AUA 2021: NAXIVA - A Phase II Neoadjuvant Study of Axitinib for Reducing Extent of Venous Tumor Thrombus in Clear Cell Renal Cell Cancer with Venous Invasion: Translational Results 

( The American Urologic Association (AUA) annual meeting included a late-breaking abstract session including a presentation by Dr. Sarah Welsh discussing translational results of the NAXIVA trial, a phase 2 neoadjuvant trial of axitinib for reducing the extent of venous tumor thrombus in clear cell renal cell cancer with venous invasion. Venous tumor thrombus extension occurs in 4-15% of cases of renal cell cancer, and although surgery is performed with curative intent, mortality is high (5-15%). The concept of neoadjuvant targeted therapy to downstage venous tumor thrombus prior to extirpative surgery is appealing in order to reduce the extent of the venous tumor thrombus surgery, and potentially reduce morbidity and mortality of the operation. The NAXIVA trial provided the first level II evidence in this patient group, assessing the response of venous tumor thrombus to axitinib. The primary endpoint, first presented at GU ASCO 2021, of the percentage of evaluable patients with an improvement in venous tumor thrombus according to the Mayo classification was positive at 26.58%. Additionally, 35.29% of patients had a change in the surgical approach to a less invasive option. Median percent reduction in venous tumor thrombus height was 21.49%. Response rate (RECIST) was 61.90% with stable disease, 14.29% with a partial response, and 9.52% with progressive disease. In this presentation, Dr. Welsh and colleagues presented the results of translational studies examining the role of the tumor microenvironment and response to axitinib.

NAXIVA was a single-arm, single agent, multi-center, phase 2 feasibility study of 8 weeks axitinib in RCC patients with clear cell RCC prior to nephrectomy/thrombectomy. There were 21 patients recruited from December 15, 2017, through January 6, 2020, at five UK sites. Extensive translational sampling (tissue, blood, urine) was performed before starting axitinib, during treatment, and at nephrectomy. Samples were processed and analyzed for circulating tumor DNA (ctDNA; shallow whole-genome sequencing), tumor microenvironment (multiparameter immunofluorescence, flow cytometry), and cytokines (multiplex assays). The trial design for NAXIVA is as follows:

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Consistent with previous studies showing low detection of ctDNA in RCC, only 3/21 patients had detectable ctDNA at baseline (2 in plasma, 1 in urine); there was no concordance in the levels or composition of ctDNA between the plasma and urine.

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No patients with detectable ctDNA at baseline showed a RECIST response or had a change in surgical approach to axitinib.  Consistent with its mechanism of action, axitinib treatment reduced vessel density (CD34+ and CD31+CD34+) in all patients:

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There was a trend towards responders showing higher baseline vessel density and area, with a greater reduction after 8 weeks treatment than non-responders. Interestingly, responders also demonstrated lower CD8+PD1+ tumor infiltration consistent with previous data suggesting such patients may respond better to TKIs than immunotherapy:

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No individual cytokine or peripheral immune cell-based biomarkers have predicted response but the multiparameter analysis is ongoing.

Dr. Welsh concluded her presentation of the translation results of the NAXIVA trial with the following take-home messages:

  • Neoadjuvant axitinib reduced the extent of venous tumor thrombus, demonstrating a 37.5% response rate, and 41% of patient having a reduced extent of surgery after 8 weeks of axitinib treatment. As such, it is possible to use systematic therapy to downstage venous tumor thrombus and reduce extent of surgery
  • Small sample number limited statistical significance for translational endpoints, however, this analysis suggests: (i) high levels of baseline ctDNA may predict poor response, (ii) short (8 weeks) of axitinib treatment may preferentially affect neo-vessels, (iii) non-responders might have a higher T cell infiltrate, but the populations are shifted towards ‘exhausted’ or ‘regulatory’ phenotypes
  • Future neoadjuvant strategies should consider combination TKI plus immune checkpoint inhibition to improve response rates (but toxicity must also be considered)


Presented by: Sarah J. Welsh, Cancer Research UK Cambridge Centre Urological Malignancies Programme, Department of Surgery, University of Cambridge, Cambridge, UK

Co-Authors: James Jones, Stephan Ursprung, Christopher Smith, Ferdia Gallagher, Grant Stewart

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.

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