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BackgroundWhether irAEs can predict the efficacy of PD-1 inhibitors in cholangiocarcinoma (CCA) has not been assessed. Therefore, this study aims to investigate the correlation between irAEs and the therapeutic effect of PD-1 inhibitors combination therapy in patients with advanced CCA.MethodsAll patients with CCA who were consecutively admitted to the inpatient unit of our hospital and received PD-1 inhibitors combination therapy between September 2020 and April 2022 were screened. In total, 106 patients with CCA were screened out. We then followed up these patients until October 2022. Due to perioperative use (n=28), less than 2 cycles of PD-1 inhibitor therapy (n=9), incomplete data (n=8) and no pathological report (n=2), 59 patients were included in the final analysis. The patients were divided into the irAEs cohort and the non-irAEs cohort according to whether they experienced irAEs or not. The Log-Rank test was performed to compare the difference in survival time between these two cohorts. We then applied multivariate COX regression analysis to investigate whether irAEs were independent prognostic factors for survival in patients with advanced CCA.ResultsFinally, 32 patients were included in the irAEs cohort and 27 patients in the non-irAEs cohort. A total of 32 patients (54.2%) had any-grade irAEs, of which 4 patients (6.8%) had grade 3-4 irAEs. The most common irAEs were thyroid toxicity (30.5%) and dermatologic toxicity (30.5%). There were no notable differences in demographics and clinical characteristics between the irAEs and non-irAEs cohorts, except for total bilirubin level (P=0.026) and relapse (P=0.016). The disease control rate (DCR) in the irAEs cohort was higher than in the non-irAEs cohort (90.6% vs 70.4%, P=0.047). Median overall survival (OS) and median progression-free survival (PFS) were better in the irAEs cohort than in the non-irAEs cohort (OS: 21.2 vs 10.0 months, P<0.001; PFS: 9.0 vs 4.4 months, P=0.003). Multivariate COX regression analysis showed that irAEs were independent prognostic factors for OS and PFS (OS: HR=0.133, 95% CI: 0.039-0.452, P=0.001; PFS: HR=0.435, 95% CI: 0.202-0.934, P=0.033).ConclusionIrAEs correlated with improved DCR, OS, and PFS in advanced CCA patients receiving PD-1 inhibitors combination therapy.

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.