Adverse events of immune checkpoint therapy alone versus when combined with vascular endothelial growth factor inhibitors: a pooled meta-analysis of 1735 patients

Background Combining immune checkpoint therapy (ICT) and vascular endothelial growth factor inhibitors (VEGFi) may result in increased treatment-related and immune-related adverse events (TRAEs and irAEs) compared to ICT alone. This metanalysis was conducted to identify prospective phase II or III clinical studies that evaluated the toxicity profile of ICT + VEGFi compared to ICT alone. Methods A systematic search was performed across all cancer types and major databases until August 10, 2022, and screening was done by two independent investigators. Inclusion criteria included phase 2 or 3 studies with at least one arm of patients treated with combination therapy and one arm treated with monotherapy. Adverse event data were pooled using a restricted maximum likelihood fixed effects model, and heterogeneity using Cochran’s Q (chi-square) test. Results 7 out of 9366 studies met the inclusion criteria, and 808 and 927 patients were treated with ICT monotherapy and a combination of ICT with VEGFi, respectively. Only one study reported irAEs, so the analysis was restricted to TRAEs. The total number of TRAEs was significantly higher in the ICT + VEGFi group (RR:1.49; 95% CI 1.37 -1.62; p=1.5×10-21), and more frequent treatment withdrawals were attributed to TRAEs (RR:3.10; 95% CI 1.12-8.59; p=0.029). The highest TRAE effect size increases noted for rash (RR 6.50; 95% CI 3.76 – 11.25; p=2.1×10-11), hypertension (RR:6.07; 95% CI 3.69–10.00; p=1.3×10-12), hypothyroidism (RR:5.02; 95% CI 3.08 – 8.19; p=8.9×10-11), and diarrhea (RR:4.94; 95% CI 3.21–7.62; p=3.8×10-13). Other significantly more frequent TRAEs included nausea, anemia, anorexia, and proteinuria. Conclusion Combination therapy with ICT and VEGFi carries a higher risk of certain TRAEs, such as rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria, compared to ICT monotherapy. More granular details on the cause of AEs, particularly irAEs, should be provided in future trials of such regimens.


Eligibility criteria
5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.
Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.
Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.

Selection process
8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

Data collection process
9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

Data items 10a
List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
10b List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

Study risk of bias assessment
11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

Effect measures
12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.

Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.
13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).
13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

Reporting bias assessment
14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).
Certainty 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Location
where item is reported assessment

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

Study characteristics
17 Cite each included study and present its characteristics.

Risk of bias in studies
18 Present assessments of risk of bias for each included study.

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

Results of syntheses 20a
For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.
20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.
20c Present results of all investigations of possible causes of heterogeneity among study results.
20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.
Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.

Certainty of evidence
22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.

Discussion
23a Provide a general interpretation of the results in the context of other evidence.
23b Discuss any limitations of the evidence included in the review.
23c Discuss any limitations of the review processes used.
23d Discuss implications of the results for practice, policy, and future research.