
==== Front
Jpn J Clin Oncol
Jpn J Clin Oncol
jjco
Japanese Journal of Clinical Oncology
0368-2811
1465-3621
Oxford University Press

38769817
10.1093/jjco/hyae067
hyae067
Review Article (Invited)
AcademicSubjects/MED00300
The correlation between immune-related adverse events and efficacy of immune checkpoint inhibitors
https://orcid.org/0000-0002-1345-5608
Fukushima Taito Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan

https://orcid.org/0000-0002-2535-6586
Kobayashi Satoshi Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan

Ueno Makoto Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan

For reprints and all correspondence: Taito Fukushima, Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa 241-8515, Japan. E-mail: taito1986e@gmail.com
9 2024
20 5 2024
20 5 2024
54 9 949958
23 11 2023
30 4 2024
06 5 2024
© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Immune checkpoint inhibitors have revolutionized cancer treatment by targeting the cytotoxic T lymphocyte antigen-4 and programmed death-1/ligand-1. Although immune checkpoint inhibitors show promising therapeutic efficacy, they often cause immune-related adverse events. Immune-related adverse events differ from the side effects of conventional chemotherapy and require vigilant monitoring. These events predominantly affect organs, such as the colon, liver, lungs, pituitary gland, thyroid and skin, with rare cases affecting the heart, nervous system and other tissues. As immune-related adverse events result from immune activation, indicating the reinvigoration of exhausted immune cells that attack both tumors and normal tissues, it is theoretically possible that immune-related adverse events may signal a better response to immune checkpoint inhibitor therapy. Recent retrospective studies have explored the link between immune-related adverse event development and clinical efficacy; however, the predictive value of immune-related adverse events in the immune checkpoint inhibitor response remains unclear. Additionally, studies have focused on immune-related adverse events, timing of onset and immunosuppressive treatments. This review focuses on pivotal studies of the association between immune-related adverse events and outcomes in patients treated with immune checkpoint inhibitors.

The validity of immune-related adverse events as surrogate markers of the efficacy of immune checkpoint inhibitor treatment remains unclear. This review examines the pivotal studies on immune-related adverse events.

immune checkpoint inhibitors
immune-related adverse events
efficacy
nivolumab
pembrolizumab
atezolizumab
ipilimumab
==== Body
pmcIntroduction

Immune checkpoint inhibitors (ICIs) have ushered in a new era of cancer therapy, significantly reshaping the treatment landscape for patients with advanced malignancies. These agents, including monoclonal antibodies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), have shown remarkable efficacy, particularly in solid tumor treatment. By disrupting the mechanisms that enable malignancies to evade immune surveillance, ICIs reactivate the T cell immune response against cancer, offering a promising approach for patients with advanced or metastatic disease (1,2). However, the immune system activation induced by ICI treatment can lead to immune-mediated inflammation in various organs and tissues, with a particular susceptibility observed in the skin, endocrine system, gastrointestinal tract and lungs (3–5).

Immune-related adverse events (AEs) (irAEs) significantly affect the treatment efficacy. Although many irAEs tend to be mild and resolve spontaneously, they pose potentially life-threatening risks in a few severe cases (6,7). Given that irAEs result from immune activation, a pertinent question arises: can the development of irAEs serve as a predictor of ICI therapy response?

Numerous studies have explored the relationship between irAEs and treatment efficacy, particularly in patients with melanoma and non-small cell lung cancer (NSCLC). Nevertheless, the association between irAEs and ICI efficacy is multifaceted, with critical factors such as irAE type, severity, timing of onset and management potentially influencing treatment outcomes. Moreover, potential confounding factors must be considered when evaluating the association between the occurrence of irAEs and survival. Patients with longer survival times may exhibit a higher incidence of irAEs owing to prolonged therapeutic agent exposure. Consequently, the validity of irAEs as surrogate markers of ICI treatment efficacy remains unclear.

To address these pivotal questions and provide a comprehensive overview of the current state of knowledge, this review focuses on previously published studies that investigated the association between irAEs and treatment efficacy. We searched PubMed for terms relevant to the theme of our study.

Biological mechanisms of irAEs

IrAEs are a spectrum of inflammatory responses against normal tissues triggered by heightened activity of the immune system owing to ICIs. The mechanisms underlying irAEs are complex and involve multiple components of the immune system. The activation of self-reactive T cells is one of the mechanisms that can induce irAEs. This is exemplified by myocarditis cases in which T cell infiltration into the myocardium is observed, suggesting a mechanism of shared antigen recognition between tumors and affected organs (8,9). Vitiligo occurs most commonly in patients with melanoma and is likely related to immune reactivity to melanosomal antigens (10). The expansion of T cell clones in the systemic circulation has also been linked to irAEs (11). Patients with elevated pretreatment levels of central memory T cells originating from CD4+ or CD8+ lymphocytes are predisposed to severe irAEs (12). Furthermore, the activation of B cells and the increased production of autoantibodies contribute to the occurrence of irAEs. Several studies have found an association between the presence of autoantibodies and the development of irAEs (13,14). Direct toxicity in normal tissues expressing checkpoint proteins is another facet of ICIs. Studies on hypophysitis have revealed that CTLA-4 expression in normal pituitary cells may enhance the toxicity associated with anti-CTLA-4 therapy (15,16). Evidence also indicates that inflammatory cytokines and microbiomes do play a role in the development of irAEs. For example, elevated baseline levels of IL-17 have been significantly correlated with later development of severe colitis (17). In a prospective study on advanced melanoma, patients with severe irAEs had a higher pre-treatment fecal abundance of the subclass Bacteroides intestinalis than those without irAEs (18). Although the mechanisms underlying irAEs have not been fully elucidated, understanding them and identifying predictive biomarkers for irAEs remain critical for optimizing patient outcomes.

Relationship between irAEs and treatment efficacy for different cancer types

NSCLC

Numerous studies have explored the association between irAEs and treatment efficacy in patients with NSCLC. Table 1 provides an overview of these studies (19–27). Socinski et al. analyzed pooled data from three Phase 3 clinical trials (IMpower130 (28), IMpower132 (29) and IMpower150 (30)) to evaluate the relationship between irAE occurrence and treatment outcomes with atezolizumab (27). Among the 1577 patients in the atezolizumab-containing arm, 753 (48%) developed irAEs, with 37% classified as Grades 1–2 and 11% as Grades 3–5. The most common irAEs were skin rash (28%), liver dysfunction (15%) and thyroid dysfunction (12%). Patients with irAEs exhibited longer overall survival (OS) compared with those without irAEs in the atezolizumab-containing arm (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.65–0.87). Similar trends were observed in the landmark analyses at 1, 3, 6 and 12 months. Notably, among all landmark subgroups, patients with Grades 1–2 irAEs demonstrated improved OS compared with those with grade 3–4 irAEs or those without irAEs. The HRs (95% CI) were 0.78 (0.65–0.94) at 1 month, 0.74 (0.63–0.87) at 3 months, 0.77 (0.65–0.90) at 6 months and 0.72 (0.59–0.89) at 12 months. In the Impower130, Impower132 and Impower150 trials, atezolizumab was administered concomitantly with chemotherapy. Chemotherapy can induce adverse effects, making the diagnosis of irAEs challenging. Nevertheless, an association between irAEs and therapeutic efficacy has been suggested in combination therapies. Grangeon et al. (23) reported 270 patients with NSCLC who were treated with ICI. Most patients (89.3%) received anti-PD-1 antibodies, whereas the remaining patients (10.7%) received anti-PD-L1 antibodies. Among these patients, 44% experienced irAEs, with endocrine (20%), skin (7%) and gastrointestinal (7%) systems being the most commonly affected sites. Patients developing irAEs exhibited improved objective response rates (ORRs) (odds ratio [OR], 4.9; 95% CI, 2.18–11.05; P < 0.0001), progression-free survival (PFS) (HR, 0.42; 95% CI, 0.32–0.78; P < 0.001) and OS (HR, 0.29; 95% CI, 0.18–0.46; P < 0.001) compared with those without irAEs. Further analysis by irAE type revealed that patients experiencing thyroid dysfunction had statistically significant improvements in OS (HR, 0.46; 95% CI, 0.25–0.86; P = 0.01) and PFS (HR, 0.58; 95% CI, 0.39–0.85; P = 0.005) compared with patients who did not experience thyroid dysfunction. In a retrospective analysis, Ricciuti et al. evaluated the outcomes of 195 patients with NSCLC treated with nivolumab (21). Among these patients, 43.6% developed irAEs, with hyperthyroidism or hypothyroidism being the most common (20%). Multivariable analysis demonstrated that the development of irAEs was positively associated with longer PFS (HR, 0.48; 95% CI, 0.34–0.67; P < 0.0001). Furthermore, irAEs were significantly associated with improved ORR, PFS and OS in 12- and 6-week landmark analyses. Shankar et al. investigated multisystem irAEs in a cohort of 623 patients with lung cancer (25). Of these, 148 patients (24%) developed single irAEs, whereas 58 patients (9.3%) experienced multisystem irAEs. Among the combinations of multisystem irAEs observed, pneumonia thyroiditis (n = 7, 14%), hepatitis thyroiditis (n = 5, 10%) and dermatitis pneumonitis (n = 5, 10%) were the most prevalent. Multisystem irAEs were significantly associated with prolonged OS and PFS compared with both single irAEs and patients without irAEs.

Table 1 Relationship between irAEs and treatment efficacy

Author	Tumor type	ICIs	OS	PFS	Ref	
Factor	HR (95% CI)	P value	Factor	HR (95% CI)	P value	
Teraoka	NSCLC	Nivolumab				Early irAEs		0.01	19	
Haratani	NSCLC	Nivolumab	IrAEs	0.282 (0.101–0.667)	0.003	IrAEs	0.525 (0.287–0.937)	0.03	20	
Ricciuti	NSCLC	Nivolumab	IrAEs	0.38 (0.26–0.56)	<0.0001	IrAEs	0.48 (0.34–0.67)	< 0.0001	21	
Owen	NSCLC	Nivolumab	IrAEs	2.75 (1.54–4.92)	<0.001	IrAEs			22	
Grangeon	NSCLC	Nivolumab, pembrolizumab or atezolizumab	IrAEs	0.29 (0.18–0.46)	<0.001	IrAEs	1.42 (0.32–0.57)	< 0.001	23	
Cortellini	NSCLC	Nivolumab or pembrolizumab	IrAEs	0.53 (0.41–0.69)	<0.001	IrAEs	0.57 (0.45–0.72)	< 0.001	24	
Shankar	NSCLC	Anti-PD-1
or PD-L1 Ab	One irAE
Multiple irAEs	0.86 (0.66–1.12)
0.57 (0.38–0.85)	0.26
0.005	One irAE
Multiple irAEs	0.68 (0.55–0.85)
0.39 (0.28–0.55)	0.001
< 0.001	25	
Hsiehchen	NSCLC	Anti-PD-1
or PD-L1 Ab	Late irAEs	0.90 (0.83–0.98)	0.02	Late irAEs	0.93 (0.87–0.99)	0.03	26	
Socinski	NSCLC	Atezolizumab	IrAEs
Grade 1/2 irAEs	0.69 (0.60–0.78)
 a					27	
Downey	Melanoma	Ipilimumab	IrAEs		< 0.0001				31	
Horvat	Melanoma	Ipilimumab	IrAEs		0.60	b			32	
Weber	Melanoma	Nivolumab				c			33	
Freeman	Melanoma	Nivolumab	IrAEs
Skin rash
Vitiligo	0.423 (0.243–0.735)
0.184 (0.036–0.94)	< 0.001
0.001
0.012				34	
Indini	Melanoma	Nivolumab or pembrolizumab	IrAEs	0.39 (0.18–0.81)	0.007	IrAEs	0.47 (0.26–0.86)	0.016	35	
Bisschop	Melanoma	Pembrolizumab	High grade irAEs	0.51 (0.28–0.97)	< 0.001	High grade irAEs	0.54 (0.30–0.98)	< 0.001	36	
Eggermont	Melanoma	Pembrolizumab	d						37	
Xu	HCC	Anti-PD-1 Ab	IrAEs	6.4 (1.404–29.275)	0.017				38	
Lu	HCC	Anti-PD-1 Ab				IrAEs
Skin rash	0.22 (0.09–0.58)	0.002
<0.001	39	
Ng	HCC	Not available	IrAEs
Grade ≥ 3 irAEs	0.49 (0.32, 0.74)
0.40 (0.21, 0.76)	<0.001
0.005	IrAEs
Grade ≥ 3 irAEs	0.48 (0.33, 0.69)
0.57 (0.34, 0.95)	<0.001
0.030	40	
Fukushima	HCC	Atezolizumab	Grade 1/2 irAEs	0.086 (0.012–0.641)	0.017	Grade 1/2 irAEs	0.339 (0.166–0.691)	0.003	41	
Zhou	HCC	Pembrolizumab	Hypothyroidism	0.641 (0.489–0.901)	0.017				42	
Verzoni	RCC	Nivolumab	IrAEs	0.57 (0.35–0.93)	0.02				43	
Ishihara	RCC	Nivolumab	IrAEs		<0.001		0.0072		44	
Washino	RCC	Nivolumab and Ipilimumab	IrAEs
Multiple irAEs	0.328 (0.165–0.648)
0.245 (0.110–0.544)	0.001
<0.001	IrAEs
Multiple irAEs	0.334 (0.151–0.737)
0.267(0.113–0.628)	0.007
0.002	45	
Masuda	GI	Nivolumab	IrAEs	0.11	<0.001	IrAEs	0.17	<0.001	46	
Ando	GI	Nivolumab or Pembrolizumab	IrAEs		0.002	IrAEs		0.01	47	
Das	GI	Nivolumab or Pembrolizumab	IrAEs	0.11 (0.03–0.36)	<0.001	IrAEs	0.13(0.05–0.3)	<0.001	48	
Zhao	GI	Anti-PD-1 Ab	IrAEs	0.57 (0.42–0.77)	<0.001				49	
a Grade 1/2 irAEs was associated with longer OS in landmark subgroups (1, 3, 6 and 12 months).

b No association of TTF (P = 0.86) with irAEs.

c IrAEs were associated with higher ORR (P < 0.001). No association was observed between the PFS and irAEs.

d IrAEs were associated with a longer RFS (HR, 0.61; 95% CI, 0.39–0.95; P = 0.03).

IrAEs, immune-related adverse events; ICI, immune checkpoint inhibitor; OS, overall survival; HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; NSCLC, non-small cell lung cancer; Ab, antibody; HCC, hepatocellular carcinoma; RCC, renal cell carcinoma; GI, gastrointestinal cancer; TTF, time-to-treatment failure; ORR, overall response rate; RFS, recurrence-free survival.

Melanoma

Numerous studies have explored the correlation between irAEs and treatment efficacy in patients with melanomas (31–37). A retrospective analysis conducted by Freeman et al. (34) included 148 patients treated with nivolumab. The incidence of irAEs was 68.2%. Significantly, patients with irAEs of any grade exhibited a marked difference in OS compared with those without irAEs (P < 0.001). Moreover, this study highlighted a significant association between rash, vitiligo and OS in patients with metastatic disease (P = 0.004 and 0.028, respectively). Indini et al. (35) reported that the occurrence of irAEs was linked to prolonged PFS (HR, 0.47; 95% CI, 0.26–0.86; P = 0.016) and OS (HR, 0.39; 95% CI, 0.18–0.81; P = 0.007) in 173 patients treated with anti-PD-1 antibodies (nivolumab or pembrolizumab). Furthermore, among the various irAEs, the presence of vitiligo displayed a trend toward improved OS compared with other irAEs (P = 0.061). Bisschop et al. (36) investigated the relationship between pembrolizumab-related AEs and treatment efficacy in 147 patients treated with pembrolizumab, using prospectively collected data. Their analysis revealed that patients with AEs were more likely to achieve disease control than those without AEs in a multivariate logistic regression analysis (low-grade AEs vs. no AEs: OR = 12.8, P = 0.0002; high-grade AEs vs. no AEs: OR = 38.5, P = 0.0001). Additionally, Cox regression analysis demonstrated a lower risk of death (HR, 0.51; 95% CI, 0.28–0.97) and disease progression (HR, 0.54; 95% CI, 0.30–0.98) over time for patients with high-grade AEs compared with those without AEs. Eggermont et al. (37) reported a secondary analysis of the EORTC18071 Phase 3 clinical trial, which included patients with stage III melanoma treated with ipilimumab or placebo. Cox models with time-varying covariates were used to estimate the association between irAEs and recurrence-free survival (RFS). Among 1019 patients with stage III melanoma, 509 received pembrolizumab, and the pembrolizumab arm had an irAE incidence of 37.4%. Importantly, the occurrence of irAEs was associated with longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39–0.95; P = 0.03). In contrast, Horvat et al. (32) reported different findings, unlike many other studies that demonstrated a favorable correlation between irAEs and efficacy. In a study involving 298 patients treated with ipilimumab, 85% of patients experienced irAEs. No differences in OS (P = 0.60) or time-to-treatment failure (P = 0.86) were detected when patients were stratified by the presence or absence of irAEs of any grade. This study also investigated the impact of steroid treatment, with 35% of the patients requiring steroids; however, no significant difference in OS was observed between the steroid and non-steroid groups. Vitiligo may reflect an immune response induced by the recognition of antigens shared between normal melanocytes and melanoma cells (10); however, the association between other irAEs and treatment efficacy involves multiple factors distinct from vitiligo. Including the studies by Horvat et al., some reports have yielded limited associations with treatment efficacy. Baseline characteristics, severity, timing of irAE onset and effective management can also influence the relationship between irAEs and treatment efficacy.

Hepatocellular carcinoma

Although investigations into the correlation between irAEs and the treatment efficacy of atezolizumab plus bevacizumab are limited to only one study, other reports have predominantly focused on single-agent ICIs (38–42). Kennedy et al. (40) conducted a retrospective analysis of 168 patients with hepatocellular carcinoma (HCC). Single-agent ICIs were administered to 82.7% of the patients, with 17.3% receiving combination therapy. Among the patients, 57.7% developed irAEs, with 53.6% experiencing grade 1/2 and 14.3% experiencing grade 3 or higher irAEs. Multivariate analysis revealed that irAE occurrence was associated with extended PFS (HR, 0.48; 95% CI, 0.33–0.69; P < 0.001) and OS (HR, 0.49; 95% CI, 0.32–0.74; P < 0.001). Additionally, the development of G3/4 irAEs, the occurrence of two or more irAEs and skin disorders were also linked to prolonged PFS and OS. Zhou et al. conducted a retrospective analysis of 190 patients with HCC treated with the single-agent pembrolizumab (42). Among these, 72.6% experienced irAEs. The most frequent AEs were transaminase elevation (18.4%), diarrhea (14.2%), skin disorders (13.2%) and thyroid dysfunction (13.2%). Multivariate analysis showed that thyroid dysfunction was associated with extended time to progression (HR, 0.613; 95% CI, 0.362–0.886; P = 0.018) and OS (HR, 0.641; 95% CI, 0.489–0.901; P = 0.017). A retrospective multicenter study conducted in Japan investigated the correlation between irAEs and treatment efficacy in 150 patients with HCC treated with atezolizumab plus bevacizumab (41). Among these patients, 21.3% developed irAEs, with 15.3% experiencing grade 1/2 and 6.0% experiencing grade 3/4 irAEs. The most common AEs were endocrine (7.3%) and skin (6.0%) disorders. Patients who developed irAEs exhibited improved PFS and OS compared with those without irAEs. The subgroup with endocrine disorders showed superior PFS (P = 0.008) and OS (P = 0.031) compared with patients without endocrine disorders. Multivariate analysis demonstrated that grade 1/2 irAEs contributed to prolonged PFS (HR, 0.339; 95% CI, 0.166–0.691; P = 0.003) and OS (HR, 0.086; 95% CI, 0.012–0.641; P = 0.017). Landmark analysis at 9 weeks also confirmed that grade 1/2 irAEs were associated with extended PFS and OS. Patients with HCC who developed irAEs showed better HR than those with other cancer types; however, the details remain unknown. With abundant locoregional therapies, such as transarterial chemoembolization, radiation and radiofrequency ablation, actively pursuing conversion therapy for responsive cases may contribute to prolonging survival.

Renal cell carcinoma

In the context of renal cell carcinoma (RCC), several studies have focused on irAEs associated with nivolumab or nivolumab + ipilimumab combination therapy. Verzoni et al. conducted a retrospective analysis of 389 patients with RCC treated with nivolumab (43). Among these patients, irAEs were observed in 20% of the patients, with the most common being skin rashes (8%), gastrointestinal disorders (5%) and endocrine disorders (4%). The occurrence of irAEs was strongly associated with prolonged OS (HR, 0.57; 95% CI, 0.35–0.93; P = 0.02). Similar results were observed in the landmark analysis at 6 weeks. Ishihara et al. analyzed 47 patients with a history of targeted therapy who received nivolumab (44). Almost half the patients (48.9%) experienced irAEs, with skin rashes being the most frequent (52.2%). Patients who developed irAEs exhibited improved PFS and OS compared with those who did not experience irAEs. Multivariate analysis revealed that the occurrence of irAEs was associated with longer PFS (HR, 0.25; P = 0.0009). Washino et al. conducted a multicenter retrospective study involving 129 patients treated with nivolumab and ipilimumab combination therapy (45). To address immortal time bias, the authors employed landmark analysis and a Cox model with time-dependent variables. A total of 74.4% of the patients experienced irAEs. The development of irAEs was positively associated with OS (HR, 0.328; 95% CI, 0.165–0.648; P = 0.001) and PFS (HR, 0.334; 95% CI, 0.151–0.737; P = 0.007). Additionally, patients who experienced multiple irAEs exhibited longer OS (HR, 0.507; 95% CI, 0.235–1.097; P = 0.085 or HR, 0.245; 95% CI, 0.110–0.544; P < 0.001) and PFS (HR, 0.572; 95% CI, 0.316–1.036; P = 0.085 or HR, 0.267; 95% CI, 0.113–0.628; P = 0.002) compared with those who experienced single or no irAEs.

Gastrointestinal cancer

There is evidence for an association between irAEs and treatment efficacy in patients with gastrointestinal cancer (GC). Masuda et al. reported that the absence of irAEs (HR, 9.54; 95% CI, 3.34–27.30) was linked to poorer OS in a cohort of 65 patients with gastric cancer treated with nivolumab (46). Similarly, Ando et al. found that irAEs were associated with improved PFS (HR, 2.08; 95% CI, 1.34–3.21) in 108 patients with gastric cancer treated with nivolumab or pembrolizumab (47). Das et al. conducted a retrospective study on 76 patients with GC who received nivolumab or pembrolizumab (48). The study included various cancer types such as HCC (42%), colorectal carcinoma (38%) and other cancers (20%), including gastric, pancreatic, bile duct, neuroendocrine and duodenal cancers. Approximately 46% of the patients had high microsatellite instability. IrAEs were observed in 43% of patients. Patients with irAEs experienced significantly longer median PFS and OS compared with those without irAEs (PFS: HR, 0.13; 95% CI, 0.05–0.3; P < 0.001; OS: HR, 0.11; 95% CI, 0.03–0.36; P < 0.001). Among patients who experienced irAEs, there were no significant differences in PFS and OS based on the initial irAE severity, steroid use or time to onset. Zhao et al. conducted a retrospective study on 136 patients with esophageal cancer treated with camrelizumab, an anti-PD-1 therapy (49). A majority of the patients (89.7%) received platinum-based chemotherapy as first-line therapy and 59.6% experienced irAEs. Patients who developed irAEs achieved a significantly higher ORR and longer OS than those who did not. Multivariate analysis demonstrated the presence of irAEs as an independent prognostic factor for OS (HR, 0.57; 95% CI, 0.42–0.77; P = 0.0002).

Other malignancies

Maher et al. conducted a pooled analysis of seven trials to evaluate the efficacy of ICIs (atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab) in metastatic or locally advanced urothelial cancer (50). Immune-mediated AEs (imAEs) were defined as AEs of special interest (AESIs) associated with treatments requiring topical or systemic corticosteroids. Each trial demonstrated a significant association between the development of a related AESI/imAE and treatment response, with related AESIs occurring in 52–73% of responding patients. An analysis of responders regarding the relationship between AESI or imAEs development and OS, adjusted for baseline covariates, revealed an improvement in OS among patients who developed an AESI (HR, 0.45; 95% CI, 0.39–0.53) or imAEs (HR, 0.53; 95% CI, 0.43–0.66). Foster et al. analyzed 108 patients with metastatic head and neck cancer treated with anti-PD-1 antibodies, regardless of their PD-L1 status, based on the presence or absence of irAEs (51). Among these, 45.4% experienced irAEs, with dermatological events being the most common (35.0%). In a 22-week landmark analysis, both PFS and OS were longer in patients with irAEs than in those without irAEs. Multivariate analyses demonstrated that irAEs remained associated with ORR (OR, 3.23; 95% CI, 1.12–9.29; P = 0.03), PFS (HR, 0.49; 95% CI, 0.30–0.78; P = 0.003) and OS (HR, 0.49; 95% CI, 0.30–0.79; P = 0.04).

Meta-analysis

Meta-analyses were conducted to determine the association between irAEs and treatment efficacy. Hussaini et al. performed a meta-analysis of 51 studies involving various cancer types to examine the relationship between irAEs and efficacy (52). A positive association was observed between the development of irAEs and PFS (HR, 0.51; 95% CI, 0.42–0.63; P < 0.001) and OS (HR, 0.46; 95% CI, 0.35–0.62; P < 0.001) in patients treated with ICIs, irrespective of disease site, ICI type or irAEs. Similar findings have been reported by Huilin et al. (53). The authors reviewed 34 trials, reporting superior outcomes in patients expressing irAEs for both OS (HR, 0.57; 95% CI, 0.44–0.74; P < 0.001), PFS (HR, 0.50; 95% CI, 0.37–0.67; P < 0.001) and ORR (OR, 4.72; 95% CI, 3.48–6.40; P < 0.001). In the present review, the associations with this region were also analyzed. It is noteworthy that in cases where irAEs occurred, Asian patients showed better OS and PFS than those of North America and Europe. However, contradictory results have been reported. Amoroso et al. conducted an analysis focusing only on randomized trials of ICIs (54). The authors examined 62 trials by employing a weighted linear regression with a logarithmic scale for their analysis. In contrast to numerous previous studies, this study showed low-strength correlations between irAEs and OS in different cancer types. The authors concluded that the incidence of irAEs should not be considered a valid surrogate for OS when evaluating the efficacy of ICI therapy.

Relationship between each irAE type and treatment efficacy

In addition to the association between irAEs and treatment efficacy, several studies have investigated the relationship between irAE type and treatment outcomes. A meta-analysis conducted by Zhou et al., which included 30 trials covering various cancer types, revealed that patients who developed irAEs experienced a significant benefit in OS compared with those who did not develop irAEs (HR, 0.54; 95% CI, 0.45–0.65; P < 0.001) (55). Subgroup analyses further indicated that the occurrence of endocrine, dermatological and gastrointestinal irAEs was significantly associated with favorable OS (endocrine: HR 0.52; 95% CI, 0.44–0.62; P < 0.001; dermatological: HR, 0.45; 95% CI, 0.35–0.59; P < 0.001; gastrointestinal: HR, 0.68; 95% CI, 0.51–0.89; P = 0.005). Cheung et al. conducted a systematic review to assess whether thyroiditis could serve as a surrogate marker for improved outcomes (56). This review included 47 studies of various cancer types, with PD-1 inhibitors being the most commonly administered ICI. The development of thyroiditis was associated with improved OS (HR, 0.52; 95% CI, 0.43–0.62; P < 0.001) and PFS (HR, 0.58; 95% CI, 0.50–0.67; P < 0.001). Yaxin et al. performed a meta-analysis of 23 studies involving various cancer types and 22 749 patients to examine the relationship between cutaneous irAEs and survival outcomes (57). The occurrence of cutaneous irAEs was associated with improved OS (HR, 0.61; 95% CI, 0.52–0.72; P < 0.001) and PFS (HR, 0.52; 95% CI, 0.41–0.65; P < 0.001). These results remained consistent across subgroups stratified by study design, geographic region, ICI type and cancer type and aligned with the overall estimate of OS and PFS improvement. Additionally, gastrointestinal and hepatic irAEs have been reported. Yamada et al. analyzed 661 patients with various types of cancer (58). Gastrointestinal irAEs occurred in 5.6 and 16.1% of patients in the PD-1/PD-L1 and CTLA-4 groups, respectively, with a significantly higher incidence in the CTLA-4 group (P = 0.008). Patients who continued ICI treatment despite the development of gastrointestinal irAEs had significantly prolonged OS compared with those who did not experience gastrointestinal irAEs (P = 0.035). Yamamoto et al. explored the association between severe liver irAEs and prognosis in patients with NSCLC (59). Among 365 patients who received ICI treatment, 19 experienced severe liver irAEs. Patients with liver irAEs had significantly longer PFS (P = 0.010) and OS (P = 0.007) than those without liver irAEs.

Relationship between timing of irAEs onset and treatment efficacy

Several studies have explored the relationship between the timing of irAE onset and treatment efficacy. Hsiehchen et al. conducted an analysis focusing on the timing of irAE onset and its association with treatment efficacy in patients with NSCLC treated with PD-1/PD-L1 inhibitors (26). The authors examined two independent cohorts, one comprising 154 patients from a single institution, and a multicenter cohort of 433 patients. In both cohorts, late-onset irAEs occurring >3 months after the initiation of ICI treatment were associated with higher rates of radiographic response, as well as longer PFS and OS. Multivariable Cox regression analysis in the single institution cohort demonstrated that a longer time to irAE onset was associated with extended PFS (HR, 0.93; 95% CI, 0.87–0.99; P = 0.03) and OS (HR, 0.90; 95% CI, 0.83–0.98; P = 0.02). Contradictory results were reported by Ghisoni et al. (60), who reviewed all published registered trials on NSCLC and melanoma involving 622 patients, leading to the approval of ICIs by the FDA and EMA in December 2019. The cumulative probabilities of irAE onset after treatment initiation were 42.8, 51.0 and 57.3% at 6, 12 and 24 months, respectively. A time-dependent model was used to account for the immortal time bias introduced by late-onset toxicities. In both cohorts (NSCLC and melanoma), there were no significant associations between the incidence of irAEs and OS (P = 0.67 and 0.19, respectively).

Management of irAEs

Relationship between immunosuppression therapy and treatment efficacy

The management of immunotherapy toxicities was based on the recommendations proposed in the guidelines of the American Society of Clinical Oncology and the European Society of Medical Oncology (61,62). For the treatment of moderate to severe irAEs, a series of therapies targeting T cells, B cells, cytokines and autoantibodies are recommended in addition to steroids. Steroids are generally prescribed as the first-line treatment for irAEs, as recommended by current guidelines. However, the potential impact of steroids on the prognosis of irAEs has been reported and several studies have been conducted on this topic (Table 2). Stribek et al. (63) conducted a study involving 196 patients with NSCLC treated with ICIs and investigated the correlation between steroid administration, irAEs and outcomes. Steroid administration, defined as the use of >10 mg prednisolone equivalent for 10 days, was observed in 46.3% of patients. The results showed that steroid administration owing to irAEs did not significantly affect OS compared with steroid-naïve patients (P = 0.38). Bai et al. (64) conducted a retrospective study of 947 patients with melanomas treated with anti-PD-1 monotherapy and examined the impact of high-dose glucocorticoids on outcomes. The authors considered the peak dose of ≥60 mg prednisone equivalent once a day as the threshold for high-dose glucocorticoid use and used the endpoints of post-irAEs PFS/OS. The study revealed that early-onset irAEs (within 8 weeks of anti-PD-1 initiation) with high-dose glucocorticoids use were independently associated with poorer post-irAEs PFS (HR, 5.37; 95% CI, 2.10–13.70; P < 0.001) and post-irAEs OS (HR, 5.95; 95% CI, 2.20–16.09; P < 0.001) for 8-week landmark analysis. Van Not et al. (65) reported an association between the use of immunosuppressants for irAEs and prognosis in 771 patients with advanced melanoma treated with first-line ipilimumab and nivolumab. Among the 350 patients who required immunosuppression owing to severe irAEs, 235 received steroids alone and 115 received steroids in combination with second-line immunosuppressants. The most common irAEs were colitis and hepatitis. After adjusting for potential confounding factors, patients treated with steroids along with second-line immunosuppressants tended to have a higher risk of disease progression (adjusted HR, 1.40; 95% CI, 1.00–1.97; P = 0.05) and a greater risk of mortality (adjusted HR, 1.54; 95% CI, 1.03–2.30; P = 0.04) compared with patients treated with steroids alone. Several other studies have reported an association between steroid therapy for irAEs and treatment efficacy; however, the results are inconsistent (32,66,67). Given that the severity of irAEs and continuation of ICI treatment can also influence treatment efficacy, multiple factors are involved in treatment efficacy. Considering that the use of steroids and immunosuppressive agents may affect treatment efficacy, it is necessary to develop appropriate treatment plans.

Table 2 Relationship between immunosuppressive therapy and treatment efficacy

Author	Tumor type	ICIs	Immunosuppression
treatment	Impact on prognosis	Results	Ref	
Horvat	Melanoma	Ipilimumab	Steroids	No significant impact	No difference in OS (P = 0.97) and TTF (P = 0.07) between patients with and without steroids.	32	
Skribek	NSCLC	Anti-PD-1
or PD-L1 Ab	Steroids	No significant impact	No difference in OS (P = 0.380) and PFS (P = 0.308) between patients with and without steroids.	63	
Bai	Melanoma	Anti-PD-1	Steroids	Negative	Patients who received high-dose glucocorticoids for early-onset irAEs showed significantly shorter OS (P < 0.001) and PFS (P < 0.001) compared with those who did not.	64	
Olivier	Melanoma	Ipilimumab
and nivolumab	Steroids with any second-line immunosuppressant	Negative	Treatment with steroids plus second-line immunosuppressants showed significantly shorter median PFS (P = 0.01) and OS (P = 0.04) compared with steroids alone.	65	
Mouri	NSCLC	Nivolumab, pembrolizumab,
or atezolizumab	Steroids	Negative	Treatment with steroids showed significantly shorter median PFS (P < 0.037) compared with patients without steroids.	66	
Paderi	NSCLC, melanoma and RCC	Nivolumab, pembrolizumab
or atezolizumab	Steroids	No significant impact	No difference in PFS (P = 0.358) between patients receiving early treatment with steroids and those without steroids.	67	

Rechallenge of ICIs

Whether to rechallenge with ICIs after the onset of irAEs should be determined individually based on the treatment efficacy, type of symptoms and severity. Rechallenge is possible if the grade is below Grade 1, but for Grades 2 and above, the appropriateness of resuming treatment or permanently discontinuing it varies depending on the type of symptoms. However, even in the presence of severe irAEs, resuming administration may contribute to a prolonged prognosis, and there have been several reports on the efficacy and safety of rechallenge. In a study that rechallenged 452 patients with irAEs with ICIs, 28.8% experienced recurrence of the initial irAEs. The symptoms with a higher risk of recurrence were colitis (OR = 1.77), hepatitis (OR = 3.38) and pneumonia (OR = 2.26) (68). In studies focusing on NSCLC, rechallenge with ICIs for Grade 2 or higher resulted in no occurrence of Grade 4 or 5 irAEs; however, recurrence of the same or de novo irAEs was reported in 60% of the cases (69). There was no difference in the prognosis between the rechallenge and non-rechallenge groups. The safety of resuming anti-PD-1 antibody therapy in patients with melanoma who discontinued anti-CTLA-4 and PD-1 blockade combination therapy because of irAEs was assessed (70). Rechallenge resulted in 50% of patients developing irAEs, whereas the occurrence of the same irAEs as with combination therapy was 18%. Only one case of Grade 5 toxicity was observed. Considering the less severe toxicity after combination therapy followed by monotherapy rechallenge, this approach may be worth considering.

Variations in toxicity with ICI combinations

As previously discussed, the correlation between irAEs and therapeutic efficacy has been reported not only with ICI monotherapy but also with ICI combination therapies, as well as combinations of tyrosine kinase inhibitors (TKIs) or cytotoxic agents. However, caution is warranted in therapeutic management because of the increasing frequency of irAEs associated with combination therapies. Meta-analyses have demonstrated that the combination of anti-PD-1 and anti-CTLA-4 antibodies is associated with an increased risk of irAEs (71). Caution should be exercised even for rare events because the incidence of myocarditis and neurotoxic events is higher with ICI combination therapy than with ICI monotherapy (72,73). Additionally, an increase in fatal irAEs, such as myocarditis, has been reported (7). It is also recognized that the addition of TKIs or cytotoxic agents elevates the severity and frequency of treatment-related AEs compared with ICIs alone (74). Meta-analysis showed that the incidence of all-grade diarrhea following ICI treatment combined with TKIs or cytotoxic agents was higher than that following ICI monotherapy (75). Several analyses focusing on organ-specific irAEs following combination therapy with ICIs and TKIs have been reported. In a study involving 20 516 patients, the frequency of pneumonia with combination therapy of nivolumab and TKIs was 25.7%, compared with 6.4% with nivolumab monotherapy and 4.6% with TKI monotherapy (76). In another study involving 106 patients with various cancers, the frequency of thyroid function abnormalities with combination therapy of ICIs and TKIs was 63.2%, including 10.4% with hyperthyroidism, 39.6% with subclinical hypothyroidism and 13.2% with overt hypothyroidism (77). Combination therapy with ICIs and TKIs may have a different AE profile than ICI monotherapy and should be approached with caution.

Conclusion

The association between irAEs and treatment efficacy has been the subject of extensive research, particularly in the context of ICIs across various malignancies. In this review, we focused on organ-specific data owing to their accessibility; however, considering the mechanisms of irAEs, cross-organ analysis is also necessary. Reports have indicated a correlation between irAEs and prognosis regardless of the organ involved (78). Although most studies have suggested a positive association between irAEs and treatment efficacy, it is important to acknowledge that some reports have presented conflicting findings. It is crucial to consider potential confounding factors, especially when assessing late-onset irAEs, as only patients who survive longer may develop irAEs, potentially biasing the survival data. Many studies have attempted to address this bias using landmark analyses and Cox models with time-dependent variables. However, there are additional challenges to evaluating these studies. The diagnosis of mild irAEs can sometimes elude the attending physician, which can affect the analysis. For instance, symptoms such as nausea, vomiting, appetite loss, weight loss, general weakness and fatigue are challenging to diagnose owing to their nonspecific nature, potentially stemming from various conditions beyond irAEs alone. When administered concurrently with chemotherapy, distinguishing between irAEs and the side effects commonly associated with chemotherapy, such as liver impairment, diarrhea and rashes, is particularly challenging. Therefore, when interpreting the results of these studies, potential problems must be taken into account. Overall, irAEs show promise as potential biomarkers for ICI treatment. However, the underlying mechanisms and impacts of specific irAE types, severity and timing of disease onset require further investigation.

Conflict of interest statement

Taito Fukushima reports honoraria for lectures from Chugai Pharmaceutical. Satoshi Kobayashi reports honoraria for lectures from AstraZeneca, MSD, Ono Pharmaceutical and Chugai Pharmaceutical. Makoto Ueno reports honoraria for lectures from AstraZeneca, MSD, Ono Pharmaceutical and Chugai Pharmaceutical. Makoto Ueno is a member of an Advisory Committee of AstraZeneca, MSD and Ono Pharmaceutical.
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References

1. Wei SC , DuffyCR, AllisonJP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov  2018;8 :1069–86. 10.1158/2159-8290.CD-18-0367.30115704
2. Sanmamed MF , ChenL. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell  2018;175 :313–26. 10.1016/j.cell.2018.09.035.30290139
3. Postow MA , SidlowR, HellmannMD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med  2018;378 :158–68. 10.1056/NEJMra1703481.29320654
4. Martins F , SofiyaL, SykiotisGP, et al.  Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol  2019;16 :563–80. 10.1038/s41571-019-0218-0.31092901
5. Passat T , TouchefeuY, GervoisN, JarryA, BossardC, BennounaJ. Physiopathological mechanisms of immune-related adverse events induced by anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies in cancer treatment. Bull Cancer  2018;105 :1033–41. 10.1016/j.bulcan.2018.07.005.30244981
6. Hofmann L , ForschnerA, LoquaiC, et al.  Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer  2016;60 :190–209. 10.1016/j.ejca.2016.02.025.27085692
7. Wang DY , SalemJE, CohenJV, et al.  Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol  2018;4 :1721–8. 10.1001/jamaoncol.2018.3923.30242316
8. Johnson DB , BalkoJM, ComptonML, et al.  Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med  2016;375 :1749–55. 10.1056/NEJMoa1609214.27806233
9. Berner F , BomzeD, DiemS, et al.  Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer. JAMA Oncol  2019;5 :1043–7. 10.1001/jamaoncol.2019.0402.31021392
10. Byrne KT , TurkMJ. New perspectives on the role of vitiligo in immune responses to melanoma. Oncotarget  2011;2 :684–94. 10.18632/oncotarget.323.21911918
11. Subudhi SK , AparicioA, GaoJ, et al.  Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad Sci U S A  2016;113 :11919–24. 10.1073/pnas.1611421113.27698113
12. Lozano AX , ChaudhuriAA, NeneA, et al.  T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nat Med  2022;28 :353–62. 10.1038/s41591-021-01623-z.35027754
13. Hasan Ali O , BomzeD, RingSS, et al.  BP180-specific IgG is associated with skin adverse events, therapy response, and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors. J Am Acad Dermatol  2020;82 :854–61. 10.1016/j.jaad.2019.08.045.31449902
14. Mammen AL , RajanA, PakK, et al.  Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1. Ann Rheumat Dis  2019;78 :150–2. 10.1136/annrheumdis-2018-213777.30185415
15. Iwama S , De RemigisA, CallahanMK, SlovinSF, WolchokJD, CaturegliP. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med  2014;6 :230ra45. 10.1126/scitranslmed.3008002.
16. Caturegli P , Di DalmaziG, LombardiM, et al.  Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am J Pathol  2016;186 :3225–35. 10.1016/j.ajpath.2016.08.020.27750046
17. Tarhini AA , ZahoorH, LinY, et al.  Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer  2015;3 :39. 10.1186/s40425-015-0081-1.26380086
18. Andrews MC , DuongCPM, GopalakrishnanV, et al.  Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med  2021;27 :1432–41. 10.1038/s41591-021-01406-6.34239137
19. Teraoka S , FujimotoD, MorimotoT, et al.  Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study. J Thoracic Oncol  2017;12 :1798–805. 10.1016/j.jtho.2017.08.022.
20. Haratani K , HayashiH, ChibaY, et al.  Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol  2018;4 :374–8. 10.1001/jamaoncol.2017.2925.28975219
21. Ricciuti B , GenovaC, De GiglioA, 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. J Cancer Res Clin Oncol  2019;145 :479–85. 10.1007/s00432-018-2805-3.30506406
22. Owen DH , WeiL, BertinoEM, et al.  Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer. Clin Lung Cancer  2018;19 :e893–900. 10.1016/j.cllc.2018.08.008.30197259
23. Grangeon M , TomasiniP, ChaleatS, et al.  Association between immune-related adverse events and efficacy of immune checkpoint inhibitors in non-small-cell lung cancer. Clin Lung Cancer  2019;20 :201–7. 10.1016/j.cllc.2018.10.002.30442524
24. Cortellini A , ChiariR, RicciutiB, et al.  Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients. Clin Lung Cancer  2019;20 :237–47.e1. 10.1016/j.cllc.2019.02.006.30885550
25. Shankar B , ZhangJ, NaqashAR, et al.  Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol  2020;6 :1952–6. 10.1001/jamaoncol.2020.5012.33119034
26. Hsiehchen D , NaqashAR, EspinozaM, et al.  Association between immune-related adverse event timing and treatment outcomes. Oncoimmunology  2022;11 :2017162. 10.1080/2162402X.2021.2017162.35003896
27. Socinski MA , JotteRM, CappuzzoF, et al.  Association of immune-related adverse events with efficacy of atezolizumab in patients with non-small cell lung cancer: pooled analyses of the phase 3 IMpower130, IMpower132, and IMpower150 randomized clinical trials. JAMA Oncol  2023;9 :527–35. 10.1001/jamaoncol.2022.7711.36795388
28. West H , McCleodM, HusseinM, et al.  Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol  2019;20 :924–37. 10.1016/S1470-2045(19)30167-6.31122901
29. Nishio M , BarlesiF, WestH, et al.  Atezolizumab plus chemotherapy for first-line treatment of nonsquamous NSCLC: results from the randomized phase 3 IMpower132 trial. J Thoracic Oncol  2021;16 :653–64. 10.1016/j.jtho.2020.11.025.
30. Socinski MA , JotteRM, CappuzzoF, et al.  Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med  2018;378 :2288–301. 10.1056/NEJMoa1716948.29863955
31. Downey SG , KlapperJA, SmithFO, et al.  Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res  2007;13 :6681–8. 10.1158/1078-0432.CCR-07-0187.17982122
32. Horvat TZ , AdelNG, DangTO, 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. J Clin Oncol  2015;33 :3193–8. 10.1200/JCO.2015.60.8448.26282644
33. Weber JS , HodiFS, WolchokJD, et al.  Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol  2017;35 :785–92. 10.1200/JCO.2015.66.1389.28068177
34. Freeman-Keller M , KimY, CroninH, RichardsA, GibneyG, WeberJS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res  2016;22 :886–94. 10.1158/1078-0432.CCR-15-1136.26446948
35. Indini A , Di GuardoL, CimminielloC, et al.  Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma. J Cancer Res Clin Oncol  2019;145 :511–21. 10.1007/s00432-018-2819-x.30539281
36. Bisschop C , WindTT, BlankCU, et al.  Association between pembrolizumab-related adverse events and treatment outcome in advanced melanoma: results from the Dutch expanded access program. J Immunother  2019;42 :208–14.31145233
37. Eggermont AMM , KicinskiM, BlankCU, 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. JAMA Oncol  2020;6 :519–27. 10.1001/jamaoncol.2019.5570.31895407
38. Xu S , LaiR, ZhaoQ, ZhaoP, ZhaoR, GuoZ. Correlation between immune-related adverse events and prognosis in hepatocellular carcinoma patients treated with immune checkpoint inhibitors. Front Immunol  2021;12 :794099. 10.3389/fimmu.2021.794099.34950153
39. Lu L , XingK, WeiW, et al.  Immune-related adverse events predict responses to PD-1 blockade immunotherapy in hepatocellular carcinoma. Int J Cancer  2021;149 :959–66. 10.1002/ijc.33609.
40. Ng KYY , TanSH, TanJJE, et al.  Impact of immune-related adverse events on efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma. Liver Cancer  2022;11 :9–21. 10.1159/000518619.35222504
41. Fukushima T , MorimotoM, KobayashiS, et al.  Association between immune-related adverse events and survival in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Oncologist  2023;28 :e526–33. 10.1093/oncolo/oyad090.37023703
42. Zhou JM , XiongHF, ChenXP, ZhangZW, ZhuLP, WuB. Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: a retrospective study. World J Gastrointest Oncol  2023;15 :689–99. 10.4251/wjgo.v15.i4.689.37123056
43. Verzoni E , CartenìG, CortesiE, et al.  Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J Immunother Cancer  2019;7 :99. 10.1186/s40425-019-0579-z.30944023
44. Ishihara H , TakagiT, KondoT, et al.  Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Urol Oncol  2019;37 :355.e21–9. 10.1016/j.urolonc.2019.03.003.
45. Washino S , ShirotakeS, TakeshitaH, et al.  Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. Int J Clin Oncol  2023;28 :1651–8. 10.1007/s10147-023-02406-x.37658926
46. Masuda K , ShojiH, NagashimaK, et al.  Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab. BMC Cancer  2019;19 :974. 10.1186/s12885-019-6150-y.31638948
47. Ando T , UedaA, OgawaK, et al.  Prognosis of immune-related adverse events in patients with advanced gastric cancer treated with nivolumab or pembrolizumab: a multicenter retrospective analysis. In Vivo  2021;35 :475–82. 10.21873/invivo.12281.33402499
48. Das S , CiomborKK, HaraldsdottirS, et al.  Immune-related adverse events and immune checkpoint inhibitor efficacy in patients with gastrointestinal cancer with food and drug administration-approved indications for immunotherapy. Oncologist  2020;25 :669–79. 10.1634/theoncologist.2019-0637.31943525
49. Zhao YN , CongD, ZhangW, JiaY, BaiY. Immune-related adverse events as independent prognostic factors for camrelizumab in patients with esophageal squamous cell carcinoma: a retrospective cohort study. J Gastrointest Oncol  2023;14 :733–43. 10.21037/jgo-23-75.37201088
50. Maher VE , FernandesLL, WeinstockC, et al.  Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody. J Clin Oncol  2019;37 :2730–7. 10.1200/JCO.19.00318.31116675
51. Foster CC , CoueyMA, KochannySE, et al.  Immune-related adverse events are associated with improved response, progression-free survival, and overall survival for patients with head and neck cancer receiving immune checkpoint inhibitors. Cancer  2021;127 :4565–73. 10.1002/cncr.33780.34547103
52. Hussaini S , ChehadeR, BoldtRG, et al.  Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors - a systematic review and meta-analysis. Cancer Treat Rev  2021;92 :102134. 10.1016/j.ctrv.2020.102134.33302134
53. Xu H , XuX, GeW, LeiJ, CaoD. The association between immune-related adverse events and the prognosis of solid cancer patients treated with immunotherapy: a systematic review and meta-analysis. Ther Adv Med Oncol  2020;12 :175883592098054. 10.1177/1758835920980546.
54. Amoroso V , GalloF, AlbertiA, et al.  Immune-related adverse events as potential surrogates of immune checkpoint inhibitors' efficacy: a systematic review and meta-analysis of randomized studies. ESMO Open  2023;8 :100787. 10.1016/j.esmoop.2023.100787.36842300
55. Zhou X , YaoZ, YangH, LiangN, ZhangX, ZhangF. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med  2020;18 :87. 10.1186/s12916-020-01549-2.32306958
56. Cheung YM , WangW, McGregorB, HamnvikOR. Associations between immune-related thyroid dysfunction and efficacy of immune checkpoint inhibitors: a systematic review and meta-analysis. Cancer Immunol Immunother  2022;71 :1795–812. 10.1007/s00262-021-03128-7.35022907
57. Du Y , WuW, ChenM, DongZ, WangF. Cutaneous adverse events and cancer survival prognosis with immune checkpoint inhibitor treatment: a systematic review and meta-analysis. JAMA Dermatol  2023;159 :1093–101. 10.1001/jamadermatol.2023.3003.37672255
58. Yamada K , SawadaT, NakamuraM, et al.  Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival. World J Gastroenterol  2021;27 :7190–206. 10.3748/wjg.v27.i41.7190.34887637
59. Yamamoto T , ItoT, HaseT, et al.  Immune-related liver injury is a poor prognostic factor in patients with nonsmall cell lung cancer treated with immune checkpoint inhibitors. Cancer Invest  2022;40 :189–98. 10.1080/07357907.2021.1994586.34658277
60. Ghisoni E , WickyA, BouchaabH, et al.  Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: an overlooked aspect in immunotherapy. Eur J Cancer  2021;149 :153–64. 10.1016/j.ejca.2021.03.010.33865201
61. Schneider BJ , NaidooJ, SantomassoBD, et al.  Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol  2021;39 :4073–126. 10.1200/JCO.21.01440.34724392
62. Haanen J , CarbonnelF, RobertC, et al.  Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol  2017;28 :iv119–42. 10.1093/annonc/mdx225.28881921
63. Skribek M , RounisK, AfsharS, et al.  Effect of corticosteroids on the outcome of patients with advanced non-small cell lung cancer treated with immune-checkpoint inhibitors. Eur J Cancer  2021;145 :245–54. 10.1016/j.ejca.2020.12.012.33419647
64. Bai X , HuJ, Betof WarnerA, et al.  Early use of high-dose glucocorticoid for the management of irAE is associated with poorer survival in patients with advanced melanoma treated with anti-PD-1 monotherapy. Clin Cancer Res  2021;27 :5993–6000. 10.1158/1078-0432.CCR-21-1283.34376536
65. van  NotOJ, VerheijdenRJ, van den  EertweghAJM, et al.  Association of immune-related adverse event management with survival in patients with advanced melanoma. JAMA Oncol  2022;8 :1794–801. 10.1001/jamaoncol.2022.5041.36301521
66. Mouri A , KairaK, YamaguchiO, et al.  Effect of systemic steroid use for immune-related adverse events in patients with non-small cell lung cancer receiving PD-1 blockade drugs. J Clin Med  2021;10 :3744. 10.3390/jcm10163744.
67. Paderi A , GambaleE, BotteriC, et al.  Association of systemic steroid treatment and outcome in patients treated with immune checkpoint inhibitors: a real-world analysis. Molecules  2021;26 :5789. 10.3390/molecules26195789.
68. Dolladille C , EderhyS, SassierM, et al.  Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol  2020;6 :865–71. 10.1001/jamaoncol.2020.0726.32297899
69. Guo M , VanderWaldeAM, YuX, VidalGA, TianGG. Immune checkpoint inhibitor rechallenge safety and efficacy in stage IV non-small cell lung cancer patients after immune-related adverse events. Clin Lung Cancer  2022;23 :686–93. 10.1016/j.cllc.2022.07.015.36050243
70. Pollack MH , BetofA, DeardenH, et al.  Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol  2018;29 :250–5. 10.1093/annonc/mdx642.29045547
71. Zhou X , YaoZ, BaiH, et al.  Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis. Lancet Oncol  2021;22 :1265–74. 10.1016/S1470-2045(21)00333-8.34391508
72. Mahmood SS , FradleyMG, CohenJV, et al.  Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol  2018;71 :1755–64. 10.1016/j.jacc.2018.02.037.29567210
73. Spain L , WallsG, JulveM, et al.  Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann Oncol  2017;28 :377–85. 10.1093/annonc/mdw558.28426103
74. Saxena P , SinghPK, MalikPS, SinghN. Immunotherapy alone or in combination with chemotherapy as first-line treatment of non-small cell lung cancer. Curr Treat Options Oncol  2020;21 :69. 10.1007/s11864-020-00768-2.32720019
75. Nielsen DL , JuhlCB, ChenIM, KellermannL, NielsenOH. Immune checkpoint inhibitor-induced diarrhea and colitis: incidence and management. A systematic review and meta-analysis. Cancer Treat Rev  2022;109 :102440. 10.1016/j.ctrv.2022.102440.35917654
76. Oshima Y , TanimotoT, YujiK, TojoA. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol  2018;4 :1112–5. 10.1001/jamaoncol.2017.4526.29327061
77. Tsai K , MaH, LiangTZ, et al.  The combined effect of immune checkpoint inhibitors and tyrosine kinase inhibitors on thyroid function. Thyroid  2024;34 :158–66. 10.1089/thy.2023.0542.38069567
78. Matsuoka H , HayashiT, TakigamiK, et al.  Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody. BMC Cancer  2020;20 :656. 10.1186/s12885-020-07142-3.32664888
