Adverse effects of immune checkpoint inhibitors in advanced endometrial cancer: A systematic review and meta-analysis.

Abstract

5610 Background: Immune checkpoint inhibitors (ICIs) in combination with chemotherapy have become a standard first-line treatment for advanced endometrial cancer with increased response rate and progression free survival. While immune-related adverse effects (irAEs) are expected, it is interesting to know the rate of all treatment-related adverse effects (TRAEs). This meta-analysis evaluates the spectrum of adverse effects related to ICIs. Methods: Search of the PubMed, EMBASE and Cochrane Library for publications up to December 2024 yielded six randomized controlled trials (RCTs), namely RUBY, NRG-GY018, DUO-E, KEYNOTE-B21, AtTend, and MITO END-3 for this analysis. Uniformly, the experiment arms were ICIs plus paclitaxel and carboplatin, while the control arms were same chemotherapy agents, except the DUO-E trial included Olaparib in one of the experimental arms. The primary outcomes of this study were the pooled events of TRAEs and irAEs, analyzed using a random-effects model with RevMan 5.4. Results: A total of 3952 patients were included from 6 RCTs. The use of ICI was associated with irAEs, such as hypothyroidism, hyperthyroidism, rash and pneumonitis(Table). It was also associated with increased incidence of serious TRAEs (RR 1.64, 95%CI 1.09-2.48, p=0.02) and higher treatment discontinuation rates (RR 1.44, 95%CI 1.13-1.83, p=0.004). There was greater risk of hematologic toxicities, including anemia (RR:1.25, 95% CI 1.05-1.49), leukopenia (RR:1.40, 95% CI 1.10-1.77), and thrombocytopenia (RR:1.43, 95% CI 1.06-1.93) in ICI arm. ICI arm was at greater risk of hepatotoxicity (RR: 4.47, 95% CI 1.17-17.15), vomiting (RR: 1.43, 95% CI 1.19-1.73) and hypertension (RR:1.93, 95% CI 1.11-3.36). There were no significant differences in peripheral neuropathy (RR:0.96, 95%CI 0.89-1.04), fatigue (RR:1.04, 95%CI 0.95-1.13), infusion related reactions (RR: 1.11, 95% CI 0.51-2.39), arthralgias (RR:0.58, 95% CI 0.21-1.57), or fatal TRAEs between the two treatment groups(RR:1.21,95% CI 0.69-2.12). Conclusions: Advanced endometrial cancer treatment with ICIs is linked to a diverse array of adverse effects. Patients in the ICI and chemotherapy arm demonstrated an increased risk of hematologic toxicity, hepatotoxicity, irAEs and higher treatment discontinuation rate compared to chemotherapy alone. However, no notable difference was observed in fatal TRAEs. Events Number of studies (n) Number of patients included (N) Risk Ratio, 95% Confidence Interval P value TRAEs Any grade 6 3830 1.00 [0.99-1.00] 0.25 Serious 5 2095 1.64 [1.09-2.48] 0.02 Leading to discontinuation of treatment 4 2524 1.44 [1.13-1.83] 0.004 Immune mediated Fatal 5 2095 1.21 [0.69-2.12] 0.51 Any irAE 4 2524 2.30 [1.59-3.31] <0.00001 Rash 4 2159 2.96 [1.31-6.69] 0.009 Hyperthyroidism 4 2802 3.32 [2.22-4.97] <0.00001 Hypothyroidism 6 3830 3.98 [2.87-5.52] <0.00001 Pneumonitis 4 2802 2.48 [1.18-5.18] 0.02