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Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors – A systematic review and meta-analysis

  • Syed Hussaini
    Affiliations
    Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
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  • Rania Chehade
    Affiliations
    Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
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  • Ronald Gabriel Boldt
    Affiliations
    Division of Experimental Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
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  • Jacques Raphael
    Affiliations
    Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
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  • Phillip Blanchette
    Affiliations
    Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
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  • Saman Maleki Vareki
    Correspondence
    Corresponding authors at: Department of Oncology, London Health Sciences Centre – Western University, 800 Commissioners Road East, Room A3-940, London, Ontario N6A 5W9, Canada.
    Affiliations
    Division of Experimental Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada

    Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada

    Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada
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  • Ricardo Fernandes
    Correspondence
    Corresponding authors at: Department of Oncology, London Health Sciences Centre – Western University, 800 Commissioners Road East, Room A3-940, London, Ontario N6A 5W9, Canada.
    Affiliations
    Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada

    Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada
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Published:December 02, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102134

      Highlights

      • Immune checkpoint inhibitors can induce immune-related adverse events (irAEs), potentially life-threatening.
      • There is evidence suggesting a potential association between toxicities and clinical benefit.
      • This systematic review showed that there appears to be an association between the development of irAEs and anti-tumor effect by ICI.
      • This systematic review provides real-world data showing increased likelihood of response to ICI and improved progression free-survival, overall survival and response rate in patients who experienced an irAE, across all solid tumors and regardless of type of ICI.

      Abstract

      Background

      The use of immune checkpoint inhibitors (ICIs) has become standard therapy in many tumor sites. The aim of this study is to systematically review the literature to determine whether the incidence of immune-related adverse events (irAEs) after the use of ICIs is associated with clinical outcomes in all solid malignancies.

      Methods

      Embase and PubMed were searched from January 1st, 2000 until March 14, 2020 for relevant studies assessing the relationship between irAEs and treatment efficacy. Outcome measures of interest included: incidence of irAEs, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).

      Results

      Of 3384 unique citations, 51 studies met inclusion criteria. Studies included melanoma (n = 21), lung (n = 19), renal (n = 4), urothelial (n = 1), head and neck (n = 2) and gastrointestinal cancers (n = 1). In patients with metastatic melanoma (n = 1474), the development of irAEs (irAE + versus irAE-) was associated with better weighted average OS (15.24 months (95% CI 9.95 to 20.5) versus 8.94 months (95% CI 7.76 to 10.1), HR = 0.46 (n = 640, CI 0.35–0.62, p < 0.00001), PFS (17.61 months (95% CI 10.1 to 25.1) versus 2.23 months (95% CI 1.77 to 2.68), HR = 0.51 (n = 1763, CI 0.42–0.63, p < 0.00001), and ORR (37.67% (95% CI 32.8 to 42.5) versus. 23.44% (95% CI 17.8 to 29.1). Similarly, in lung cancer patients, the ORR (irAE + versus. irAE-) was 41.49% (95% CI 36.5 to 46.5) versus 18.01% (95% CI 13.5 to 22.6). The weighted average PFS and OS were 8.97 months (95% CI 7.14 to 10.8) versus 3.06 months (95% CI 2.4 to 3.72) with HR = 0.46 (n = 1575, CI 0.39–0.54, p < 0.00001) and 19.07 months (95% CI 14.3 to 23.8) versus 7.45 months (95% CI 5.34 to 9.56) HR = 0.40 (n = 1085, CI 0.30–0.51, p < 0.00001), respectively. Improved treatment efficacy in patients who developed irAEs was also seen in renal cell carcinoma, urothelial and head and neck cancers. Notably, grade 3 or 4 irAEs were associated with increased ORR but worse OS.

      Conclusion

      A positive association was noted between the development of irAEs and ORR, PFS, and OS in patients treated with ICIs, irrespective of disease site, type of ICI and irAE. Grade 3 or higher toxicities resulted in better ORR, but worse OS.

      Keywords

      Abbreviations:

      irAEs (immune-related adverse events, positive (+), negative (−)), ICIs (immune checkpoint inhibitors), ORR (objective response rate), PFS (progression-free survival), mPFS (median progression free survival), OS (overall survival), mOS (median overall survival), CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-L1 (programmed cell death-ligand 1), NSCLC (non-small cell lung cancer), MeSH (medical subjects heading), PICOS (population-intervention-comparator-outcome-study design), ILD (interstitial lung disease), BMI (body mass index), CRC (colorectal cancer), RCC (renal cell cancer), HCC (hepatocellular carcinoma), GA/GEJ (gastric/gastroesophageal-junctional cancer), HNSCC (head & neck squamous cell cancer), SD (stable disease), PD (progressive disease), PR (partial response), CR (complete response), MSI-H (microsatellite instability-high), TTP (time to progression)

      Introduction

      Immunotherapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm in many tumor types and improved survival in a subset of patients with advanced or metastatic cancers [
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • et al.
      Overall survival with combined nivolumab and ipilimumab in advanced melanoma.
      ,
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      ,
      • Steins M.
      • Chow L.Q.
      • Vokes E.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ,
      • Overman M.J.
      • McDermott R.
      • Leach J.L.
      • et al.
      Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
      ]. The prominent members of this class of agents include ipilimumab, a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor; nivolumab and pembrolizumab, anti–programmed cell death 1 (PD-1) agents; and atezolizumab, durvalumab, and avelumab that are anti–programmed cell death-ligand 1 (PD-L1) agents. ICIs have been widely used for the treatment of melanoma, non-small cell lung cancer, renal cancer, and other solid tumors and hematologic malignancies, not only in the metastatic, but also in the adjuvant settings [
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • et al.
      Overall survival with combined nivolumab and ipilimumab in advanced melanoma.
      ,
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      ].
      Despite the clinical efficacy, ICIs can induce various immune-related adverse events (irAEs) limiting their use in many patients. ICIs may affect peripheral tolerance to autoantigens, resulting in autoantibody formation, which could be associated with irAEs in various organs. ICIs can also unleash T-cells with subsequent production of pro-inflammatory cytokines such as interferon-γ and tumor necrosis factor, which may result in excessive off-tumor inflammation and autoimmunity. Most irAEs, tend to be mild and self-limiting, but in few severe cases (grade 3 or 4) potentially life-threatening events can occur [
      • Steins M.
      • Chow L.Q.
      • Vokes E.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ].
      While there is growing evidence suggesting a potential association between toxicities and clinical benefit in some cancer types [
      • Fujii T.
      • Naing A.
      • Rolfo C.
      • Hajjar J.
      Biomarkers of response to immune checkpoint blockade in cancer treatment.
      ], the relationship between irAEs and clinical benefit is yet to be resolved. Retrospective studies have demonstrated a relationship between irAEs and response rates, time to treatment failure and survival [
      • Judd 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.
      ,
      • Horvat T.Z.
      • Adel N.G.
      • Dang T.O.
      • et al.
      Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center.
      ]. Therefore, it is highly desirable to identify predictive biomarkers of both efficacy and toxicity associated with the use of ICIs, which would likely help guide treatment decisions.
      Given the widespread use of ICIs in many tumor sites, we systematically reviewed and analyze the literature to determine whether the incidence of irAEs after the use of ICIs is associated with treatment efficacy. We set to determine whether the relationship between irAEs and efficacy was restricted to certain disease sites or if this was a disease-site agnostic association. We also determined if type of toxicity correlated with outcomes and PD-L1 expression level and its relationship to the rate of irAEs. Lastly, we analyzed the severity of toxicity and its impact on outcome.

      Methods

      Study objective and inclusion criteria
      This systematic review was designed to summarize and provide a qualitative and quantitative review in the form of a meta-analysis to address the following research question: “Is there a survival improvement in patients diagnosed with advanced cancer and treated with ICIs who have developed irAEs?”
      We employed the Population-Intervention-Comparator-Outcome-Study Design (PICOS) framework to structure the research question and its corresponding literature search. The population of interest was patients with advanced solid tumors, with no additional restrictions in place. The intervention of interest was treatment with immunotherapy, more specifically ICIs including CTLA-4, PD-1 and PD-L1 inhibitors. The outcomes of interest included incidence of adverse events, objective response rates, progression-free survival, and overall survival in populations with and without the development of irAEs. We also collected information on median age, sex, disease site, line of therapy, grade 3 or higher toxicity and type of toxicity.
      Inclusion criteria used during Stage 1 (i.e. citation review) and Stage 2 (i.e. full-text review) screening closely mirrored the above PICOS criteria, with additional details used to determine inclusion status. Abstracts and animal studies were excluded.
      Literature search
      With the assistance of an experienced information specialist, an electronic search strategy was designed and performed to seek relevant citations from EMBASE and PubMed published up until March 14th, 2020. Bibliographies of included studies were also searched for relevant articles. Key terms and their medical subjects heading (MeSH) are provided along with the full search strategy in Appendix B.
      Study selection and data collection
      Stage 1 screening was performed by four reviewers (SH, RF, RC, SMV), working independently, who screened all citations retrieved from the electronic search. Disagreements were discussed and resolved between reviewers. Stage 2 screening consisted of a full-text review of all potentially relevant citations by four reviewers working independently (SH, RF, RC, SMV) to determine the final set of included articles. Both levels of screening started with a pilot exercise to ensure there was a consistent use of eligibility criteria across reviewers. A PRISMA flow diagram was prepared to summarize the study selection process (Supplementary Fig. 1). Once the final set of included studies was established, data were extracted by three reviewers (SH, RF, RC) independently using a pre-designed form implemented in Microsoft Excel version 2010 (Microsoft Corporation, Seattle, Washington, USA); any discrepancies were resolved by consensus discussion.
      The following information was collected from each study: disease site, number of patients, immune checkpoint inhibitor drug, line of therapy, median number of cycles administered, PD-L1 expression level, median age, gender (% male), percentage of patients developing irAEs, type of irAE, OS in patients with irAEs, PFS in patients with irAEs, ORR in patients with irAEs, OS in patients without irAEs, PFS in patients without irAEs, ORR in patients without irAEs. If studies included assessment of multiple disease sites and individual disease site OS, PFS and ORR were provided, this data was extracted and listed separately. If only cumulative outcomes were provided, these studies were assessed in a disease-site agnostic manner.
      Data analysis
      Upon the assessment of patient and study characteristics to determine sufficient clinical and methodological homogeneity between studies, we conducted a meta-analysis using the generic inverse-variance method using a random-effects model to get pooled HR for OS and PFS provided original study HRs and confidence intervals were available for the specified outcomes. Disease sites with three or fewer studies did not have a pooled HR performed. I2 statistics were used to estimate the proportion of the variability of the results attributed to heterogeneity rather than sampling error. I2 levels of 25% or less correspond to a low heterogeneity. Weighted averages were calculated for studies reporting OS, PFS and ORR data in patients with and without irAEs. Pooled HRs, power and I2 statistics were calculated using the RevMan software, Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Data from the meta-analysis, along with a descriptive overview of the results, is presented.
      Reporting of finding from this study was guided by the PRISMA statement and a completed PRISMA checklist is provided in Appendix A [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      Results

      Studies included
      After removing duplicate studies, the electronic literature searches identified 1090 citations in the Embase and 2294 citations in the PubMed for a total of 3384 citations. Stage 1 screening identified 131 potentially relevant studies. Stage 2 excluded 80 studies for the following reasons: study data was not pertinent to irAEs site, severity, timing of onset and correlation with ICIs effectiveness (n = 69), no relevant data (n = 8), abstract only (n = 3). Fifty-one studies met the inclusion criteria and were included in the review. Supplementary Fig. 1 shows an overview of the selection process.
      Study characteristics
      The sample sizes in the included 51 studies ranged from 15 to 1019 patients (median n = 105). Seven studies looked at multiple disease sites [
      • Judd 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.
      ,
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Nobashi T.
      • Baratto L.
      • Reddy S.A.
      • et al.
      Predicting response to immunotherapy by evaluating tumors, lymphoid cell-rich organs, and immune-related adverse events using FDG-PET/CT.
      ,
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ,
      • Fujii T.
      • Colen R.R.
      • Bilen M.A.
      • et al.
      Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.
      ,
      • Shafqat 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.
      ,
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      ]. Disease-site specific studies included advanced melanoma (n = 18), lung (n = 19), renal (n = 4), urothelial (n = 1), head and neck (n = 2) and gastrointestinal cancer (n = 1). Drug-specific studies included nivolumab (n = 11), pembrolizumab (n = 3), ipilimumab plus nivolumab (n = 1), others (n = 1) while the remaining studies included various ICI drugs (n = 24). With respect to study design, 49 out of the 51 studies were retrospective. Two studies were prospective in design [

      Berner 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. 2020;5(7):1043–1047. doi: 10.1001/jamaoncol.2019.0402.

      ,
      • Eggermont A.M.M.
      • Kicinski M.
      • Blank C.U.
      • et al.
      association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: A secondary analysis of a randomized clinical trial.
      ]. Forty-two studies provided at least one or more of ORR, PFS, and OS data while eight studies provided hazard ratios and graphs with extrapolatable data. All 51 studies reported incidence of irAEs of any grade. Thirteen studies looked specifically at individual or organ-specific side effects [
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ,
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      ,

      Berner 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. 2020;5(7):1043–1047. doi: 10.1001/jamaoncol.2019.0402.

      ,
      • Lee Y.J.
      • Kim H.T.
      • Won C.H.
      • et al.
      Characterization and prognostic significance of cutaneous adverse events to anti-programmed cell death-1 therapy.
      ,
      • Peiro I.
      • Palmero R.
      • Iglesias P.
      • et al.
      Thyroid dysfunction induced by nivolumab: searching for disease patterns and outcomes.
      ,
      • Chan L.
      • Hwang S.J.E.
      • Byth K.
      • et al.
      Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Hasan Ali O.
      • Diem S.
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      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      ,

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Hua C.
      • Boussemart L.
      • Mateus C.
      • et al.
      Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumabvitiligo and melanoma responsevitiligo and melanoma response.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ,
      • Campredon P.
      • Mouly C.
      • Lusque A.
      • et al.
      Incidence of thyroid dysfunctions during treatment with nivolumab for non-small cell lung cancer: retrospective study of 105 patients.
      ,
      • Fukihara J.
      • Sakamoto K.
      • Koyama J.
      • et al.
      Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors.
      ]. The average incidence of any grade irAE in studies looking at any toxicity was 46.5%.
      Melanoma
      Of the 18 studies included, 7 reported numeric OS data, 4 reported numeric PFS data and 9 reported ORR data [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Eggermont A.M.M.
      • Kicinski M.
      • Blank C.U.
      • et al.
      association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: A secondary analysis of a randomized clinical trial.
      ,
      • Chan L.
      • Hwang S.J.E.
      • Byth K.
      • et al.
      Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Hua C.
      • Boussemart L.
      • Mateus C.
      • et al.
      Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumabvitiligo and melanoma responsevitiligo and melanoma response.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ,
      • Fujisawa Y.
      • Yoshino K.
      • Otsuka A.
      • et al.
      Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients.
      ,
      • Dick J.
      • Lang N.
      • Slynko A.
      • et al.
      Use of LDH and autoimmune side effects to predict response to ipilimumab treatment.
      ,
      • Eigentler T.K.
      • Schlaak M.
      • Hassel J.C.
      • et al.
      Effectiveness and tolerability of ipilimumab: experiences from 198 patients included in a named-patient program in various daily-practice settings and multiple institutions.
      ,
      • Indini A.
      • Di Guardo L.
      • Cimminiello C.
      • et al.
      Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma.
      ,
      • Farolfi A.
      • Ridolfi L.
      • Guidoboni M.
      • et al.
      Ipilimumab in advanced melanoma: reports of long-lasting responses.
      ,
      • Wen X.
      • Ding Y.
      • Li J.
      • et al.
      The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.
      ,
      • Schadendorf D.
      • Wolchok J.D.
      • Hodi F.S.
      • et al.
      Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials.
      ,
      • Otsuka M.
      • Sugihara S.
      • Mori S.
      • et al.
      Immune-related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: a single-center retrospective study in Japan.
      ,
      • Attia P.
      • Phan G.Q.
      • Maker A.V.
      • et al.
      Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
      ,
      • Downey S.G.
      • Klapper J.A.
      • Smith F.O.
      • et al.
      Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.
      ,
      • Okada N.
      • Kawazoe H.
      • Takechi
      • Kenshi
      • et al.
      Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study.
      ,
      • Ascierto P.A.
      • Simeone E.
      • Sileni V.C.
      • et al.
      Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort.
      ]. Seventeen studies were retrospective. The sample sizes ranged from 15 to 1019 subjects. Five studies assessed ipilimumab specifically [
      • Dick J.
      • Lang N.
      • Slynko A.
      • et al.
      Use of LDH and autoimmune side effects to predict response to ipilimumab treatment.
      ,
      • Eigentler T.K.
      • Schlaak M.
      • Hassel J.C.
      • et al.
      Effectiveness and tolerability of ipilimumab: experiences from 198 patients included in a named-patient program in various daily-practice settings and multiple institutions.
      ,
      • Farolfi A.
      • Ridolfi L.
      • Guidoboni M.
      • et al.
      Ipilimumab in advanced melanoma: reports of long-lasting responses.
      ,
      • Attia P.
      • Phan G.Q.
      • Maker A.V.
      • et al.
      Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
      ,
      • Okada N.
      • Kawazoe H.
      • Takechi
      • Kenshi
      • et al.
      Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study.
      ]. Nivolumab was assessed in 3 studies [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Otsuka M.
      • Sugihara S.
      • Mori S.
      • et al.
      Immune-related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: a single-center retrospective study in Japan.
      ]. Five studies looked at any ICI (including ipilimumab and nivolumab combination, pembrolizumab, nivolumab or ipilimumab) [
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ,
      • Fujisawa Y.
      • Yoshino K.
      • Otsuka A.
      • et al.
      Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients.
      ,
      • Indini A.
      • Di Guardo L.
      • Cimminiello C.
      • et al.
      Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma.
      ,
      • Wen X.
      • Ding Y.
      • Li J.
      • et al.
      The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.
      ,
      • Schadendorf D.
      • Wolchok J.D.
      • Stephen Hodi F.
      • et al.
      Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials.
      ,
      • Chan L.
      • Kyaw M.
      • Hons M.
      • Hon M.
      • Carlino M.S.
      Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.
      ]. The patient population reported in these 18 studies were all patients with stage IV or locally advanced melanoma. See Table 1.
      Table 1Melanoma.
      Studyn=IO DrugirAE (% of patients)OS in irAE+ (months)OS in irAE- (months)PFS in irAE+ (months)PFS in irAE- (months)ORR in irAE+ (%)ORR in irAE-(%)Comments
      Topalian et al
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      107Nivolumab84.132738.50%0%
      Nakamura et al
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      35Nivolumab25.7%44.40%7%Assessed rates of vitiligo
      Hua et al
      • Hua C.
      • Boussemart L.
      • Mateus C.
      • et al.
      Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab.
      67Pembrolizumab25%71%28%Assessed rates of vitiligo
      Attia et al
      • Attia P.
      • Phan G.Q.
      • Maker A.V.
      • et al.
      Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
      56Ipilimumab36%5%
      Downey at al
      • Downey S.G.
      • Klapper J.A.
      • Smith F.O.
      • et al.
      Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.
      139Ipilimumab62%22% and 28%2%22% in grade 1/2 and 28% in grade 3/4 toxicity
      Okada et al
      • Okada N.
      • Kawazoe H.
      • Takechi
      • Kenshi
      • et al.
      Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study.
      15Ipilimumab53.00%75%14.20%
      Ascierto et al
      • Ascierto P.A.
      • Simeone E.
      • Sileni V.C.
      • et al.
      Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort.
      855Ipilimumab

      Nivolumab
      33%10.109.736%32%
      Abu-sbeih et al
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      346Pembrolizumab

      Ipilimumab

      Nivolumab
      8.70%HR for OS 0.53 (CI 0.37–0.76, p < 0.01)

      HR for PFS 0.56 (CI 0.41–0.76, p < 0.01)
      Fujisawa et al
      • Fujisawa Y.
      • Yoshino K.
      • Otsuka A.
      • et al.
      Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients.
      60Nivolumab

      78%
      Dick et al
      • Dick J.
      • Lang N.
      • Slynko A.
      • et al.
      Use of LDH and autoimmune side effects to predict response to ipilimumab treatment.
      86Ipilimumab41%2311232Data extrapolated from Kaplan-Meier curve
      Eigentler et al
      • Eigentler T.K.
      • Schlaak M.
      • Hassel J.C.
      • et al.
      Effectiveness and tolerability of ipilimumab: experiences from 198 patients included in a named-patient program in various daily-practice settings and multiple institutions.
      196Ipilimumab31.40%15.66.2
      Indini et al
      • Indini A.
      • Di Guardo L.
      • Cimminiello C.
      • et al.
      Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma.
      173Pembrolizumab

      Nivolumab
      59%21.99.7
      Farolfi et al
      • Farolfi A.
      • Ridolfi L.
      • Guidoboni M.
      • et al.
      Ipilimumab in advanced melanoma: reports of long-lasting responses.
      30Ipilimumab76.731493Assess Grade 3/4 toxicity only
      Wen et al
      • Wen X.
      • Ding Y.
      • Li J.
      • et al.
      The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.
      28Pembrolizumab

      Ipilimumab
      29%Not reached7Not reached3
      Schadendorf et al
      • Schadendorf D.
      • Wolchok J.D.
      • Hodi F.S.
      • et al.
      Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials.
      409Nivolumab

      Ipilimumab
      38.30%8.4*10.8*58.30%50.20%PFS in patients who stopped IO due to irAE versus. patients who continued treatment
      Chan et al
      • Chan L.
      • Kyaw M.
      • Hons M.
      • Hon M.
      • Carlino M.S.
      Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.
      82Pembrolizumab

      Nivolumab
      62%HR 0.46
      Otsuka et al
      • Otsuka M.
      • Sugihara S.
      • Mori S.
      • et al.
      Immune-related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: a single-center retrospective study in Japan.
      27Nivolumab33%10.036.6310.032.144%9%
      Eggermont et al
      • Eggermont A.M.M.
      • Kicinski M.
      • Blank C.U.
      • et al.
      association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: A secondary analysis of a randomized clinical trial.
      1019Pembrolizumab61.5%HR 0.61
      Table 1. Studies looking at irAE and efficacy in advanced melanoma treated with CPI therapy. irAE = Immune-related adverse event. OS = Overall Survival. PFS = Progression Free Survival. ORR = Objective Response Rate. “-“ denotes data not reported in original publication.
      Objective response rate
      In the studies reporting ORR data (n = 1301), the weighted average ORR was 37.67% (95% CI 32.8 to 42.5) versus 23.44% (95% CI 17.8 to 29.1) in irAE + versus irAE- patients [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Hua C.
      • Boussemart L.
      • Mateus C.
      • et al.
      Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumabvitiligo and melanoma responsevitiligo and melanoma response.
      ,
      • Attia P.
      • Phan G.Q.
      • Maker A.V.
      • et al.
      Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
      ,
      • Downey S.G.
      • Klapper J.A.
      • Smith F.O.
      • et al.
      Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.
      ,
      • Okada N.
      • Kawazoe H.
      • Takechi
      • Kenshi
      • et al.
      Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study.
      ,
      • Ascierto P.A.
      • Simeone E.
      • Sileni V.C.
      • et al.
      Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort.
      ,
      • Schadendorf D.
      • Wolchok J.D.
      • Stephen Hodi F.
      • et al.
      Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials.
      ].
      Progression-free survival
      Only eight studies reported PFS data [
      • Eggermont A.M.M.
      • Kicinski M.
      • Blank C.U.
      • et al.
      association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: A secondary analysis of a randomized clinical trial.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Dick J.
      • Lang N.
      • Slynko A.
      • et al.
      Use of LDH and autoimmune side effects to predict response to ipilimumab treatment.
      ,
      • Farolfi A.
      • Ridolfi L.
      • Guidoboni M.
      • et al.
      Ipilimumab in advanced melanoma: reports of long-lasting responses.
      ,
      • Wen X.
      • Ding Y.
      • Li J.
      • et al.
      The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.
      ,
      • Otsuka M.
      • Sugihara S.
      • Mori S.
      • et al.
      Immune-related adverse events correlate with improved survival in patients with advanced mucosal melanoma treated with nivolumab: a single-center retrospective study in Japan.
      ,
      • Schadendorf D.
      • Wolchok J.D.
      • Stephen Hodi F.
      • et al.
      Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials.
      ,
      • Chan L.
      • Kyaw M.
      • Hons M.
      • Hon M.
      • Carlino M.S.
      Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.
      ]. PFS data from Schadendorf et al. was not included as it compared PFS in patients who had stopped ICIs due to irAEs versus patients who did not stop treatment after developing irAEs [
      • Schadendorf D.
      • Wolchok J.D.
      • Stephen Hodi F.
      • et al.
      Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials.
      ]. In the study by Wen et al. PFS and OS were not reached in metastatic melanoma patients (n = 28) treated who developed irAEs on ipilimumab, nivolumab or both [
      • Wen X.
      • Ding Y.
      • Li J.
      • et al.
      The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.
      ]. In patients that did not develop irAEs, PFS was three months, and OS was seven months. In the remaining 3 studies (n = 143) reporting numeric data, weighted average PFS was 17.61 months (95% CI 10.1 to 25.1) versus 2.23 months (95% CI 1.77 to 2.68) in irAE + versus irAE- patients. In studies that provided HR data, HR for mPFS was 0.51 (n = 1,736, CI 0.42–0.63, p < 0.00001) (see Fig. 1a) [
      • Eggermont A.M.M.
      • Kicinski M.
      • Blank C.U.
      • et al.
      association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: A secondary analysis of a randomized clinical trial.
      ,
      • Chan L.
      • Hwang S.J.E.
      • Byth K.
      • et al.
      Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ,
      • Dick J.
      • Lang N.
      • Slynko A.
      • et al.
      Use of LDH and autoimmune side effects to predict response to ipilimumab treatment.
      ,
      • Indini A.
      • Di Guardo L.
      • Cimminiello C.
      • et al.
      Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma.
      ]. Study heterogeneity was low with an I2 of 0%. Diarrhea and fever were the most common side effects in this group.
      Figure thumbnail gr1a
      Fig. 1Forest plots for (a) progression free survival (PFS) in advanced melanoma patients that developed irAEs versus patients that did not, (b) overall survival (OS) in advanced melanoma patients that developed irAEs versus patients that did not, (c) progression free survival (PFS) in advanced NSCLC patients that developed irAEs versus patients that did not, (d) overall survival (OS) in advanced NSCLC patients that developed irAEs versus patients that did not.
      Figure thumbnail gr1b
      Fig. 1Forest plots for (a) progression free survival (PFS) in advanced melanoma patients that developed irAEs versus patients that did not, (b) overall survival (OS) in advanced melanoma patients that developed irAEs versus patients that did not, (c) progression free survival (PFS) in advanced NSCLC patients that developed irAEs versus patients that did not, (d) overall survival (OS) in advanced NSCLC patients that developed irAEs versus patients that did not.
      Figure thumbnail gr1c
      Fig. 1Forest plots for (a) progression free survival (PFS) in advanced melanoma patients that developed irAEs versus patients that did not, (b) overall survival (OS) in advanced melanoma patients that developed irAEs versus patients that did not, (c) progression free survival (PFS) in advanced NSCLC patients that developed irAEs versus patients that did not, (d) overall survival (OS) in advanced NSCLC patients that developed irAEs versus patients that did not.
      Figure thumbnail gr1d
      Fig. 1Forest plots for (a) progression free survival (PFS) in advanced melanoma patients that developed irAEs versus patients that did not, (b) overall survival (OS) in advanced melanoma patients that developed irAEs versus patients that did not, (c) progression free survival (PFS) in advanced NSCLC patients that developed irAEs versus patients that did not, (d) overall survival (OS) in advanced NSCLC patients that developed irAEs versus patients that did not.
      Overall survival
      Seven studies assessed OS in irAE− versus irAE+ patients [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ,
      • Dick J.
      • Lang N.
      • Slynko A.
      • et al.
      Use of LDH and autoimmune side effects to predict response to ipilimumab treatment.
      ,
      • Eigentler T.K.
      • Schlaak M.
      • Hassel J.C.
      • et al.
      Effectiveness and tolerability of ipilimumab: experiences from 198 patients included in a named-patient program in various daily-practice settings and multiple institutions.
      ,
      • Indini A.
      • Di Guardo L.
      • Cimminiello C.
      • et al.
      Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma.
      ,
      • Farolfi A.
      • Ridolfi L.
      • Guidoboni M.
      • et al.
      Ipilimumab in advanced melanoma: reports of long-lasting responses.
      ]. In total, 1474 patients with advanced or metastatic melanoma, were treated with either ipilimumab, nivolumab, pembrolizumab or combination of ipilimumab and nivolumab. The weighted average OS was 15.24 months (95% CI 9.95 to 20.5) in patients with any grade irAEs versus 8.94 months (95% CI 7.76 to 10.1) patients with no irAEs. In studies providing HR data, HR for mOS was 0.46 (n = 640, CI 0.35–0.62, p < 0.00001, I2 = 0%) (see Fig. 1b) [
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ,
      • Dick J.
      • Lang N.
      • Slynko A.
      • et al.
      Use of LDH and autoimmune side effects to predict response to ipilimumab treatment.
      ,
      • Indini A.
      • Di Guardo L.
      • Cimminiello C.
      • et al.
      Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma.
      ]. The most commonly reported irAEs were diarrhea and rash.
      Non-small cell lung cancer
      Nineteen studies looked at irAEs in advanced NSCLC treated with ICIs. Eight provided numeric OS data [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung CancerImmune-Related Adverse Events and Nivolumab Efficacy in NSCLCImmune-Related Adverse Events and Nivolumab Efficacy in NSCLC.
      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Owen D.H.
      • Wei L.
      • Bertino E.M.
      • et al.
      Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer.
      ]. Nine studies provided PFS data [

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung CancerImmune-Related Adverse Events and Nivolumab Efficacy in NSCLCImmune-Related Adverse Events and Nivolumab Efficacy in NSCLC.
      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study.
      ,
      • Teraoka 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.
      ,
      • Toi 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.
      ]. Ten reported ORR [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Hasan Ali O.
      • Diem S.
      • Markert E.
      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study.
      ,
      • Teraoka 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.
      ,
      • Toi 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.
      ,
      • Sato K.
      • Akamatsu H.
      • Murakami E.
      • et al.
      Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.
      ]. OS in irAE+ patients was not reached in the Haratani et al. study [
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung CancerImmune-Related Adverse Events and Nivolumab Efficacy in NSCLCImmune-Related Adverse Events and Nivolumab Efficacy in NSCLC.
      ]. Eighteen studies were retrospective in design. Berner et al.’s study was a prospective cohort study [

      Berner 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. 2020;5(7):1043–1047. doi: 10.1001/jamaoncol.2019.0402.

      ] Sample sizes ranged from 38 to 613 subjects. Nivolumab was the drug utilized in all 19 studies and the only drug utilized in all but eight of these studies. These remaining eight studies included pembrolizumab and atezolizumab as well [

      Berner 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. 2020;5(7):1043–1047. doi: 10.1001/jamaoncol.2019.0402.

      ,
      • Lee Y.J.
      • Kim H.T.
      • Won C.H.
      • et al.
      Characterization and prognostic significance of cutaneous adverse events to anti-programmed cell death-1 therapy.
      ,

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Fukihara J.
      • Sakamoto K.
      • Koyama J.
      • et al.
      Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Owen D.H.
      • Wei L.
      • Bertino E.M.
      • et al.
      Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer.
      ,
      • Ahn B.-C.
      • Pyo K.-H.
      • Xin C.-F.
      • et al.
      Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.
      ,
      • Sugano T.
      • Seike M.
      • Saito Y.
      • et al.
      Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer.
      ] (See Table 2).
      Table 2NSCLC.
      Studyn=IO DrugirAE (% of patients)OS in irAE+ (months)OS in irAE- (months)PFS in irAE+ (months)PFS in irAE- (months)ORR in irAE+ (%)ORR in irAE- (%)Comments
      Topalian et al
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      129Nivolumab70.50%117.523%3%
      Fujimoto et al
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study.
      613Nivolumab10%5.82.137%18%
      Haratani et al
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of immune-related adverse events with nivolumab efficacy in non-small cell lung cancer.
      134Nivolumab51%Not reached11.19.24.8
      Hasan Ali et al
      • Hasan Ali O.
      • Diem S.
      • Markert E.
      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      40Nivolumab17%42%7%Skin Toxicity only
      Osorio et al

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      48Pembrolizumab21%401482Thyroid toxicity only
      Teraoka et al
      • Teraoka 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.
      43Nivolumab44%6.41.537%17%
      Sato et al
      • Sato K.
      • Akamatsu H.
      • Murakami E.
      • et al.
      Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.
      38Nivolumab28.90%not reached (HR 0.10)1.6363.60%7.40%
      Ricciuti et al
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      195Nivolumab43.60%17.8048.502.0043.50%10%
      Cortellini et al
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      559Nivolumab

      Pembrolizumab
      41.30%20.508.5010.104.1046.50%25.70%
      Campredon et al
      • Campredon P.
      • Mouly C.
      • Lusque A.
      • et al.
      Incidence of thyroid dysfunctions during treatment with nivolumab for non-small cell lung cancer: retrospective study of 105 patients.
      105Nivolumab14.30%Please see comments
      Owen et al
      • Owen D.H.
      • Wei L.
      • Bertino E.M.
      • et al.
      Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer.
      91Nivolumab

      Pembrolizumab

      Atezolizumab
      30%24.305.3
      Toi et al
      • Toi 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.
      70Nivolumab40%123.657%12%
      Ahn et al
      • Ahn B.-C.
      • Pyo K.-H.
      • Xin C.-F.
      • et al.
      Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.
      155Nivolumab

      Pembrolizumab
      38.1%24.0511.637.393.27
      Berner et al
      • Berner 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.
      73Nivolumab

      Pembrolizumab
      34.2%HR 0.29HR 0.22Skin toxicity only
      Fukihara et al
      • Fukihara J.
      • Sakamoto K.
      • Koyama J.
      • et al.
      Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors.
      170Nivolumab

      Pembrolizumab
      16%8.7233.46.143%25%Pneumonitis only
      Jin Lee et al
      • Lee Y.J.
      • Kim H.T.
      • Won C.H.
      • et al.
      Characterization and prognostic significance of cutaneous adverse events to anti-programmed cell death-1 therapy.
      211Nivolumab

      Pembrolizumab
      16.4%HR 0.29Skin Toxicity only
      Peiro et al
      • Peiro I.
      • Palmero R.
      • Iglesias P.
      • et al.
      Thyroid dysfunction induced by nivolumab: searching for disease patterns and outcomes.
      55Nivolumab14.6%HR 0.40Thyroid toxicity only
      Sugano et al
      • Sugano T.
      • Seike M.
      • Saito Y.
      • et al.
      Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer.
      130Nivolumab

      Pembrolizumab

      Atezolizumab
      30%15.93.363%22%
      Table 2. Studies looking at irAE and efficacy in advanced NSCLC treated with IO therapy. irAE = Immune-Related Adverse Event. OS = Overall Survival. PFS = Progression-Free Survival. ORR = Objective Response Rate. “−” denotes data not reported in original publication.
      Objective response rate
      In the nine studies reporting OS data, a total of 1817 patients with advanced NSCLC were treated with either nivolumab (n = 1633), pembrolizumab (n = 166) or atezolizumab (n = 18) [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Hasan Ali O.
      • Diem S.
      • Markert E.
      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Sugano T.
      • Seike M.
      • Saito Y.
      • et al.
      Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer.
      ,
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study.
      ,
      • Teraoka 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.
      ,
      • Toi 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.
      ,
      • Sato K.
      • Akamatsu H.
      • Murakami E.
      • et al.
      Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.
      ]. The weighted average ORR was 41.49% (95% CI 36.5 to 46.5) versus 18.01% (95% CI 13.5 to 22.6) in irAE+ versus irAE- patients. Only Toi et al. reported data on type of response in patients with irAEs versus without [
      • Toi 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.
      ]. Of 70 patients, 28 had irAEs. Partial response (PR) and stable disease (SD) were seen in 16 (57%) and 10 (35.7%) of patients with irAEs, respectively, while only 2 (7.1%) patients had progressive disease (PD). In the non-irAE group (42 out of 70 patients), there was 1 (2.4%) complete response (CR) seen. PR and SD were seen in 4 (9.5%) and 13 (30.9%) of patients, respectively. PD was seen in 24 (57.1%) of patients.
      Progression-free survival
      In the nine studies reporting PFS data, a total of 2117 advanced NSCLC patients were treated with either nivolumab (n = 1663), pembrolizumab (n = 279) or atezolizumab (n = 18) [

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Fukihara J.
      • Sakamoto K.
      • Koyama J.
      • et al.
      Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors.
      ,
      • Sugano T.
      • Seike M.
      • Saito Y.
      • et al.
      Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer.
      ,
      • Kim K.H.
      • Hur J.Y.
      • Cho J.
      • et al.
      Immune-related adverse events are clustered into distinct subtypes by T-cell profiling before and early after anti-PD-1 treatment.
      ,
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung CancerImmune-Related Adverse Events and Nivolumab Efficacy in NSCLCImmune-Related Adverse Events and Nivolumab Efficacy in NSCLC.
      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study.
      ,
      • Teraoka 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.
      ,
      • Toi 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.
      ]. The weighted average PFS was 8.97 months (95% CI 7.14 to 10.8) versus 3.06 months (95% CI 2.4 to 3.72) in irAE + and irAE- patients with any type or grade toxicity, respectively (n = 1947). The PFS data from the Fukihara et al. study was not included in the calculated weighted average as it compared PFS in patients with interstitial lung disease (ILD) versus non-ILD cases (which included other irAEs) [
      • Fukihara J.
      • Sakamoto K.
      • Koyama J.
      • et al.
      Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors.
      ]. Pooled HR for PFS (9 studies, n = 1575) was 0.46 (CI 0.39–0.54, p < 0.00001, I2 = 8%) (see Fig. 1c) [

      Berner 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. 2020;5(7):1043–1047. doi: 10.1001/jamaoncol.2019.0402.

      ,
      • Lee Y.J.
      • Kim H.T.
      • Won C.H.
      • et al.
      Characterization and prognostic significance of cutaneous adverse events to anti-programmed cell death-1 therapy.
      ,

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Toi 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.
      ,
      • Sugano T.
      • Seike M.
      • Saito Y.
      • et al.
      Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer.
      ,
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of immune-related adverse events with nivolumab efficacy in non-small cell lung cancer.
      ,
      • Kim K.H.
      • Hur J.Y.
      • Cho J.
      • et al.
      Immune-related adverse events are clustered into distinct subtypes by T-cell profiling before and early after anti-PD-1 treatment.
      ].
      Overall survival
      In the eight studies reporting OS data, a total of 1347 patients were treated with either nivolumab (n = 953), pembrolizumab (n = 237) or atezolizumab (n = 1) [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Fukihara J.
      • Sakamoto K.
      • Koyama J.
      • et al.
      Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors.
      ,
      • Chan L.
      • Kyaw M.
      • Hons M.
      • Hon M.
      • Carlino M.S.
      Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.
      ,
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of immune-related adverse events with nivolumab efficacy in non-small cell lung cancer.
      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Owen D.H.
      • Wei L.
      • Bertino E.M.
      • et al.
      Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer.
      ]. The median OS was not reached in the Haratani et al. study [
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung CancerImmune-Related Adverse Events and Nivolumab Efficacy in NSCLCImmune-Related Adverse Events and Nivolumab Efficacy in NSCLC.
      ]. The weighted average OS in irAE+ patients with any type and grade of toxicity was 19.07 months (95% CI 14.3 to 23.8) versus 7.45 months (95% CI 5.34 to 9.56) in the irAE- population. Pooled HR (6 studies, n = 1085) was 0.40 (CI 0.33–0.48, p < 0.00001, I2 = 0%) (see Fig. 1d) [

      Berner 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. 2020;5(7):1043–1047. doi: 10.1001/jamaoncol.2019.0402.

      ,
      • Peiro I.
      • Palmero R.
      • Iglesias P.
      • et al.
      Thyroid dysfunction induced by nivolumab: searching for disease patterns and outcomes.
      ,

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ,
      • Ricciuti 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: long-term outcomes from a multi-institutional analysis.
      ,
      • Cortellini A.
      • Chiari R.
      • Ricciuti B.
      • et al.
      Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients.
      ,
      • Kim K.H.
      • Hur J.Y.
      • Cho J.
      • et al.
      Immune-related adverse events are clustered into distinct subtypes by T-cell profiling before and early after anti-PD-1 treatment.
      ].
      Renal cell carcinoma
      A retrospective study tested body mass index (BMI), irAEs and gene expressions as potential biomarkers associated with resistance and outcomes in RCC [

      Luke BWLPLRBMCRFLFSGASPIDSMVAVB and JJ. BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma. J Transl Med. 2019.

      ]. In 90 patients treated with either pembrolizumab, nivolumab or atezolizumab, 26.7% (24 patients) developed irAEs. Nineteen out of 24 patients that developed an irAE did not have primary resistance, which was defined as clinical or radiographic progression on first CT after treatment initiation. Median PFS was 20.52 months versus 10.13 months in irAE+ versus irAE- patients (HR 0.42, 95% CI 0.17–0.99, p = 0.04) that did not have primary resistance to treatment. However, no difference in median OS was noted (28.73 versus. 30.67 months in irAE+ versus. irAE− patients, respectively (HR 0.80, 95% CI 0.20–3.19, p = 0.75).
      Topolian et al. provided subgroup data on patients with metastatic RCC [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ]. Thirty-four patients were treated with nivolumab and 85.3% developed any grade irAEs, while 17.6% developed grade 3 or higher toxicity. ORR was 34.5% versus 0%, respectively, and OS was 31 months versus 4.5 months in irAE+ versus irAE− patients.
      Elias et al. studied 90 metastatic RCC patients treated with various ICIs [
      • Elias R.
      • Yan F.
      • Singla N.
      • et al.
      Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients.
      ]. Median OS was 35.9 months versus 26.5 months in irAE + versus irAE- patients. HR was 0.376 (95% CI 0.179–0.792; p = 0.010).
      Ishihara et al. reported an improved PFS in RCC patients treated with nivolumab with any grade irAE (13.1 months versus 4.87 months, HR 0.25, 95% CI 0.11–0.56) [
      • Ishihara H.
      • Takagi T.
      • Kondo T.
      • et al.
      Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab.
      ]. OS was also improved in irAE+ patients but in only those with less than grade 3 toxicity (grade < 3 versus irAE−: p = 0.0124; grade ≥ 3 versus irAE−: p = 0.136). OS was not reached in the any-grade irAE+ group versus 26 months in the irAE- group (p = 0.0072). ORR was 60.9% versus 12.5% in irAE+ versus irAE− patients, respectively. PR and CR were seen in 11/23 (47.8%) and 3/23 (13.0%) patients in the irAE+ group versus 3/24 (12.5%) and 0/23 (0%) in the irAE- group. PD was seen in 2/23 (8.70%) in the irAE+ group versus 9/24 (37.5%) in the irAE- group. SD was seen in 7/23 (30.4%) versus 12/24 (50%) of patients.
      Urothelial cancer
      Shabto et al. reported ORR of 33.0% versus 8% in metastatic urothelial carcinoma patients who developed irAEs while on treatment with either pembrolizumab or nivolumab [
      • Shabto J.M.
      • Martini D.J.
      • Liu Y.
      • et al.
      Association between immune-related adverse events (irAEs) and clinical outcomes (CO) in advanced urothelial cancer patients (pts) treated with immunotherapy (IO).
      ]. 13.4% of patients developed any grade irAE. At a median follow-up of 15 months, 100% of irAE+ patients were alive, compared to 38% irAE− patients.
      Head and neck cancers
      Foster et al. reported an ORR of 30.6% versus 12.3% (p = 0.02) in metastatic head and neck cancer patients (n = 114) with or without irAEs on treatment with either pembrolizumab or nivolumab [
      • Foster C.C.
      • Kochanny S.
      • Khattri A.
      • et al.
      Association of immune-related adverse events (irAEs) with improved response, progression-free survival, and overall survival for patients with metastatic head and neck cancer receiving anti-PD-1 therapy.
      ]. 42.9% of patients developed any grade irAEs, while 10% developed a grade 3 or higher toxicity. Median OS was 12.5 months versus 6.8 months (p = 0.007) in irAE+ versus irAE− patients. Median PFS was 6.9 months versus 2.1 months (p = 0.0004), respectively.
      Gastrointestinal cancers
      A retrospective review by Das et al. included patients (n = 61) with microsatellite instability-high (MSI-H) colorectal cancer (CRC, n = 27), hepatocellular carcinoma (HCC, n = 28) and gastric/gastroesophageal-junctional cancer (GA/GEJ, n = 6) [
      • Das S.
      • Ciombor K.K.
      • Haraldsdottir S.
      • et al.
      Immune checkpoint inhibitors (ICIs) in gastrointestinal (GI) cancer: immune-related adverse events (IRAEs) and efficacy.
      ]. 39.3% of patients experienced irAEs. The median PFS was 32.4 months (95% CI, 32.4-NR) in patients that exhibited irAEs compared to 4.8 months in irAE- patients (95% CI, 2.9–8.7, p = 0.0001). Median OS was 32.4 months (95% CI 32.4-NR) in irAE + patients versus 8.5 months in irAE- patients (95% CI 6-NR, p = 0.0036).
      Combined disease site studies
      Seven studies included here looked at multiple disease sites [
      • Judd 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.
      ,
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Nobashi T.
      • Baratto L.
      • Reddy S.A.
      • et al.
      Predicting response to immunotherapy by evaluating tumors, lymphoid cell-rich organs, and immune-related adverse events using FDG-PET/CT.
      ,
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ,
      • Fujii T.
      • Colen R.R.
      • Bilen M.A.
      • et al.
      Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.
      ,
      • Shafqat 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.
      ,
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      ]. All were retrospective in design. The sample sizes ranged from 40 to 524 subjects. Of these studies, the Topalian et al. study provided outcome data for individual disease sites, and this disease site-specific data was added to the respective sections in our results [
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ] (See Table 3).
      Table 3Combined studies.
      StudyDisease Sitesn=IO DrugirAE (%, any grade)OS in irAE+

      (months)
      OS in irAE- (months)PFS in irAE+ (months)PFS in irAE- (months)ORR in irAE+ (%)ORR in irAE- (%)Comments
      Judd et al
      • Judd 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.
      HNSCC

      UC

      NSCLC

      RCC
      160Nivolumab

      Ipilimumab
      40%52%14%
      Kostine et al
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      Melanoma

      NSCLC

      RCC

      HNSCC

      GI/HCC

      Blood Ca

      UC

      Merkel

      Glioblastoma
      524Nivolumab

      Pembrolizumab

      Ipilimumab

      Atezolizumab

      Avelumab

      Durvalumab

      Tremelimuab

      MSB0011359C
      6.60%85.7%35.3%Assessed rheumatologic toxicities only
      Min-Lee et al
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      Lung

      Cutaneous

      HNSCC

      GI

      GU

      Reproductive

      Hematologic
      114Nivolumab

      Pembrolizumab

      Atezolizumab
      17.50%65%17%Assessed dermatitis only
      Fujii et al
      • Fujii T.
      • Colen R.R.
      • Bilen M.A.
      • et al.
      Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.
      NSCLC

      RCC

      CRC

      Gynecologic

      Sarcoma/GIST

      Melanoma

      Breast

      Pancreatic

      Others
      290Pembrolizumab

      Nivolumab

      Ipilimumab

      Ipi/Nivo combo
      34%1587.52.525%6%Compared outcome data in G3/4 versus G1/2 patients
      Shafqat et al
      • Shafqat 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.
      NSCLC

      Melanoma

      RCC

      UC

      HNSCC

      Other
      157Nivolumab

      Pembrolizumab

      Atezolizumab
      28.724.44.2
      Table 4. Studies looking at irAE and efficacy in multiple disease sites treated with various CPI therapies. irAE = Immune-Related Adverse Event. OS = Overall Survival. PFS = Progression Free Survival. ORR = Objective Response Rate. NSCLC = Non-small cell lung cancer. GU = genitourinary. HNSCC = Head & Neck Squamous Cell Cancer. UC = Urothelial Cancer. RCC = Renal Cell Cancer. CRC = Colorectal Cancer. “-“ denotes data not reported in original publication.
      Objective response rate
      Three studies provided ORR [
      • Judd 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.
      ,
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ,
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      ]. All were retrospective in design with sample sizes between 114 and 524 patients. Only dermatitis was assessed in the Min-Lee study, while rheumatologic adverse events were studied in the Kostine et al. retrospective review [
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ,
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      ]. Taking this into consideration, the weighted average ORR in irAE+ patients was 75.99% compared to 28.41% in irAE− patients.
      Progression-free survival
      The Shafqat et al. retrospective study was the only other study to provide PFS data outside of Fujii et al.’s study [
      • Fujii T.
      • Colen R.R.
      • Bilen M.A.
      • et al.
      Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.
      ,
      • Shafqat 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.
      ]. Patients with NSCLC (n = 49), melanoma (n = 43), RCC (n = 30), urothelial (n = 4), head and neck (n = 19) and other (n = 12) cancers were included. Various ICIs were used. Out of 157 patients, 45 (28.7%) developed any grade irAEs. PFS was 24.4 months in the irAE+ group versus 4.2% in the irAE− (HR 0.339, 95% CI 0.187–0.617, p < 0.001).
      Overall survival
      The Fujii et al. retrospective analysis was the only study to provide OS data, in addition to PFS and ORR [
      • Fujii T.
      • Colen R.R.
      • Bilen M.A.
      • et al.
      Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.
      ]. 290 patients were included NSCLC n=(35), RCC (n = 33), CRC (n = 31), Sarcoma/GIST (n = 28), gynecologic (n = 26), melanoma (n = 22), Breast (n = 16), head and neck (n = 16), pancreatic (n = 15), gastric/GE junction (n = 10), HCC/CCC (n = 6) and other rare tumors (n = 52). Any grade irAE was reported in 98 patients (34%). Fifteen patients (5.2%) developed grade 3 or 4 toxicity. In patients with grade 3 or higher toxicity, OS was 15 months versus 8 months (HR: 0.60, 95% CI 0.30–1.20, p = 0.10).
      Grade of toxicity
      A retrospective study of 290 patients with advanced cancers treated with ICIs showed that patients with Grade 3 or higher toxicity had higher response rates (25 versus 6%; p = 0.039) and longer median time to progression (30 weeks versus 10 weeks; p = 0.0040) compared to patients with less than grade 3 toxicity [
      • Fujii T.
      • Colen R.R.
      • Bilen M.A.
      • et al.
      Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.
      ]. A trend towards improved median OS was also seen at 15 months compared to 8 months (HR = 0.6, 95% CI 0.3–1.2, p = 0.10) in the respective populations.
      A small retrospective study by Farolfi et al. compared time to progression (TTP) and OS outcomes in patients with grade 1 or 2 versus grade 3 or 4 toxicity after treatment with ipilimumab for advanced melanoma [
      • Farolfi A.
      • Ridolfi L.
      • Guidoboni M.
      • et al.
      Ipilimumab in advanced melanoma: reports of long-lasting responses.
      ]. Patients with grade 3 or 4 toxicity had significant improvement in TTP (9 months versus 3 months, p = 0.02) and OS (31 months versus 4 months, p = 0.010). 8 of 30 patients developed grade 3 or 4 toxicity while 14 developed grade 1 or 2 toxicity.
      Judd et al. studied the use of pembrolizumab or nivolumab in non-melanoma advanced malignancies, including NSCLC (n = 81), RCC (n = 43), HNSCC (n = 23), UC (n = 20) and other disease sites (n = 3) [
      • Judd 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.
      ]. Out of 160 patients, 64 (40%) developed any grade irAEs. ORR was 14% versus 32% versus 20% in irAE-, grade 1 or 2 irAE and grade 3 or 4 irAE, respectively (p = 0.09). Although it was thought that as less patients had grade 3 or higher toxicity, it did not have adequate power to determine any correlation. Secondly, as patients with higher grade toxicities are sicker and in potentially life-threatening conditions, accurate assessment of tumor response was thought to be more difficult.
      Type of toxicity
      Gastrointestinal
      A large retrospective study by Abu-Sbeih et al. in metastatic melanoma patients treated with ICIs assess rates of GI-irAEs and its correlation with outcomes [
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ]. Out of 346 patients, 173 had either diarrhea or colitis (50%). 79 patients had grade 3 or 4 diarrhea while 44 had grade 3 or 4 colitis. Any grade GI-irAEs were associated with improved OS (HR 0.53, 95% CI 0.36–0.78, p < 0.01). The use of immunosuppression to treat the GI-irAE did not affect OS. PFS was also longer in patients with GI-irAE (HR 0.56, p < 0.01). This correlation in improved OS and PFS was seen regardless of whether patients received anti-CTLA4-based therapy or anti-PD-1/L1 monotherapy. Patients that developed pancreatic toxicity had worse outcomes (n = 28 (8.1%), HR 2.17, P < 0.01). No correlation with improved outcomes was seen with patients developing hepatotoxicity (n = 65 (18.8%), HR for OS = 0.94, p = 0.78, HR for PFS = 1.04, p = 0.85). It also did not reveal any correlation with non-GI irAE and improved outcomes (skin toxicity showed a trend towards improved PFS and OS but was not statistically significant).
      Rheumatologic
      Kostine et al. specifically looked at rheumatologic side effects in all disease sites and all ICI drugs and its impact on ORR [
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      ]. Out of 524 patients, 6.6% developed either inflammatory arthritis (resembling rheumatoid arthritis (n = 7), polymyalgia rheumatica (n = 11) or psoriatic arthritis (n = 2) or non-inflammatory arthritis (n = 15). Patients with rheumatologic toxicity had a significantly higher ORR than patients without rheumatologic toxicity (85.7% versus 35.3%; P < 0.0001). Subgroup analysis confirmed that ORR was improved regardless of tumor site.
      Skin
      Another retrospective study that was not included in our review (due to only HR reported) assessed types of toxicity and association with OS [
      • Freeman-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.
      ]. Interestingly, only rash (HR, 0.423; 95% CI, 0.243 to 0.735; p = 0.001) and vitiligo (HR, 0.184; 95% CI, 0.036 to 0.94; p = 0.012) were shown to have a significant relationship to OS. Diarrhea or colitis (HR = 0.616, p = 0.106), hyperthyroidism (HR = 2.439, p = 0.17), hypothyroidism (HR = 0.37, p = 0.127), mucositis (HR = 0.09, p = 0.093), myalgias (HR = 0.313, p = 0.418) and pneumonitis (HR 0.346, p = 0.459) did not show a statistically significant association with improved OS. This data correlates well with six studies included in our review that looked at vitiligo and other skin toxicities as they showed a relationship between the onset of these cutaneous side effects and improved outcomes [
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ,
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Hasan Ali O.
      • Diem S.
      • Markert E.
      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      ,
      • Hua C.
      • Boussemart L.
      • Mateus C.
      • et al.
      Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumabvitiligo and melanoma responsevitiligo and melanoma response.
      ,
      • Wen X.
      • Ding Y.
      • Li J.
      • et al.
      The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.
      ,
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non–Small-Cell Lung CancerImmune-Related Adverse Events and Nivolumab Efficacy in NSCLCImmune-Related Adverse Events and Nivolumab Efficacy in NSCLC.
      ]. All except two of these studies only looked at patients with advanced melanoma. In the Hasan-Ali et al. retrospective analysis, 40 NSCLC patients treated with nivolumab also showed similar ORR in patients who developed any skin toxicity (42%) versus those without (7%) [
      • Hasan Ali O.
      • Diem S.
      • Markert E.
      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      ]
      Higher mortality was shown in patients that developed skin toxicity after treatment with ipilimumab and nivolumab for advanced melanoma in a retrospective study by Fujisawa et al. [
      • Fujisawa Y.
      • Yoshino K.
      • Otsuka A.
      • et al.
      Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients.
      ]. A multivariate analysis showed a HR of 2.78 (p = 0.048) for overall survival. This could potentially be explained by the type of skin toxicity seen as no cases of vitiligo were seen, which has previously been well correlated with improved outcomes [
      • Nakamura Y.
      • Tanaka R.
      • Asami Y.
      • et al.
      Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study.
      ,
      • Hua C.
      • Boussemart L.
      • Mateus C.
      • et al.
      Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumabvitiligo and melanoma responsevitiligo and melanoma response.
      ,
      • Wen X.
      • Ding Y.
      • Li J.
      • et al.
      The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.
      ]. The skin toxicities that were seen included skin rash, pruritus and erythroderma, all of which were associated with worse outcomes. This is still contrary to the outcomes seen in the other 4 studies, which also had patients develop any type of skin toxicity [
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ,
      • Hasan Ali O.
      • Diem S.
      • Markert E.
      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      ,
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of immune-related adverse events with nivolumab efficacy in non-small cell lung cancer.
      ,
      • Akano Y.
      • Kuribayashi K.
      • Funaguchi N.
      • et al.
      Analysis of pleiotropic effects of nivolumab in pretreated advanced or recurrent non-small cell lung cancer cases.
      ]. Akano et al.’s retrospective study of advanced NSCLC patients treated with nivolumab specifically showed skin rash to be associated with significantly longer PFS (p = 0.0016) and OS (p = 0.0036) compared to patients that do not develop a rash [
      • Akano Y.
      • Kuribayashi K.
      • Funaguchi N.
      • et al.
      Analysis of pleiotropic effects of nivolumab in pretreated advanced or recurrent non-small cell lung cancer cases.
      ].
      Endocrine
      Osorio et al. published a small retrospective study with 48 NSCLC patients treated with pembrolizumab who were assessed for immune-related thyroid toxicity [

      Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. 2017;(December 2016):583-589. doi:10.1093/annonc/mdw640.

      ]. Ten patients (21%) developed thyroid dysfunction and had an OS of 40 months (HR, 0.29; 95% CI 0.09–0.94; P = 0.04) compared to 14 months in patients who did not develop thyroid dysfunction (data extrapolation from charts).
      The aforementioned study by Fujisawa et al. showed endocrine toxicity (thyroid and pituitary) to be significantly associated with improved OS (HR 0.22, p = 0.015) [
      • Fujisawa Y.
      • Yoshino K.
      • Otsuka A.
      • et al.
      Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients.
      ]. Lung, GI, liver and pyrexia were not significantly associated with survival.
      The colitis focused study mentioned above did not improve OS in patients that suffered endocrine-related toxicity (n = 36 (10.4%), HR 0.58, p < 0.01) [
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ].
      Campredon et al. assessed thyroid toxicity in advanced NSCLC patients treated with nivolumab [
      • Campredon P.
      • Mouly C.
      • Lusque A.
      • et al.
      Incidence of thyroid dysfunctions during treatment with nivolumab for non-small cell lung cancer: retrospective study of 105 patients.
      ]. Fifteen out of 105 patients (14.3%) experienced thyroid dysfunction. Thirteen developed thyrotoxicosis which was transient in 5 patients. Two developed isolated hypothyroidism. A trend towards improved OS was seen at 9 months (HR 0.16, p = 0.07). Median PFS was not statistically different (HR 0.78, p = 0.540).
      Pulmonary
      A retrospective multicenter cohort study by Fujimoto et al. in patients with advanced NSCLC treated with nivolumab showed an all-grade pneumonitis rate of 10% (61 out of 613 patients) [
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study.
      ]. Thirty-one patients had grade 3 or higher toxicity with 3 patients dying as a consequence. Patients that developed pneumonitis had higher response rates (37% versus 18%) and longer PFS (5.8 months versus 2.1 months, p = 0.002) compared to patients without pneumonitis. There was; however, no significant difference seen on 2-months landmark analysis in PFS between the two groups (7.9 months versus 5.9 months, p = 0.872).
      Pyrexia
      Teraoke et al. showed pyrexia to be associated with a trend towards longer PFS (6.4 months versus 2.1 months, p = 0.26) in advanced NSCLC treated with nivolumab [
      • Teraoka 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.
      ]. A weak trend towards improved ORR was also seen (65% versus 35%, p = 0.29).
      PD-L1 expression level
      The association between PD-L1 expression and irAEs could not be assessed in our review as very few studies included PD-L1 data [
      • Teraoka 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.
      ,
      • Sato K.
      • Akamatsu H.
      • Murakami E.
      • et al.
      Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.
      ]. Teraoke et al. assessed PD-L1 levels and association with irAE [
      • Teraoka 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.
      ]. No significant difference was noted in rates of irAE and PD-L1 expression level. A small retrospective study by Sato el. did not show a statistically significant difference in rates of irAE in patients with PD-L1 expression > 50%, 1–49% and 0% [
      • Sato K.
      • Akamatsu H.
      • Murakami E.
      • et al.
      Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.
      ].
      Type of checkpoint inhibitor therapy
      Abu-Sbeih et al. compared the rates of GI-irAEs in metastatic melanoma patients receiving either anti-CTLA-4 antibodies or anti-PD-1/L1 antibodies [
      • Abu-Sbeih H.
      • Ali F.S.
      • Qiao W.
      • et al.
      Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.
      ]. Out of 848 patients that received CTLA-4-based therapy, 132 (15.6%) developed GI-irAE compared to 41 (3.6%) out of 1135 patients that received PD-1/L1 inhibitors. HR for OS in patients receiving anti-CTLA-4-based therapy and who developed GI-irAEs was 0.53 (p < 0.01) while HR for PFS was 0.46 (p < 0.01). Likewise, patients who received anti-PD1/L1 monotherapy and developed any grade diarrhea or colitis had improved OS (HR 0.27, p < 0.01) and PFS (HR 0.51, p = 0.03). This study showed outcomes based on irAE are similar for either CTLA-4-based treatment or PD1/L-1-based therapy.

      Discussion

      Identifying reliable biomarkers of response to ICIs has been the focus of intensive research since the initiation of the use of ICIs in treating malignancies [
      • Maleki Vareki S.
      • Garrigos C.
      • Duran I.
      Biomarkers of response to PD-1/PD-L1 inhibition.
      ]. Early clinical observations in the era of novel immunotherapeutics, hinted at a potential link between developing irAEs and increased response rates and consequently improved survival in those patients. Many retrospective studies have been reviewed in our study assessing the relationship between irAEs and the efficacy of ICIs. Most of the data reported in our review pertains to the use of ICIs in advanced/metastatic melanoma and NSCLC, the two disease sites that earned the earliest approval for using ICIs. There are however studies looking at other disease sites including RCC, Urothelial cancer, Head and Neck Squamous cell cancer and others [
      • Judd 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.
      ,
      • Shafqat 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.
      ,
      • Kostine M.
      • Rouxel L.
      • Barnetche T.
      • et al.
      Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.
      ,

      Luke BWLPLRBMCRFLFSGASPIDSMVAVB and JJ. BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma. J Transl Med. 2019.

      ,
      • Elias R.
      • Yan F.
      • Singla N.
      • et al.
      Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients.
      ,
      • Shabto J.M.
      • Martini D.J.
      • Liu Y.
      • et al.
      Association between immune-related adverse events (irAEs) and clinical outcomes (CO) in advanced urothelial cancer patients (pts) treated with immunotherapy (IO).
      ,
      • Foster C.C.
      • Kochanny S.
      • Khattri A.
      • et al.
      Association of immune-related adverse events (irAEs) with improved response, progression-free survival, and overall survival for patients with metastatic head and neck cancer receiving anti-PD-1 therapy.
      ,
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Nobashi T.
      • Baratto L.
      • Reddy S.A.
      • et al.
      Predicting response to immunotherapy by evaluating tumors, lymphoid cell-rich organs, and immune-related adverse events using FDG-PET/CT.
      ,
      • Min Lee C.K.
      • Li S.
      • Tran D.C.
      • et al.
      Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study.
      ]. In the 51 studies that met the inclusion criteria, the retrospective study by Ascierto et al. was the only study that did not show a correlation between irAEs and treatment efficacy [
      • Ascierto P.A.
      • Simeone E.
      • Sileni V.C.
      • et al.
      Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort.
      ]. Notably, this was the largest study (n = 833) included in this review. The remainder of the studies showed a significant improvement in PFS, OS and ORRs in patients who developed irAEs versus those that did not. This was irrespective of the disease site and the type of ICI used. In patients with grade 3 or higher toxicity, the lack of statistical significance seen in OS data could be due to increased mortality related to higher toxicity.
      Tissue cross reactivity as an explanation for the relationship between irAEs and ICI efficacy
      The similarities between antigens presented on tumor cells and normal healthy tissues is one of the leading hypotheses for the development of irAEs in patients treated with ICIs [
      • Hasan Ali O.
      • Diem S.
      • Markert E.
      • et al.
      Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
      ]. Antigen sharing, or cross reactivity, leads to a T-cell-mediated response to not just tumor cells but to healthy cells as well. An immune system that has been activated would potentially target these non-tumor sites as well. Development of vitiligo in metastatic melanoma patients treated with ICIs is a clinical manifestation of this phenomenon. Mechanistically, increased melanocyte-specific CD8+ T-cell activity against shared antigens between melanocytes and melanoma cells causes vitiligo [
      • Fujisawa Y.
      • Yoshino K.
      • Otsuka A.
      • et al.
      Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients.
      ].
      Clinical implications
      The association noted between the development of irAEs and improved disease outcomes is an interesting dilemma that oncologists face. Tolerability of ICIs with no or minimal adverse events is potentially indicative of lack of efficacy. In contrast, the development of moderate or severe irAEs can serve as a surrogate marker of response to ICIs. This association makes it critical to monitor these side effects, which are treated effectively with appropriate use of steroids and other immunosuppressive agents. Close follow-up and low thresholds for investigative work-ups are essential in making sure that a patient that does develop irAEs is promptly treated, such that any treatment interruption can be resumed in a timely manner. Earlier reporting of symptoms would identify more irAEs with lower severity (grade 1 or 2) which could be treated with supportive measures without having to withhold ICI therapy [
      • Naing Aung
      Being realistic and optimistic in curing cancer.
      ]. Diagnosing these irAEs earlier may also prevent progression to higher levels of toxicity which may subsequently prevent a patient from safely resuming treatment. Thus, patient education on symptoms to monitor for and report is also crucial. More research is needed in discovering other predictive biomarkers that may allow us to determine who may develop adverse events and potentially derive greater benefit from ICIs.
      Limitations
      Our study has several limitations. First, almost all of the data collected was from retrospective studies and not from prospective clinical trials, leading to information bias. Secondly, study and population heterogeneity were extensive and as such, the weighted average outcomes reported should be interpreted accordingly. Many studies did not provided HRs with 95% CI that could be used to perform a meta-analysis for a pooled value for OS and PFS. Third, our study is heavily skewed towards patients treated for advanced or metastatic melanoma and NSCLC. This is to be expected as these disease sites had earlier FDA approval for the use of ICIs than some of the less studied disease sites. Lastly, a vast majority of the patients were also treated with either nivolumab (anti-PD-1) or pembrolizumab (anti-PD-1), with very few patients receiving anti-CTLA-4 or anti-PD-L1 antibodies, thus it would be difficult to generalize our study’s findings to patients that have received ICIs other than anti-PD-1 inhibitors.

      Conclusion

      There appears to be an intimate association between autoimmunity with the irAEs and anti-tumor effect of checkpoint inhibitors. As the use of ICIs continues to expand, it will become more crucial that early detection and management of these irAEs becomes paramount in order to maximize duration of treatment while minimizing toxicities for patients. Prospective studies are needed to provide validation of novel biomarkers to be used and integrated into clinical practice. The development of a pan-omics strategy, taking into account the immune-related toxicities, would allow for a more personalized analysis and help with clinical decision-making.

      Ethics approval

      No ethics approval required

      Consent for publication

      Provided.

      Availability of data and Material

      Appendices and Supplementary Material will be provided.

      Funding

      This work was supported by two grants from the London Regional Cancer Program’s Catalyst Grant Program, Keith Smitt Translational Research Grants awarded to SMV and RF.

      Author contributions

      Design / Conception: S.H., S.M.V, R.F, RG.B,
      Data collection and analysis: S.H., R.C., S.M.V, R.F.
      Manuscript writing and review: all authors

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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