Neoadjuvant Axitinib May Successfully Downstage Venous Tumor Thrombus Extension in Clear Cell RCC

Treatment with neoadjuvant axitinib (Inlyta) appeared to have successful downstaging of venous tumor thrombus (VTT) extension to the renal vein or inferior vena cava in patients with clear cell renal cell carcinoma (RCC), according to findings from the phase 2 NAXIVA study (NCT03494816).

Within the overall population (n = 20), investigators reported an overall response rate, defined as reduction in the extend of VTT by Mayo level after 8 weeks of therapy, of 35%. Broken down by location, response rates were 37.5% (6/16) for inferior vena cava (IVC) VTT and 25% (1/4) for renal vein–only VTT. No patients had an increase in Mayo level VTT. In total, 41.2% of patients who received surgery had less invasive surgery than anticipated.

In the single-arm, open-label, multisite feasibility study, patients with M0 and M1 disease were treated with axitinib for 8 weeks. Patients received axitinib at an initial dose of 5 mg followed by 7 mg and 10 mg every 2 weeks as tolerated. Dose reductions were permitted, and patients paused treatment from 36 hours to 7 days prior to surgery at week 9. The study’s primary end point was VTT response with secondary end points included change in surgical approach, change in VTT length, response rate, and surgical morbidity (FIGURE).

FIGURE. Patients with clear cell renal cell carcinoma may experience successfully downstaging of venous tumor thrombus extent with neoadjuvant axitinib.

To be included in the trial, patients were required to have either renal vein (cT3a) or IVC ITT (cT3b or cT3c), N0/1, M0/1, and biopsy-confirmed clear cell RCC. Additional enrollment criteria included eligibility for immediate surgical resection, an ECOG performance status of 0 or 1, less than 2 g of urinary protein per 24 hours, a creatinine ratio of less than 200 mg/mmol, and serum creatinine of 1.5 ULN or less or an estimated creatine clearance of 30 mL per minute.

Surgical approach was determined based on MRI scan following axitinib treatment, in addition to treatment with an adjuvant venous procedure. Intraoperative procedures included thrombus milked into renal vein and side clamped; infrahepatic IVC clamping with no liver mobilization; retrohepatic IVC clamping below hepatic veins plus liver mobilization; suprahepatic infradiaphragmatic clamping; and suprahepastic supradiaphragmatic clamping.

A total of 21 patients across 5 centers were evaluable, although 1 patient was later found to not have VTT and was considered ineligible for assessment. Stable Mayo level was noted in 65% of patients. In the population with stable Mayo level, 7 of 13 patients experienced a reduction in VTT length after 8 weeks of treatment with axitinib, with 75% of patients overall (15/20) experiencing any degree of VTT reduction. Moreover, the response rate was 32.8% by inference procedures for Simon’s 2-stage minimax design (P = 3.395 × 10⁻⁵).

Investigators also reported that 20% of patients experienced an increase in VTT length, 2 of whom underwent surgery. Moreover, direct of VTT change at the week 3 MRI scan appeared to be predictive of response at 9 weeks. One patient achieved a partial response (PR) by RECIST criteria at 3 weeks, 19 had stable disease, and 1 had data missing. The PR rate increased to 41.2% by week 9.

A total of 17 patients received surgery and 4 patients did not. Reasons for not undergoing surgery included disease progression (n = 2) and partial response with performance status decline (n = 1). At week 9, a single patient with M0 disease achieved stable disease but declined surgery.

The most common serious adverse effects (AEs) included myasthenia gravis, pathologic fracture, hyperglycaemia, left cerebellar mass development, wound pain, confusion, and hyperkaliemia. No grade 4/5 AEs were reported.

Reference

Stewart GD, Welsh SJ, Ursprung S, et al. A phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA). Published online June 23, 2022. Brit J Can. doi:10.1038/s41416-022-01883-7