Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor.
NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity.
In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype.
NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery.
Clinical trial registration
NAXIVA was a single-arm, multi-centre, phase 2 study including 20 patients with resectable clear cell renal cell carcinoma (ccRCC) and venous tumour thrombus (VTT). Patients were pre-treated up to 8 weeks with axitinib before surgery. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned and 35% (7/20) of patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with renal vein (RV)-only VTT. No patients had an increase in Mayo level.
This is the largest prospective study today assessing single agent VEGFR-TKI in tumour thrombus reduction and its effect on surgical management. Tumour thrombectomy is a complex and morbid operation and therefore reducing the size of thrombus is an appealing attempt.
In this trial, majority of patients had tumour thrombus reduction in 2-51% and 12-68 mm in length and 4 patients had thrombus length growth 1-34 mm. Surgical plan to less invasive or less extensive after reduction of tumour thrombus was amended in less than half of the cases. Notably, patients with planned venovenous bypass and hypothermic cardiac arrest did not require these manoeuvres after reduction of thrombus. Nevertheless, it is unknown, if this would consequently have any survival advantage as yet overall survival has not been proven significantly different when the thrombus locates in any part of IVC (1). However, survival difference has been demonstrated after thrombectomies in renal vein in contrast to IVC (1). Six patients experienced intraoperative complications which was mainly bleeding. Overall postoperative complications were reported in 35%, Clavien-Dindo grade ≥3 11.8%, mortality 5.9% which is similar to thrombectomies without medical treatment (2). Earlier attempts of neoadjuvant trials with pazopanib and axitinib (3,4) to reduce the size of the tumour and consequently to perform a partial nephrectomy is feasible but morbidity is high and its long term relevance remains unclear. Also neoadjuvant nivolumab in high risk RCC has demonstrated perioperative surgical feasibility (5). Despite the positives, neoadjuvant therapy also entails risks of non-responders such as metastatic progression (11%) and becoming unfit for surgery (1 patient). In the trial, 4 enrolled patients were precluded from surgery for mainly these reasons. However, rapidly progressing tumours under medical therapy are also poor candidates for surgery and it could be used as a litmus test for biologically aggressive disease.
Survival in patients with tumour thrombus is also driven by tumour biology and neoadjuvant studies are excellent ways for describing the changes in tumour microenvironment (6). Here, the authors found association between responders and non-responders; non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype. Further analysis could describe microenvironment changes also in the thrombus since it could differ from the primary tumour.
NAXIVA provides the first level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery.