Correlation between immune-related adverse events and the efficacy of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: systematic review and meta-analysis

Zhang, Qian; Wang, Wei; Qi, Yuan; Li, Li; Wang, Yuchao; Chi, Chuanzhen; Xu, Chunhua

doi:10.1007/s00280-021-04375-2

Cited by 17 publications

(11 citation statements)

References 44 publications

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“…In addition, the relation of the pooled result was stable, and it showed no signi cant change in the sensitivity analysis. The primary outcome indicated that thyroid-related AEs might be a predictive factor of ICI e cacy in cancer patients, which was also demonstrated in previous studies 52,53 . However, the common etiology of the process remains unknown.…”

Section: Discussionsupporting

confidence: 76%

Thyroid-related Adverse Events Caused by Immune Checkpoint Inhibitors Associated with Therapeutic Outcomes in Cancer Patients: a systematic review and meta-analysis

Wei

Hong

Zhou

et al. 2023

Preprint

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Introduction: The development of immune checkpoint inhibitors (ICIs) marked a revolutionary milestone in the immunotherapy of cancers. Although ICIs have shown survival benefits and potential clinical prospects, these drugs also triggered a myriad of autoimmune side effects, termed immune-related adverse events (irAEs). Notably, thyroid-related adverse events (AEs) are one of the most common immune-related adverse events (irAEs) in immunotherapy, also frequently with the clinical consequences for the patients. It need a consequent analysis to tell the difference between the general thyrotoxicosis and the thyroid irAEs. As the association between side effects caused by ICIs and survival outcomes of cancer patients remains unknown, we performed a meta-analysis to evaluate the thyroid-related AEs and ICI effects on the prognosis of cancer patients. Material and method: The aim of this meta-analysis was to assess the effect of thyroid irAEs on the prognosis of cancer patients treated with ICIs. A literature search of published articles related to thyroid-related AEs in patients with ICI therapy was conducted in PubMed, Embase, and Medline on May 2, 2022. Revman software were used to assess the quality or risk of bias of included studies, and Stata software for the effect size measures to be pooled. The hazard ratios (HR) were used to assess the correlation between thyroid-related AEs and the overall survival (OS) and progression-free survival (PFS) with ICI therapy. Subgroup analyses were performed for the impact of thyroid-related AEs by a type of cancer and a PD-(L)1 monotherapy. Heterogeneity and publication bias were also assessed by Begg’s funnel plot. Result: A total of 28 studies and 29 cohorts comprising 17058 patients were included in this meta-analysis. All the studies are low level in the risk of bias and have over 50 cases in the sample sizes. Compared to the non-irAEs in the thyroid, the occurrence of thyroid-related AEs was significantly related to improved OS (HR: 0.51; 95% CI: 0.44-0.60; P < 0.01) and PFS (HR: 0.56; 95% CI: 0.47-0.66; P < 0.01). In addition, our subgroup analysis suggested that patients with NSCLC had a better survival benefit in terms of OS (HR: 0.41; 95% CI: 0.35–0.48; P <0.01) and PFS (HR: 0.57; 95% CI: 0.49–0.66; P <0.01) when treated with ICI therapy when developing thyroid-related AEs. Under the PD-(L)1 monotherapy, it also showed a better OS and PFS of patients with different cancers or a single NSCLC. Conclusion: The results indicated a significant correlation between thyroid-related AEs and improved survival outcomes for cancer patients with ICI therapy, especially for NSCLC. However melanoma have not shown a positive relation with the occurrence of thyroid irAEs. For other malignances, thyroid-related AEs might be a predictive factor for ICI efficacy.

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Section: Discussionsupporting

confidence: 76%

Thyroid-related Adverse Events Caused by Immune Checkpoint Inhibitors Associated with Therapeutic Outcomes in Cancer Patients: a systematic review and meta-analysis

Wei

Hong

Zhou

et al. 2023

Preprint

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“…Similar data has been observed in an Asian study about patients treated with ICIs in which DFS is higher in the subset of patients who developed toxicity ( 28 ). Other similar series have been published reporting similar outcomes ( 29 , 30 ).…”

Section: Association Between Iraes and Prognosis In Solid Tumorssupporting

confidence: 68%

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer

Iranzo

Callejo²,

Assaf³

et al. 2022

Front. Med.

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In recent years, immunotherapy-based regimens have been included into the treatment's algorithm of several cancer types. Programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) interact with their ligands found on the surface of antigen presenting cells (APC) or tumor cells (PD-L1/2 and CD80/86). Through these interactions, stimulatory or inhibitory signals are established. Immune checkpoint inhibitors (ICIs), block these interactions, and when administered not only as monotherapy but also as part of combination regimens, have shown to improve survival results in multiple advanced cancers leading to an increasing number of patients treated with ICI and, as a consequence, a rise in the number of patients developing immune-related adverse events (irAEs). Presence of irAEs has been associated with greater benefit from treatment, especially when blocking PD-L1. Recent data suggests that treatment benefit persists after discontinuation of ICIs due to a treatment related adverse event, regardless of the grade. Patients experiencing grade 3-4 irAEs are at risk of toxicity recurrence after reintroducing immunotherapy and therefore, the decision to resume the treatment is challenging. In these cases, a multidisciplinary approach is always needed and several factors should be considered. Management of severe toxicities may require systemic corticosteroids which can impact on T-cell function. Due to their immunosuppressive properties, it is necessary to deeper determine how corticosteroids influence responses. In terms of overall survival (OS), the use of steroids as therapy for irAEs seems not to reduce OS and several studies have reported durable responses in patients experiencing autoimmune toxicities treated with corticosteroids.

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“…Patients with high-grade irAEs had inferior survival except at a 12-month landmark analysis, where median OS was longer than among patients without irAEs . Improved OS being limited to patients with low-grade irAEs has been corroborated by several other groups and may be explained by the life-threatening potential of high-grade events. High-grade irAEs can result in death, albeit rarely.…”

Section: Discussionmentioning

confidence: 82%

Immune-Related Adverse Events and Survival Among Patients With Metastatic NSCLC Treated With Immune Checkpoint Inhibitors

Cook,

Samuel,

Meyers

et al. 2024

JAMA Netw Open

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ImportanceImmune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non–small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined.ObjectiveTo examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs.Design, Setting, and ParticipantsThis retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line.ExposureDeveloping an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs).Main Outcomes and MeasuresThe primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival &lt;3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS.ResultsAmong the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P &lt; .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P &lt; .001).Conclusions and RelevanceIn this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.

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Correlation between immune-related adverse events and the efficacy of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: systematic review and meta-analysis

Cited by 17 publications

References 44 publications

Thyroid-related Adverse Events Caused by Immune Checkpoint Inhibitors Associated with Therapeutic Outcomes in Cancer Patients: a systematic review and meta-analysis

Thyroid-related Adverse Events Caused by Immune Checkpoint Inhibitors Associated with Therapeutic Outcomes in Cancer Patients: a systematic review and meta-analysis

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer

Immune-Related Adverse Events and Survival Among Patients With Metastatic NSCLC Treated With Immune Checkpoint Inhibitors

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