Angiogenic and Immune Predictors of Neoadjuvant Axitinib Response in Renal Cell Carcinoma with Venous Tumour Thrombus

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. We conducted a multiparametric investigation of samples collected during NAXIVA using digital pathology, flow cytometry, plasma cytokine profiling and RNA sequencing. Responders had higher baseline microvessel density and increased induction of VEGF-A and PlGF during treatment. A multi-modal machine learning model integrating features predicted response with an AUC of 0.868, improving to 0.945 when using features from week 3. Key predictive features included plasma CCL17 and IL-12. These findings may guide future treatment strategies for VTT, improving the clinical management of this challenging scenario. One Sentence SummaryA comprehensive multiparametric assessment of the effect of neoadjuvant axitinib in renal cell carcinoma patients with venous tumour thrombus was performed on tissue and peripheral blood, including an integrative machine learning model, which identified both angiogenic and immune determinants of response to therapy.