Infusion-related reactions with immune checkpoint inhibitors in genitourinary cancers: A systematic review and meta-analysis.
Authors: Fujiwara Yu , Koseki Mako , Estaris Jonathan , Elias Evelyn , Chesta Fnu , Takaoka Kensuke , Nishimura Yoshito , Gopalakrishnan Dharmesh 
Published: January 2024

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Background: Immune checkpoint inhibitors (ICIs) are widely used to treat genitourinary cancers, particularly urothelial carcinoma (UC) and renal cell carcinoma (RCC). Infusion-related reactions (IRRs) have been reported in up to 20% of all patients treated with ICIs. However, the risk of IRRs varies with the type of ICI and the accurate incidence in genitourinary cancers remains unclear. We undertook a systematic review and meta-analysis to determine the incidence of IRRs in patients with genitourinary cancers treated with ICIs. Methods: We performed a systematic search of PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized clinical trials (RCTs) evaluating ICIs (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], programmed cell death protein 1 [PD-1], and programmed death-ligand 1 [PD-L1] inhibitors) in patients with UC and RCC. The odds ratio [OR] of grade 1-5 and grade 3-5 IRRs was calculated and pooled by the random-effect model meta-analysis. Meta-analysis was performed based on study types as follows: 1) Studies with a design “ICI plus treatment A (including placebo/observation) vs. treatment A”, 2) Studies evaluating ICI monotherapy vs. chemotherapy in patients with UC, and 3) Studies assessing ICI plus vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) vs. sunitinib in patients with RCC. When IRRs were reported in studies evaluating oral VEGF-TKIs, IRRs were referred to as hypersensitivity or anaphylactic reactions, defined in each RCT. Results: We identified 12 RCTs with 10,001 participants for the meta-analysis, out of which one evaluated a CTLA-4 inhibitor while the others evaluated PD-1 or PD-L1 inhibitors. The addition of ICIs to other systemic therapies was associated with significantly higher rates of grade 1-5 IRRs (OR=2.90, 95% confidence interval [CI]: 1.16-7.29, p = 0.02) but not of grade 3-5 IRRs (OR=2.98, 95% CI: 0.64-13.74, p = 0.16). When compared to chemotherapy, PD-1 or PD-L1 inhibitor monotherapy was not associated with an increase in either grade 1-5 (OR=0.86, 95% CI: 0.25-2.95, p = 0.81) or grade 3-5 IRRs (OR=1.13, 95% CI: 0.07-18.19, p = 0.93) in patients with UC. When compared to sunitinib in patients with RCC, the combination of ICI plus VEGF-TKIs was not associated with an increase in either grade 1-5 (OR=5.43, 95% CI: 0.62-46.07, p = 0.13) or grade 3-5 IRRs (OR=3.49, 95% CI: 0.64-19.04, p = 0.15). Sensitivity analysis performed by removing studies evaluating avelumab did not alter the overall results (data will be presented). Conclusions: Compared to the previous standard of care without ICIs, therapies with ICIs were not associated with increased IRRs in genitourinary cancers. However, the addition of ICIs to other systemic therapies was associated with an increased incidence of IRRs. The latter merits further prospective evaluation and careful consideration while designing clinical trials.