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.