Abstract 6712: Analysis of VEGF as a potential complimentary target with immunotherapy
Authors: Newton Yulia , Szeto Christopher W. , Benz Stephen C. , Reddy Sandeep K. 
Published: September 2020

Abstract
Background: Angiogenesis is a hallmark of malignancy and greatly contributes to tumor growth and dissemination to metastatic sites. Vascular endothelial growth factors (VEGFs) are major members of angiogenesis signaling and have been shown to have immunosuppressive function. Bevacizumab (Bev), a VEGF inhibitor, in combination with immune checkpoint inhibitor (ICI) therapy and chemotherapy, has been shown in a previous clinical trial to improve outcomes in lung cancer versus chemotherapy plus Bev, even in PDL1-low and negative tumors. (IMPOWER150). Tumor mutation burden (TMB) has been established as a biomarker of ICI response, independent of PDL1. We set out to explore the relationship between VEGF signaling and TMB.
Methods: We performed a retrospective analysis of data from the NantHealth database of 2,737 commercial cases where matched WGS or WES and RNA-Seq were performed. Primary and metastatic breast tumors were included in the analysis. TMB was computed as the count of SNVs per tumor sample. Bowtie2, RSEM, and custom software are used for alignment, transcript quantification and variant analysis. Per-tumor type analysis was performed to find VEGF signaling correlates with TMB and a panel of immune markers (n = 9).
Results: Overall TMB does not correlate with PDL1, PDL2, CTLA4 and other immune markers' expression (spearman range [-0.01 - 0.15]). We also observed that overall TMB does not exhibit strong correlations with VEGF signaling markers (spearman range [-.17 - .17]), however when limited to TMB-low tumors VEGFA and VEGFD positively correlate with TMB (p = 1e-5 and 4.1e-2) and VEGFE negatively correlates with TMB (p = 1.6e-4). We then limited our analysis to PDL1-low tumors, of which the top three categories by sample counts are breast (n = 103), colon (n = 85), and sarcoma (n = 78). In whole-cohort analysis, we observed significantly higher expression of VEGFE and VEGFR2 (p = 1.4e-2 and 2.8e-2) in TMB-low tumors. When performing the same analysis in individual tissue types we observed significantly differentially higher expression of VEGFA and PGF (p = 2.1e-2 and 3.3e-2) in TMB-high colon samples, of VEGFR2 (p = 1.5e-2) in TMB-low NSCLC tumors, and of VEGFR2, FOS, and FOXO1(p = 1.9e-2, 3.4e-2, 6.2e-3) in TMB-low uterine endometrial tumors.
Conclusions: We provide evidence that targeting VEGF signaling in some tumor types, especially in tumors with low TMB, might provide a boost to therapeutic effects of checkpoint inhibitors. Our findings warrant further translational interrogation of the potential efficacy with a combination of VEGF inhibitors and ICI in various cancer types. For example, NCT03971474, a trial of ramucirumab (anti-VEGFR2 MAb) plus pembrolizumab in NSCLC, may produce differential activity in TMB-High v TMB-Low cohorts.
Citation Format: Yulia Newton, Christopher W. Szeto, Stephen C. Benz, Sandeep K. Reddy. Analysis of VEGF as a potential complimentary target with immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6712.