Biomarker and imaging characterisation of inflammatory atheroma in patients receiving immunotherapy and angiogenesis inhibitors (BIOCAPRI): a prospective study using positron emission tomography

Background Immune checkpoint inhibitors (ICI) can be a highly effective cancer therapy. In addition to myocarditis, they are associated with increased risk of myocardial infarction (MI) and stroke. This may reflect inflammatory plaque activation. Retrospective analyses of arterial inflammatory activity in patients treated with ICI have produced conflicting results and there have been no prospective studies. ICI are commonly used in conjunction with vascular endothelial growth factor inhibitors (VEGFI) which are also associated with atherothrombosis. It is unknown whether the combination alters arterial inflammation. Purpose 1) To make prospective, controlled assessment of the effect of ICI on arterial inflammation; 2) To compare arterial inflammatory effects in patients receiving ICI or VEGFI monotherapy versus those treated with ICI+VEGFI. Methods Prospective observational study of patients with cancer receiving either VEGFI monotherapy, ICI monotherapy or ICI+VEGFI. Arterial inflammation was assessed using fluorodeoxyglucose positron emission tomography computed tomography ([18F]FDG-PETCT) before and after 24 weeks of therapy. The primary outcome was change in maximal arterial tissue-to-background ratio (TBRmax) at 24 weeks. Echocardiograms and biomarker analyses were also performed. Results Fifty-five patients were enrolled (VEGF: n=15; ICI: n=20; VEGFI+ICI: n=20), mean age was 66±9 years, 29% were female, 70% had renal carcinoma and 75% were treated with palliative intent. Cardiovascular risk factors were highly prevalent and comparable in all groups; 18% had a history of MI or stroke. Compared to pre-treatment, at 24 weeks TBRmax had not increased in any group (VEGFI: 1.7±0.2 vs 1.7+0.2; ICI: 1.7±0.1 vs 1.7±0.1; VEGFI+ICI: 1.6±0.2 vs 1.8±0.2) and there was no difference in TBRmax between groups (p=0.17). Sensitivity analyses of only large or small arteries, calcified or non-calcified arterial segments and in those with or without a prior MI or stroke provided consistent results. Five were treated with methylprednisolone for immune-related toxicity (2 myocarditis; 3 colitis). There was no association between this and TBRmax findings. No ischaemic events occurred. Cancer treatment-related cardiac dysfunction occurred in 5 patients (2 VEGFI monotherapy; 3 ICI+VEGFI). Cardiac biomarkers (troponin T and N-terminal pro B-type natriuretic peptide), C-reactive protein and neutrophil:lymphocyte ratio did not differ between groups and did not rise over time. Conclusions Using gold standard PET imaging methods, we found no evidence that ICI and VEGFI (alone and in combination) are associated with substantial arterial inflammation. This is the first prospective, controlled PET study in patients treated with ICI and the first to make clinically relevant assessments in patients treated in combination with VEGFI. Further work should examine non-inflammatory thrombotic pathways in the mediation of ICI-associated ischaemic events.