Neoadjuvant axitinib plus avelumab in patients with high risk localized clear cell renal cell carcinoma: the NeoAvAx trial

Abstract

Neoadjuvant immunotherapy is more effective than adjuvant treatment in melanoma and lung cancer, but limited data are available for renal cell carcinoma (RCC). In NeoAvAx, a single arm phase II clinical study, 40 patients with high risk localized clear cell renal cell carcinoma (ccRCC) received 3 months of axitinib (VEGFR1-3 inhibitor) and avelumab (anti-PDL1) followed by nephrectomy. The primary endpoint was safety and radiographic response rate (RECIST 1.1) to systemic treatment. All patients were evaluable for the study endpoints and underwent surgical resection within 14 weeks of starting systemic therapy. Ten (25%) patients had a radiographic partial response with a median downsizing of the primary tumor of 18.7% (0-43.9%). No new safety signals were seen with Grade 3-4 adverse events in 6 (15%) patients. Fifteen (38%) patients showed a pathologic response of which three (7.5%) patients had a major pathologic response (<10% vital tumor). After a median follow-up of 52.9 months, a recurrence occurred in 22 patients (55%), and the median disease-free (DFS) survival was 25.1 months. Seven (18%) patients died of ccRCC, all of whom were pathologic non-responders. Pathological responders showed higher levels of various innate immune cells, while TLS and activated DC signatures associated with improved DFS. Treatment induced CD8 T-cell infiltration into the tumor in both pathological responders and non-responders (p=0.019). The persistence of expanded TCR-clones during treatment is associated with improved DFS (log-rank p=0.014, Cox PH HR=0.29, p=0.0041). Patients with a higher post-treatment TCR-diversity demonstrate improved DFS (log-rank p=0.002, Cox PH HR=0.125, p=0.037). Neoadjuvant treatment is safe, induces deep pathological responses in a subset of patients and may promote the development of long-lasting immune responses. Information about the pathologic response, gene expression signatures and CD8 T-cell influx may help to design personalized adjuvant therapies and individualized surveillance protocols.