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)

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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: NCT03494816.

Conflict of interest statement

GDS—educational grants from Pfizer, AstraZeneca and Intuitive Surgical; consultancy fees from Pfizer, Merck, EUSA Pharma and CMR Surgical; Travel expenses from Pfizer and Speaker fees from Pfizer. TE—employment: Roche (current), AstraZeneca (to March 2020); stock: AstraZeneca, Roche; research support: AstraZeneca, Bayer, Pfizer. FAG—research support from GE Healthcare; Grants from GSK; Consulting for AZ on behalf of the University of Cambridge. KF has received advisory, consultancy or speaker fees from ESAI, Ipsen, Roche, Novartis, Merck, Pfizer, EUSA Pharma, BMS, MSD and Sanofi and conference support from Novartis, Ipsen, MSD and EUSA Pharma and Institutional research funding from Roche, Merck and Exelixis. AB received honoraria for participation in advisory boards for Pfizer, Novartis, and Ipsen, and an educational grant from Pfizer. RJ has received educational grants from Astellas, Bayer, Clovis and Exelixis; consultancy fees from Roche, AstraZeneca, Bristol Myers Squibb, Bayer, Novartis/AAA, Astellas, Janssen, MSD, Pfizer, Merck Serono; honoraria from Roche, AstraZeneca, Bristol Myers Squibb, Bayer, Astellas, Janssen, MSD, Pfizer, Merck Serono; conference support from MSD and Bayer; advisory board payment from Roche. The remaining authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Description of Mayo level and study cohort.

a Summary of Mayo level, figure adapted from ref. [37]. b Consort diagram. *Participants who had at least one dose of the study drug were included in the evaluable population, irrespective of whether surgery was performed.

Fig. 2. Mayo level at baseline, week 3 and week 9 for eligible and evaluable patients.

Note that N105 had a RV-only VTT response receding from the medial to the insertion of the gonadal vein to lateral to it. Supplementary Fig. S1 shows examples of two IVC responder patients.

Fig. 3. Percentage change in VTT length over the axitinib treatment period.

a Line chart showing percentage change in VTT length for IVC responders, RV responders and non-responders. Waterfall plot of VTT response against tumour response at (b) 3 and (c) 9 weeks of treatment. N0601 (surgery expedited), N0605 (surgery expedited) and N0903 (exited trial due to new brain metastasis) did not have scans at week 9. Bar colour indicates the patient’s overall RECIST status distinct from VTT assessment.

Fig. 4. Immumofluorescence analysis of baseline biopsies.

Representative images of baseline biopsies stained for a blood vessels (CD31), b proliferating cells (Ki67) and e CD8 + T-cell activation status (Granzyme B and PD-1). Whole slides were scanned and quantified using automated computer image analysis on HALO (c, d, f–h two-tailed Student t test).