Angiogenic and immune predictors of neoadjuvant axitinib response in renal cell carcinoma with venous tumour thrombus.

Abstract:: Abstract Venous tumour thrombus (VTT), where the primary tumour invades the renal vein and inferior vena cava, affects 10–15% of renal cell carcinoma (RCC) patients. Curative surgery for VTT is high-risk, but neoadjuvant therapy may improve outcomes. The NAXIVA trial demonstrated a 35% VTT response rate after 8 weeks of neoadjuvant axitinib, a VEGFR-directed therapy. However, understanding non-response is critical for better treatment. Here we show that response to axitinib in this setting is characterised by a distinct and predictable set of features. We conduct a multiparametric investigation of samples collected during NAXIVA using digital pathology, flow cytometry, plasma cytokine profiling and RNA sequencing. Responders have higher baseline microvessel density and increased induction of VEGF-A and PlGF during treatment. A multi-modal machine learning model integrating features predict response with an AUC of 0.868, improving to 0.945 when using features from week 3. Key predictive features include plasma CCL17 and IL-12. These findings may guide future treatment strategies for VTT, improving the clinical management of this challenging scenario.

Authors:: R Wray, H Paverd, I Machado, J Barbieri, F Easita, AR Edwards, FA Gallagher, IA Mendichovszky, TJ Mitchell, M de la Roche, JD Shields, S Ursprung, L Wallis, AY Warren, SJ Welsh, M Crispin-Ortuzar, GD Stewart, JO Jones, NAXIVA Study Group

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