Abstract
ObjectivesImmune checkpoint inhibitors (ICIs) have brought impressive benefits to cancer patients, however often accompanied with immune-related adverse events (irAEs). We aimed to investigate the association of irAEs with efficacy and overall survival in cancer patients treated by ICIs, and further quantify the association by stratifying subgroups.MethodsPubMed, EMBASE and Cochrane library from database inception to 29 August 2019 were systematically searched. Articles reporting association of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) with irAEs in cancer patients treated with approved ICIs were included. Adjusted odds ratios (OR) with 95% confidential intervals (CIs) were calculated for ORR, and hazard ratios (HR) were used for PFS and OS.ResultsA total of 52 articles comprising 9,156 patients were included. Pooled data demonstrated a statistically significant greater probability of achieving objective tumor response for patients with irAEs compared to those without (OR 3.91, 95% CI 3.05–5.02). In overall meta-analysis, patients who developed irAEs presented a prolonged PFS (HR 0.54; 95% CI 0.46–0.62) and OS (HR 0.51; 95% CI 0.41–0.59). More specifically, irAEs in certain cancer types (NSCLC and melanoma) and organs (skin and endocrine) were robustly associated with better clinical outcomes, while this association needs further verification regarding other tumors. High grade toxicities (G3–5) were not associated with a significantly favorable PFS or OS. Additionally, the association between irAEs and clinical benefit seemed to be more definite in patients receiving PD-(L)1 blockade than CTLA-4 blockade. Pooled data from landmark analyses displayed consistent results.ConclusionsThe occurrence of irAEs predicted improved tumor response and better survival in overall cancer patients treated with ICIs. Notably, the association stayed robust in certain cancer types (NSCLC and melanoma) and organ-specific irAEs (skin and endocrine).
Highlights
With the recent tremendous advances in cancer immunotherapy, the use of immune checkpoint inhibitors (ICIs) has brought remarkable benefit to patients with variable cancers [1, 2]
The studies met the following inclusion criteria were eligible for the meta-analysis: [1] studies assessing inhibitors of PD-(L)1, cytotoxic Tlymphocyte antigen 4 (CTLA-4), or both in cancer patients; [2] studies with data available for detailed events number who achieved objective tumor response, or provided the adjusted odd ratio (OR) for objective response rate (ORR) and/or the adjusted hazard ratio (HR) for Progression Free Survival (PFS) and/or the adjusted HR for Overall Survival (OS) based upon immune-related adverse events (irAEs) presence; [3] The most informative or recent publication was selected in case of studies from the same institution with similar or duplicated subjects
Pooled data of available landmark studies revealed the occurrence of any grade of irAEs was positively associated with durable clinical benefits (PFS and OS) in cancer patients treated with ICIs
Summary
With the recent tremendous advances in cancer immunotherapy, the use of immune checkpoint inhibitors (ICIs) has brought remarkable benefit to patients with variable cancers [1, 2]. Like cytotoxic Tlymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1), play key roles in immune homeostasis by controlling immune responses, maintaining self-tolerance and preventing autoimmunity. PD-1 is mainly present on non-lymphoid cells in peripheral tissues; it generates local tolerance by dephosphorylating the Tcell receptor, leading to T-cell exhaustion [8]. Antibodies against these immune checkpoints can directly release negative immune regulation of checkpoint and reactivate anti-tumor effect of cytotoxic T cells [9]. Certain irAEs like rash, colitis, and hypophysitis are more common with CTLA-4 blockade, while pneumonitis and hypothyroidism are more frequently with PD-1 blockade [11]
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