Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Although combination therapy with immune checkpoint inhibitors (ICIs) provides a promising efficacy in multiple cancers, their use is facing challenges for a high incidence of adverse effects. This meta-analysis was conducted to compare the risks of organ-specific immune-related adverse events (IRAEs) associated with ICI monotherapy versus combination therapy among cancer patients.Methods: Electronic databases were systematically searched to include eligible randomized controlled trials (RCTs). Any-grade and 3-5 grade IRAEs (colitis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism, and hypophysitis) were extracted for meta-analysis. Two reviewers independently assessed the methodological quality. The RevMan 5.3.5 software was used for meta-analysis.Results: A total of 10 studies involving 8 RCTs with 2716 patients were included in this study. The most common any-grade adverse event was colitis (14.5%), followed by hypothyroidism (13.8%), hepatitis (10.4%), hypophysitis (10.0%), hyperthyroidism (9.3%), and pneumonitis (4.6%). Meta-analysis showed that ICI combination therapy significantly increased the risks of any-grade IRAEs in colitis [relative risk (RR), 3.56; 95% confidence interval (CI), 1.56-8.12; p < 0.05], pneumonitis (RR, 2.31; 95% CI, 1.54-3.45; p < 0.05), hepatitis (RR, 2.54; 95% CI, 1.65-3.91; p < 0.05), hypothyroidism (RR, 2.17; 95% CI, 1.71-2.76; p < 0.05), hyperthyroidism (RR, 3.13; 95% CI, 2.08-4.70; p < 0.05), and hypophysitis (RR, 3.54; 95% CI, 2.07-6.07; p < 0.05) compared with ICI monotherapy, as well as 3-5 grade IRAEs in colitis (RR, 2.50; 95% CI, 1.62-3.86; p < 0.05), pneumonitis (RR, 1.99; 95% CI, 1.00-3.93; p = 0.05), and hepatitis (RR, 2.70; 95% CI, 1.29-5.63; p < 0.05). Conclusions:This meta-analysis demonstrated that, compared with ICI monotherapy, patients receiving ICI combination therapy significantly increased organ-specific IRAEs in colitis, hypothyroidism, hepatitis, hypophysitis, hyperthyroidism, and pneumonitis. The incidence and severity of organ-specific IRAEs were drug and dose independent.

Immune Checkpoint Inhibitor-Related Pneumonitis

“…It has been suggested that lung toxicity might be a class effect of anti-PD-1 agents since pneumonitis is more frequent with PD-1 monoclonal antibodies compared to anti-cytotoxic T-lymphocyte-4 (anti-CTL-4) [13] and compared to anti-PD-L1 [31], though the latter is not a uniform finding in all studies [32]. Importantly, it seems that combination immunotherapy (anti-PD-1/PD-L1 in combination with anti-CTL-4) is associated with a higher prevalence of lung toxicity compared to monotherapy [24, 26, 33]. In a recent meta-analysis, the relative risk of pneumonitis was 2.92 (95% CI: 1.60, 5.33; p = 0.0005) in patients who received combination immunotherapy compared to patients who received monotherapy [34].…”

Immune Manifestations with Checkpoint Inhibitors in a Single Brazilian Center: Experience and Literature Review

“…In the series from the city of São Paulo, hypothyroidism was frequent (53%), hyperthyroidism was rare, followed by signs of toxicity in the hypothalamic-pituitary-adrenal axis indicated by hypophysitis (16%). However, isolated autoimmune adrenocorticotropic hormone deficiency was identified in five out of 81 patients with endocrine autoimmunity [11][12][13]. Type 1 diabetes was also observed but was uncommon; however, some have reported this disease more frequently.…”

Feasibility of Integrating a Mobile Decision-Support App into a Multicomponent CME Initiative: Developing Clinician Competence at the Point of Care

“…With nearly 75,000 screen views, the extensive use of the EIOCC IO Toxicity tool provided valuable insights into clinical practice behaviour and learner needs. For instance, a recent meta-analysis of irAEs found that pneumonitis occurred with the lowest prevalence (4.6%) of six toxicities evaluated, including colitis (14.5%) and hepatitis (10.4%) [9]. By comparison, based on the proportion of total screen views, we observed that guidelines for pneumonitis were the second-most frequently accessed (19%), following colitis (22%) and similar to hepatitis (19%); algorithms for arthritis/arthralgia (11%) and rash (11%) were much less commonly accessed.…”