NAXIVA: A phase II neoadjuvant study of axitinib for reducing extent of venous tumor thrombus in clear cell renal cell cancer (RCC) with venous invasion.

275 Background: Venous tumor thrombus (VTT) extension occurs in 4-15% cases of renal cell cancer (RCC). The Mayo classification distinguishes 4 levels of VTT extension between the renal vein and supradiaphragmatic inferior vena cava (IVC). Although surgery is performed with curative intent, mortality is high (5-15%) with complications increasing with the level of the VTT. 5-year survival rates are poor; ~40-65% in non-metastatic RCC. It is hypothesised that neoadjuvant targeted therapy could downstage the VTT reducing the extent of surgery, leading to reduced surgical morbidity and mortality, and increased survival. However, level I or II evidence is lacking. NAXIVA provides the first level II evidence in this patient group, assessing the response of VTT to axitinib. Extensive translational sampling will provide in depth interrogation of VTT (using genomics, proteomics, immunophenotyping and metabolomics) to examine the role of the tumor microenvironment of VTT and response to axitinib. Methods: NAXIVA was a single arm, single agent, multi-center phase 2 feasibility study of axitinib in patients with both metastatic and non-metastatic clear cell RCC prior to nephrectomy and thrombectomy. A Simon two stage minimax design was adopted and the trial designed for adequate power to distinguish a <5% from a >25% improvement in the Mayo VTT level. 21 patients were recruited over a 24 month period between 15/Dec/2017 and 06/Jan/2020 at 5 sites across the UK. Patients were treated with 8 weeks of axitinib (starting dose 5mg bd, increasing to 10mg bd as tolerated) prior to planned surgery. The primary endpoint was the percentage of evaluable patients with an improvement in VTT according to the Mayo classification (assessed using MRI abdomen scans at screening and week 9, prior to surgery. Secondary endpoints were percentage change in surgical approach, percentage change in VTT height, response rate (by RECIST) and evaluation of surgical morbidity assessed by Clavien-Dindo classification. Results: The percentage of evaluable patients with an improvement in VTT according to the Mayo classification was 26.58% [80% CI: 15.76%, 39.74%] (6 of 21 evaluable patients). 35.29% (6 of 17 patients who progressed to surgery) had a change in surgical approach to a less invasive option. There was a median percentage reduction in VTT height of 21.49% (SD=27.60%). The response rate (by RECIST) in the evaluable population was 61.90% SD, 14.29% PR, 9.52% PD. In terms of surgical morbidity 11.76% (2 of 17 patients who progressed to surgery) experienced a Clavien-Dindo 3 or greater complication (0 CD3, 1 CD4, 1 CD5). Conclusions: NAXIVA provides unique prospective data on the feasibility of neoadjuvant axitinib administration to down stage IVC VTT and reduce the extent of surgery. Work is ongoing to establish predictors of response. Clinical trial information: NCT03494816 .