Rheumatic immune-and nonimmune-related adverse events in phase 3 clinical trials assessing PD-(L)1 checkpoint inhibitors for lung cancer: A systematic review and meta-analysis

Veccia, Antonello; Kostine, Marie; Tison, Alice; Dipasquale, Mariachiara; Kinspergher, Stefania; Prokop, Larry J.; Grandi, Guido; Inchiostro, S.; Caffo, Orazio; Paolazzi, Giuseppe; Bortolotti, Roberto; Cornec, Divi; Berti, Alvise

doi:10.1016/j.jbspin.2022.105403

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…According to different studies, these irAEs have been reported in up to 37% of patients in clinical trials [24,30]. The pleiotropic nature of irAEs results in the affection of many organs (e.g., skin, colon, endocrine organs, joints, heart, lungs, and the musculoskeletal system), with mechanisms that vary greatly depending on the distinct checkpoint blockers [31,32]. Due to the high heterogeneity and complexity of irAEs' manifestation, they are often considered the "Achilles' heel" of ICIs (Figure 2) [33].…”

Section: Pathogenic Mechanisms Underlying Iraesmentioning

confidence: 99%

“…Notably, patients with a history of rheumatic disorders, such as RA or lupus, may have an increased predisposition to developing rheumatic irAEs during cancer immunotherapy; up to 71%, according to recent studies [138]. Rheumatic irAEs are not substantially higher in randomized controlled trials on ICIs compared to conventional treatment, indicating a potential discrepancy with real-life incidence and suggesting the likelihood of underreporting or misclassification [32].…”

Section: Musculoskeletal Iraesmentioning

confidence: 99%

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Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Casagrande,

Sopetto,

Bertalot

et al. 2024

Cancers

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The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

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Section: Pathogenic Mechanisms Underlying Iraesmentioning

confidence: 99%

Section: Musculoskeletal Iraesmentioning

confidence: 99%

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Casagrande,

Sopetto,

Bertalot

et al. 2024

Cancers

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Musculoskeletal immune-related adverse events of PD-(L)1 inhibitors in melanoma: a systematic review and meta-analysis

Roberts,

Barmettler,

Murray

et al. 2024

Immunotherapy

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Sex and anti-inflammatory treatment affect outcome of melanoma and non-small cell lung cancer patients with rheumatic immune-related adverse events

Gente,

Diekmann,

Daniello

et al. 2023

J Immunother Cancer

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BackgroundRheumatic immune-related adverse events (R-irAEs) occur in 5–15% of patients receiving immune checkpoint inhibitors (ICI) and, unlike other irAEs, tend to be chronic. Herein, we investigate the factors influencing cancer and R-irAEs outcomes with particular focus on adverse effects of anti-inflammatory treatment.MethodsIn this prospective, multicenter, long-term, observational study, R-irAEs were comprehensively analyzed in patients with malignant melanoma (MM, n=50) and non-small cell lung cancer (NSCLC, n=41) receiving ICI therapy who were enrolled in the study between August 1, 2018, and December 11, 2022.ResultsAfter a median follow-up of 33 months, progressive disease or death occurred in 66.0% and 30.0% of MM and 63.4% and 39.0% of patients with NSCLC. Male sex (progression-free survival (PFS): p=0.013, and overall survival (OS): p=0.009), flare of a pre-existing condition (vs de novo R-irAE, PFS: p=0.010) and in trend maximum glucocorticoid (GC) doses >10 mg and particularly ≥1 mg/kg prednisolone equivalent (sex-adjusted PFS: p=0.056, OS: p=0.051) were associated with worse cancer outcomes. Patients receiving disease-modifying antirheumatic drugs (DMARDs) showed significantly longer PFS (n=14, p=0.011) and OS (n=20, p=0.018). Effects of these variables on PFS and/or OS persisted in adjusted Cox regression models. Additionally, GC treatment negatively correlated with the time from diagnosis of malignancy and the latency from ICI start until R-irAE onset (all p<0.05). R-irAE features and outcomes were independent of other baseline patient characteristics in both studied cancer entities.ConclusionMale sex, flare of pre-existing rheumatologic conditions and extensive GC treatment appeared to be linked with unfavorable cancer outcomes, while DMARD use had a favorable impact. These findings challenge the current dogma of restrictive DMARD use for R-irAE and thus may pave the way to better strategies and randomized controlled trials for the growing number of patients with R-irAE.

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Rheumatic immune-and nonimmune-related adverse events in phase 3 clinical trials assessing PD-(L)1 checkpoint inhibitors for lung cancer: A systematic review and meta-analysis

Cited by 3 publications

References 39 publications

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Musculoskeletal immune-related adverse events of PD-(L)1 inhibitors in melanoma: a systematic review and meta-analysis

Sex and anti-inflammatory treatment affect outcome of melanoma and non-small cell lung cancer patients with rheumatic immune-related adverse events

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