angeles cohort [111 versus 64 days, respectively]).NRVon Pawel et al.19von Pawel J. Syrigos K. Mazieres J. et al.Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK.Ann Oncol. 2017; 28 (mdx380.017–mdx380.017)Google Scholar,bProspective.Atezolizumab8236.022.39.95.42.320.710.6NRNRKfoury et al.20Kfoury M. Voisin A.L. Nejean M. et al.Association between immune related adverse events and efficacy in patients treated with anti-PD(L)1.Ann Oncol. 2018; 29: viii400-viii441Google ScholarAnti–PD-1/PD-L1618eA total of 618 patients with different solid tumors. This cohort included 229 patients with NSCLC (37.5%). Grade 2 or higher irAEs developed in 41 of the patients with NSCLC (21.3%). Outcome results are reported for the whole population, not according to tumor subtype. In the 12-week landmark analysis, PFS (log-rank test p = 0.58) and OS (log-rank test p = 0.21). Sensitivity analysis regarding histologic and irAEs type found no association between irAEs and OS and PFS.Grade ≥228.3%eA total of 618 patients with different solid tumors. This cohort included 229 patients with NSCLC (37.5%). Grade 2 or higher irAEs developed in 41 of the patients with NSCLC (21.3%). Outcome results are reported for the whole population, not according to tumor subtype. In the 12-week landmark analysis, PFS (log-rank test p = 0.58) and OS (log-rank test p = 0.21). Sensitivity analysis regarding histologic and irAEs type found no association between irAEs and OS and PFS.NRNR14.213.423.716.2NRNRToi et al.21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google ScholarAnti–PD-1137NRfirAEs developed in 48% of patients (grade ≥3 skin reactions developed in 2%, grade ≥3 hepatitis developed in in 2%, grade ≥3 pneumonitis developed in 3%, and grade ≥3 pancreatitis developed in 1%).521310.33.4Not R11.4NRNRShafqat et al.22Shafqat H. Gourdin T. Sion A. Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy.Semin Oncol. 2018; 45: 156-163Crossref PubMed Scopus (45) Google ScholarAnti–PD-1/PD-L1157gA total of 157 patients with cancer, including 49 patients with NSCLC.11.4NRNR24.44.2NRNRNRNRirAE, immune-related adverse event; Not R, not reached; NR, not reported; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; PFS, progression-free survival; RR, relative risk.a p = 0.001.b Prospective.c Patients enrolled on the KEYNOTE001 trial at a single center.d In the KEYNOTE-001 trial, 71% of patients experienced a treatment-related AE compared with 40% in this cohort; this could be related to longer time on trial (median PFS in the overall trial versus in the University of California Los Angeles cohort [111 versus 64 days, respectively]).e A total of 618 patients with different solid tumors. This cohort included 229 patients with NSCLC (37.5%). Grade 2 or higher irAEs developed in 41 of the patients with NSCLC (21.3%). Outcome results are reported for the whole population, not according to tumor subtype. In the 12-week landmark analysis, PFS (log-rank test p = 0.58) and OS (log-rank test p = 0.21). Sensitivity analysis regarding histologic and irAEs type found no association between irAEs and OS and PFS.f irAEs developed in 48% of patients (grade ≥3 skin reactions developed in 2%, grade ≥3 hepatitis developed in in 2%, grade ≥3 pneumonitis developed in 3%, and grade ≥3 pancreatitis developed in 1%).g A total of 157 patients with cancer, including 49 patients with NSCLC. Open table in a new tab irAE, immune-related adverse event; Not R, not reached; NR, not reported; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; PFS, progression-free survival; RR, relative risk. To establish the association between irAEs and outcome, most studies of cohorts of patients with NSCLC have included either 6-week12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google Scholar, 15Haratani 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 (595) Google Scholar, 16Teraoka S. Fujimoto D. Morimoto T. et al.Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017; 12: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar or 8-week14Toi Y. Sugawara S. Kawashima Y. et al.Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab.Oncologist. 2018; 23: 1358-1365https://doi.org/10.1634/theoncologist.2017-0384Crossref PubMed Scopus (153) Google Scholar, 17Sato K. Akamatsu H. Murakami E. et al.Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.Lung Cancer. 2018; 115: 71-74Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar landmark analyses for PFS to avoid the leading-time bias due to the time-dependent nature of irAEs and also to capture all patients other than those who experienced rapid progression. Therefore, it could be argued that duration of treatment with an ICI is a major confounding factor, as longer treatment duration might in turn lead to a higher efficacy and higher risk of irAEs.12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google Scholar, 14Toi Y. Sugawara S. Kawashima Y. et al.Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab.Oncologist. 2018; 23: 1358-1365https://doi.org/10.1634/theoncologist.2017-0384Crossref PubMed Scopus (153) Google Scholar This begs the question of whether the advantage ascribed to irAEs is just a reflection of the increased rate of toxicity associated with longer treatment or, alternatively, a straightforward result of the irAEs themselves. In this regard, and supporting this latter hypothesis, recent retrospective data suggest that this association is largely independent of guarantee-time bias,18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar mainly because most patients who experienced development of irAEs presented symptoms within 8 weeks after treatment initiation.21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google Scholar In another prospective cohort study of patients with advanced NSCLC treated with nivolumab,16Teraoka S. Fujimoto D. Morimoto T. et al.Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017; 12: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar a significant association with outcome was retained even in an early (at 2 weeks) evaluation of the irAEs, backing up the true predictive value of irAEs over treatment duration. In view of the aforementioned, the increased risk of toxicity would not be directly attributable to the length of treatment. However, the results were based on only seven patients with reported early irAEs, so although informative, they are by no means sufficient to draw any conclusion. On the other hand, although irAEs were independent factors for improved response rate,14Toi Y. Sugawara S. Kawashima Y. et al.Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab.Oncologist. 2018; 23: 1358-1365https://doi.org/10.1634/theoncologist.2017-0384Crossref PubMed Scopus (153) Google Scholar, 21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google Scholar PFS,12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google Scholar, 15Haratani 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 (595) Google Scholar, 18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar, 21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google Scholar and OS,12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google Scholar, 18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar the consideration of other potential confounding covariates was restricted and any conclusions drawn must therefore be regarded with caution owing to the limited number of patients included and the short follow-up of some series. On the whole, one can clearly notice that irAEs are in general associated with a greater rate of response in most studies of patients with NSCLC treated with ICIs (see Table 1). It is therefore questionable whether despite the slightly lower responses observed in some trials such as the OAK trial,19von Pawel J. Syrigos K. Mazieres J. et al.Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK.Ann Oncol. 2017; 28 (mdx380.017–mdx380.017)Google Scholar the final OS benefit associated with irAEs was comparable among studies. The different numbers and characteristics of patients included could justify these differences. Moreover, some evidence suggests that the features of response (i.e., time to onset and depth of response) might also have an impact on outcome in patients with NSCLC who are receiving ICIs, being increased when responses are earlier and deepest.28McCoach C.E. Blumenthal G.M. Zhang L. et al.Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy.Ann Oncol. 2017; 28: 2707-2714Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 29Gauci M.-L. Lanoy E. Champiat S. et al.Long-term survival in patients responding to Anti-PD-1/PD-L1 therapy and disease outcome upon treatment discontinuation.Clin Cancer Res. 2019; 25: 946-956Crossref PubMed Scopus (79) Google Scholar Whether the greater depth of response is linked to the irAEs per se or linked to other potential predictive biomarkers also remains unknown. In this sense, pretreatment Lung Immune Prognostic Index score, combining a derived neutrophil-to-lymphocyte ratio greater than 3 and lactate dehydrogenase level greater than the upper limit of normal, correlates with worse outcomes for ICI therapy,30Mezquita L. Auclin E. Ferrara R. et al.Association of the Lung Immune Prognostic Index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer.JAMA Oncol. 2018; 4: 351-357Crossref PubMed Scopus (451) Google Scholar so whether those patients with irAEs have a lower Lung Immune Prognostic Index score than do those without irAEs would merit further prospective evaluation. Steroid treatment is one of the potential confounding factors that warrant in-depth analysis. Corticosteroids are the mainstay of treatment for irAEs, and their use as immunosuppressants is needed to ameliorate the undesired irAEs. However, whether these immunosuppressive agents may decrease the ability to generalize the results regarding the predictive value of immune toxicity is uncertain. However, patients with NSCLC who are treated with atezolizumab31von Pawel J. Bordoni R. Satouchi M. et al.Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: results from the randomised phase III OAK study.Eur J Cancer. 2019; 107: 124-132Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar or nivolumab32Gettinger S. Horn L. Jackman D. et al.Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study.J Clin Oncol. 2018; 36: 1675-1684Crossref PubMed Scopus (461) Google Scholar achieve long-term survival despite discontinuing treatment for irAEs and receiving corticosteroids. In the OAK trial,19von Pawel J. Syrigos K. Mazieres J. et al.Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK.Ann Oncol. 2017; 28 (mdx380.017–mdx380.017)Google Scholar although a superior OS benefit was observed in atezolizumab-treated patients with irAEs versus without irAEs (hazard ratio = 0.79, 95% CI: 0.60–1.05), further exploratory analyses including the use of corticosteroids for the irAEs suggested a trend toward better outcomes in those patients who were not exposed to steroids (median OS 21.9 versus 16.0 months). In another recent retrospective cohort of patients with cancer, including NSCLC, with a positive association between irAEs and longer PFS, the benefit was sustained even with the use of systemic corticosteroids for treating irAEs.22Shafqat H. Gourdin T. Sion A. Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy.Semin Oncol. 2018; 45: 156-163Crossref PubMed Scopus (45) Google Scholar Similar results apply for melanoma.22Shafqat H. Gourdin T. Sion A. Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy.Semin Oncol. 2018; 45: 156-163Crossref PubMed Scopus (45) Google Scholar Taken together, these data suggest that the positive association of irAEs and outcome in NSCLC is not hampered by the use of steroids for the treatment of irAEs, so its use in this context should not be restricted for fear of loss of any outcome advantage. In addition, there might be other influencing variables on the scene, such as PD-L1 or TMB,2Rizvi H. Plodkowski A. Tenet M. HalpennyD Long N. et al.Clinical and molecular features predicting long-term response to anti-PD(L)1 based therapy in patients with NSCLC [abstract].J Clin Oncol. 2018; 36: 9022Crossref Google Scholar which correlate with long-term response in patients with NSCLC treated with immunotherapy.2Rizvi H. Plodkowski A. Tenet M. HalpennyD Long N. et al.Clinical and molecular features predicting long-term response to anti-PD(L)1 based therapy in patients with NSCLC [abstract].J Clin Oncol. 2018; 36: 9022Crossref Google Scholar According to subgroup data evaluation, it does not seem that PD-L1 expression differs between patients with and without irAEs12Ricciuti B. Genova C. De Giglio A. et al.Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab.J Thorac Oncol. 2018; 13: S390-S391Abstract Full Text Full Text PDF Google Scholar, 15Haratani 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 (595) Google Scholar, 16Teraoka S. Fujimoto D. Morimoto T. et al.Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017; 12: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 17Sato K. Akamatsu H. Murakami E. et al.Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.Lung Cancer. 2018; 115: 71-74Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar, 19von Pawel J. Syrigos K. Mazieres J. et al.Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK.Ann Oncol. 2017; 28 (mdx380.017–mdx380.017)Google Scholar or among those patients with preexisting autoimmune markers.21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google Scholar In fact, the incidence of irAEs among patients treated with pembrolizumab in KEYNOTE 010,33Herbst R.S. Baas P. Kim D.-W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4578) Google Scholar KEYNOTE 042,34Lopes G. Wu Y.L. Kudaba I. et al.Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study [abstract].J Clin Oncol. 2018; 36: LBA4Google Scholar and KEYNOTE 02435Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6279) Google Scholar were very similar (63%, 63%, and 73%, respectively) regardless of the different cutoffs for PD-L1 expression used for inclusion (≥1% and ≥ 50%, respectively). Likewise in the CheckMate 227 trial,36Hellmann M.D. Ciuleanu T.-E. Pluzanski A. et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.N Engl J Med. 2018; 378: 2093-2104Crossref PubMed Scopus (2010) Google Scholar those patients with high TMB (defined as ≥10 mutations per megabase) reported a similar incidence of irAEs (75%). Whether any of these biomarkers might correlate with an increased risk of irAEs is an intriguing question. Yet, it would be very difficult to discern between the direct impact of each variable on outcomes. Even considering the aforementioned limitations, the initial data obtained thus far might suggest an association of irAEs with survival outcome of ICIs in patients with advanced or recurrent NSCLC; however, teasing out data from phase III clinical trials in the second- or first-line setting may help to endorse this association. Before broad adoption of irAEs as a potential predictive biomarker in NSCLC, we should seek to address several other important issues, such as a way to identify beforehand those patients in whom irAEs will develop, and for the time being, patient’s features are not providing any further backing in this respect.14Toi Y. Sugawara S. Kawashima Y. et al.Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab.Oncologist. 2018; 23: 1358-1365https://doi.org/10.1634/theoncologist.2017-0384Crossref PubMed Scopus (153) Google Scholar, 16Teraoka S. Fujimoto D. Morimoto T. et al.Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017; 12: 1798-1805Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 17Sato K. Akamatsu H. Murakami E. et al.Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.Lung Cancer. 2018; 115: 71-74Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 18Lisberg A. Tucker D.A. Goldman J.W. et al.Treatment-related adverse events predict improved clinical outcome in NSCLC patients on KEYNOTE-001 at a single center [e-pub ahead of print]. Cancer Immunol Res.https://doi.org/10.1158/2326-6066.CIR-17-0063Google Scholar, 19von Pawel J. Syrigos K. Mazieres J. et al.Association between immune-related adverse events (irAEs) and atezolizumab efficacy in advanced NSCLC: analyses from the phase III study OAK.Ann Oncol. 2017; 28 (mdx380.017–mdx380.017)Google Scholar, 21Toi Y. Sugawara S. Sugisaka J. et al.Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer [e-pub ahead of print]. JAMA Oncol.https://doi.org/10.1001/jamaoncol.2018.5860Google Scholar The potential detection of autoimmune biomarkers at baseline could instead be a better way to determine risk-benefit ratio for individual patients with NSCLC, but this observation merits further prospective evaluation. Autoimmunity regarding the development of antidrug antibodies against ICI merits further evaluation. These antidrug antibodies decrease ICI activity by inhibiting and/or increasing clearance of the drug,37U.S. Food and Drug AdministrationHighlights of prescribing information. Telcentriq (atezolizumab) injection, for intravenous use. Initial U.S. approval 2016.https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s012lbl.pdfGoogle Scholar but their influence on the onset of irAEs remains unknown. Although retrospective observations are hypothesis-generating, further endeavours toward an accurate validation are needed to rule out other potential confounding factors that may lead to drawing early wrong conclusions.