Association of immune-related adverse events with immune checkpoint inhibitor efficacy: real or imaginary?

Haratani, Koji; Hayashi, Hidetoshi; Nakagawa, Kazuhiko

doi:10.1186/s12916-020-01583-0

Cited by 11 publications

(10 citation statements)

References 10 publications

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“…Patients with irAE develop an early enhanced diversification (Oh et al 2017) and activation of the peripheral T-cell pool (Robert et al 2014) and a broadening in reactive CD8 + T-cell response, in which the newly detected T lymphocytes had a higher tumor recognition potential (Kvistborg et al 2014). This corresponds to a recent meta-analysis which has shown that the occurrence of irAE during an ICI treatment correlated with a better clinical outcome (Haratani et al 2020). Patients with malignancies with a high tumor mutational burden, such as melanoma or non-small cell lung cancer, who had been treated with anti-PD-1 therapy could run a higher risk of developing irAEs due to a higher number of presented neoantigens and, therefore, increased risk that T cells cross-react with wildtype instead of neoantigens (Bomze et al 2019).…”

Section: Introductionsupporting

confidence: 65%

Inflammatory markers in autoimmunity induced by checkpoint inhibitors

Kirchberger

Erdmann

Schüpferling

et al. 2021

J Cancer Res Clin Oncol

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Purpose Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized. Methods This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA). Results During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems. Conclusion Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.

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Section: Introductionsupporting

confidence: 65%

Inflammatory markers in autoimmunity induced by checkpoint inhibitors

Kirchberger

Erdmann

Schüpferling

et al. 2021

J Cancer Res Clin Oncol

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“…Therefore, survivorship bias should be considered to interpret the relationship between irAEs occurrence and favorable survival. Although the association of irAE occurrence and survival of cancer patients treated with ICIs remains controversial, most studies suggest that irAE occurrence was associated with ICI efficacy [ 18 , 20 , 24 – 27 ]. A meta-analysis of 30 studies demonstrated a significant association between irAE occurrence and better outcome of ICI-treated solid tumor patients, in particular for anti-PD-1 or PD-L1 inhibitors [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Patterns and outcomes of immune-related adverse events in solid tumor patients treated with immune checkpoint inhibitors in Thailand: a multicenter analysis

et al. 2021

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Background Most immune-related adverse event (irAE) patterns and treatment guidelines are based on western clinical data. We evaluated the incidence and patterns of irAEs in patients treated with immune-checkpoint inhibitors (ICI) in Thailand. Methods All solid tumor patients treated with ICIs were retrospectively reviewed in a multicenter analysis. The study aims to evaluate the incidence of irAEs and their characteristics, treatments, outcomes, and impact on survival. All irAEs were graded using the CTCAE version 4.0. Characteristics of irAEs including time to onset, duration of irAEs, specific treatments, and outcomes of irAEs were reviewed. The Chi-square or Fisher’s exact test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. A p-value < 0.05 was considered statistically significant. Results irAEs of any grade were observed in 98 of 414 patients (24%), whereas grades 3–4 irAEs were observed in 5.6%. The majority of patients (78%) were treated with monotherapy ICI (anti-PD1/PD-L1 92%). The most common all-grade irAEs were hypothyroidism (7.5%), hepatitis (6.5%), and rash (4.8%). Median onset of overall irAEs was 63 days. Pancreatitis and pneumonitis had the earliest onset at 30 and 34 days, respectively. ICIs were rechallenged in 68 of 98 patients with irAE. Eleven of sixty-eight patients (11.2%) with initial irAE had reoccurrence after ICI rechallenge. Based on a multivariate analysis, pre-existing hypothyroidism, ICI used in a clinical trial setting, and combinations of ICI/ICI were independent factors predicting irAE occurrence. Patients with irAE had a statistically significant longer overall survival (OS) when compared to patients without irAE (p = 0.019). A multivariate analysis revealed that occurrence of irAE was an independent prognostic factor for OS (HR 0.70, 95% CI 0.51–0.96; p = 0.028). Conclusion irAE was commonly observed in Thai cancer patients treated with ICIs. Most irAEs were low-grade and manageable. Re-occurrence of irAE after re-challenging ICI was not uncommonly observed. Patients who experienced irAEs might have significantly longer OS compared to patients without irAEs. However, OS in this study should be interpreted with caution since it might be affected by various tumor types, treatment settings, dosing schedule, and ICI combinations.

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“…Nevertheless, a recent meta-analysis published by Haratani et al showed this correlation, respecting the immortal time bias [ 26 ]. The same data are available for urothelial carcinoma [ 27 ], melanoma [ 28 ] or non-small cell lung cancer [ 29 ] independently.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Impact of Immune-Related Adverse Events, Glucocorticoid Use and Immunotherapy Interruption on Long-Term Survival Outcomes

Bruyère

Souquet

Dalle

et al. 2021

Cancers

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It remains unclear whether immune-related adverse events (irAEs) and glucocorticoid use could impact long-term outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective unicentric study. The objectives were to assess the impact of grade ≥3 irAEs, glucocorticoid use and the interruption of immunotherapy on progression-free survival (PFS) and overall survival (OS). In this 828-patient cohort, the first occurrence of grade ≥3 irAEs had no significant impact on PFS or OS. Glucocorticoid administration for the irAEs was associated with a significantly shorter PFS (adjusted HR 3.0; p = 0.00040) and a trend toward shorter OS. ICI interruption was associated with a significantly shorter PFS (adjusted HR 3.5; p < 0.00043) and shorter OS (HR 4.5; p = 0.0027). Glucocorticoid administration and ICI interruption were correlated. In our population of patients treated with single agent ICI, grade ≥3 irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade ≥3 irAEs reported in other studies might then be explained by the management of the irAEs.

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Association of immune-related adverse events with immune checkpoint inhibitor efficacy: real or imaginary?

Cited by 11 publications

References 10 publications

Inflammatory markers in autoimmunity induced by checkpoint inhibitors

Inflammatory markers in autoimmunity induced by checkpoint inhibitors

Patterns and outcomes of immune-related adverse events in solid tumor patients treated with immune checkpoint inhibitors in Thailand: a multicenter analysis

Investigating the Impact of Immune-Related Adverse Events, Glucocorticoid Use and Immunotherapy Interruption on Long-Term Survival Outcomes

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