Adverse events (AEs) of immune checkpoint therapy (ICT) combined with vascular endothelial growth factor inhibitors (VEGFi) vs. ICT alone: A pooled meta-analysis of 1735 patients.

person Iuliia Kovalenko UPMC Harrisburg, Harrisburg, PA info_outline Iuliia Kovalenko, Wern Lynn Ng, Yimin Geng, Raed Benkhadra, Pavlos Msaouel, Omar Alhalabi

Authors person Iuliia Kovalenko UPMC Harrisburg, Harrisburg, PA info_outline Iuliia Kovalenko, Wern Lynn Ng, Yimin Geng, Raed Benkhadra, Pavlos Msaouel, Omar Alhalabi Organizations UPMC Harrisburg, Harrisburg, PA, MD Anderson Cancer Center, Houston, TX, University of Texas Health Science Center at San Antonio, San Antonio, TX, University of Texas MD Anderson Cancer Center, Houston, TX, The University of Texas MD Anderson Cancer Center, Houston, TX Abstract Disclosures Research Funding No funding received None. Background: ICT combined with VEGFi are established as approved therapies for multiple malignancies. However, added toxicities remain unclear. We hypothesized that the combination of ICT + VEGFi has higher treatment-related AEs (TRAEs) and immune-related AEs (irAEs) compared with ICT alone. Methods: We performed a meta‐analysis to identify studies evaluating toxicity profile of ICT + VEGFi as compared to ICT. Systemic search was performed across all cancer types and major databases until August 10, 2022. Search structures, subject headings, and keywords were tailored to databases by medical research librarian. Screening of studies was done by two investigators. Inclusion criteria consisted of prospective phase II or III clinical studies which included at least one arm of patients treated with ICT + VEGFi and one arm treated with ICT alone. Restricted maximum likelihood fixed effects model was used to pool AEs data; I2 was used for heterogeneity. Results: From a total of 9366 studies found, seven met inclusion criteria. A total of 808 patients were treated with ICT while 927 were treated with ICT + VEGFi. Only one study reported irAEs. Therefore, we restricted our analysis to TRAEs. The total number of TRAEs (including grade 5) was significantly higher in ICT + VEGFi group with more frequent treatment withdrawals attributed to TRAEs. The list of TRAEs and specific effect sizes are summarized. The highest TRAE effect size increases with ICT + VEGFi were noted for rash (RR 6.50), hypertension (RR 6.07), hypothyroidism (RR 5.02), and diarrhea (RR 4.94). Conclusions: Combination therapy with ICT + VEGFi confers increased risk of specific TRAEs in comparison to ICT. Clinicians should be particularly mindful of the increased risk for rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria with ICT + VEGFi therapies. There are insufficient data on irAEs and future trials should provide more granular details on the AE cause. The risk of TRAEs in ICT + VEGFi versus ICT. Outcome Number of studies RR 95% CI P value i2 Total % of TRAEs 5 1.49 1.37 -1.62 1.5×10 -21 0.9 Grade 3-4 TRAEs 4 2.40 1.93 - 2.97 1.7×10 -15 0.68 Grade 5 TRAEs 4 2.86 1.29 - 6.31 9.1×10 -3 0 Treatment interruption due to TRAEs 5 1.28 0.99 - 1.65 5.7×10 -2 0.87 Treatment withdrawal due to TRAEs 3 3.10 1.12 - 8.59 2.9×10 -2 0 AG anemia 2 3.00 0.66 - 13.45 1.5×10 -1 0 AG anorexia 4 2.49 1.45 - 4.30 9.5×10 -4 0.23 AG lymphopenia 2 1.08 0.27 - 4.23 9×10 -1 0 AG diarrhea 5 4.94 3.21 - 7.62 3.8×10 -13 0.60 AG fatigue 4 1.18 0.82 - 1.69 3.5×10 -1 0 AG hypertension 3 6.07 3.69 - 10.00 1.3×10 -12 0 AG hypothyroidism 2 5.02 3.08 - 8.19 8.9×10 -11 0 AG nausea 4 3.10 1.93 - 5.00 3.1×10 -6 0.59 AG proteinuria 2 2.15 1.55- 2.97 3.6×10 -6 0.05 AG pruritus 2 0.70 0.43 - 1.13 1.5×10 -1 0.42 AG rash 4 6.50 3.76 - 11.25 2.1×10 -11 0.77 RR – relative risk; CI – confidence interval; AG - any grade.