Exploratory analysis from NEOAVAX, a neoadjuvant trial of avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy.

4509 Background: NEOAVAX (NCT03341845) is an open label, single arm, phase II trial, investigating 12 weeks of neoadjuvant avelumab/axitinib prior to nephrectomy in 40 pts with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4 cN0-1 M0, Grades 3-4). Dynamic on-treatment increase of CD8+ tumor infiltrating lymphocytes (TILs) in the tumour microenvironment (TME) and the primary endpoint (radiographic partial response rate (RECIST 1.1) in the primary tumour (PT) in ≥25%) were reported previously together with safety and tolerability [1]. Methods: Exploratory analysis included pathologic response in the PT according to the International Neoadjuvant Melanoma Consortium (INMC) and multiplex immune histochemistry (IHC) of the TME including CD8+, CD8-granzyme-B+, CD8+CD39+, Foxp3+ cells and MHC-I in paired samples (pre-treatment biopsy and nephrectomy) from 40 pts;. IHC data were compared to RECIST 1.1 and pathologic response in the PT, and recurrence; Visium spatial transcriptomics was performed on 18 PT from pts with diverging clinical outcome. Results: The majority of pts (n=25 (62.5%) had no pathologic response (pNR) by INMC criteria. Twelve patients (30%) had a partial (pPR) and 3 (7.5%) a major pathological response (MPR). There was no association between pathological and radiographic response of the PT. Recurrence occurred in 1 of 3 pts (33%) with MPR at 36 mo, in 7 of 12 (58%) with a pPR at a median of 12 mo and in 14 of 25 (56%) with pNR at a median of 3 mo. Of 25 pts with pNR 7 died of disease (DoD; 28%). On IHC, intratumoural CD8+CD39+ on post-treatment PT samples was significantly associated with recurrence (p<0.0001). MPR associated with spatial co-localisation of tumour cells with tissue-resident macrophages, CD8+ cytotoxic T-cells, memory T-cells and B-cells. Gene Set Enrichment Analysis (GSEA) results for Reactome pathways in each Visium tumor spot cluster demonstrated intratumoural heterogeneity in post-treatment PT in select patients. Conclusions: Pathologic response and IHC post-treatment influx of CD8+CD39+ TILs associates with prolonged disease-free survival following neoadjuvant avelumab/axitinib. Particularly, pts with MPR had distinct spatial co-localisation gene signatures of tumour and immune cells in the TME. Despite 3 months of treatment, 62.5% of pts had no pathologic responses (defined by INMC as >50% vital tumour remaining in the tumour bed). [1] Bex A et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx), in 2022 ASCO Genitourinary Cancers Symposium . Journal of Clinical Oncology, Volume 40, Number 6_suppl, https://doi.org/10.1200/JCO.2022.40.6_suppl.2. Clinical trial information: NCT03341845 .