Vasculo-immune modulatory effects of anti-VEGF therapy in metastatic clear cell renal cell carcinoma: The A-PREDICT trial.

Abstract

572 Background: Anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors and checkpoint inhibitors (CPI) a standard-of-care treatment for clear cell renal cell carcinoma (ccRCC). We investigated the biology underpinning benefit of anti-VEGFR TKI in the phase II A-PREDICT trial (NCT01693822), evaluating pre- and post-treatment, fresh multiregion tumour biopsies in patients with metastatic ccRCC treated with first-line axitinib. Methods: We analysed 123 tumour samples from 52 patients, 28 with paired pre/post-treatment samples. Post-treatment samples included week-9, nephrectomy, and on-progression timepoints. ‘Responders’ had progression-free survival (PFS) ≥6 months (n=35), ‘non-responders’ with PFS <6 months (n=17). We applied a custom Nanostring panel for gene expression analysis and multiplex immunofluorescence (mIF) for orthogonal validation. Wilcoxin test was used to analyze paired observations. Results: At baseline, angiogenesis scores were similar between responders and non-responders (p=0.22). Post-treatment, the angiogenesis, vascular sprouting, and endothelial cell proliferation signature scores were significantly decreased (p=0.023, 0.0034, & 0.0082, respectively) in all patients, suggesting suppression of angiogenesis and neovascularisation irrespective of clinical outcomes. mIF in 3 patients (with PFS of 3, 5.6, & 100 months) confirms widespread intratumoral vessel depletion. Immune deconvolution analysis shows total levels of T cells and CD8 + T cells were similar pre- and post-treatment, suggesting axitinib did not enhance immune cell trafficking. Rather, axitinib promoted increased levels of exhausted CD8 + T cells post-treatment (p=0.01). M2 tumour-associated macrophages increased post-treatment in responders (p=0.033) but not in non-responders (p=0.44). A minority of patients had durable (>2 years) responses to axitinib (n=7/65, 6 with tissue for analysis). In these patients, we found higher levels of pre-treatment intratumoral cytotoxic immune cells (p=0.041) and NK cells (p=0.015) compared to patients with primary resistant disease. Conclusions: Axitinib suppressed angiogenesis and neovascularisation leading to intratumoral vessel depletion, and therapy response associates with features of an immunosuppressive TME. Baseline endogenous immune priming appears critical for durable response to anti-VEGF therapy. These data are relevant to understanding the clinical efficacy of combined anti-VEGF and CPI regimens. Clinical trial information: NCT01693822 .