Activity and Safety of Avelumab in High-Grade Neuroendocrine Tumors and Poorly Differentiated Neuroendocrine Carcinomas Progressive after Chemotherapy (AveNEC Trial)

Abstract Purpose: Neuroendocrine neoplasms grade 3 (NEN G3) are rare tumors with poor prognosis and no established second-line therapy. The role of immune checkpoint blockade in these aggressive tumors remains unclear. Patients and Methods: The phase II AveNEC study evaluated the effect of avelumab (AVE, 10 mg/kg i.v. every 2 weeks) in 60 patients with well-differentiated high-grade neuroendocrine tumors (N = 22) or poorly differentiated neuroendocrine carcinomas (N = 38) progressing after ≥1 prior chemotherapy (excluding Merkel cell carcinoma and small cell lung cancer). Results: The best overall response according to immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) was partial response (PR) in three (5%) and stable disease (SD) in nine (15%) patients, with a disease control rate at 16 weeks of 15% (3 PRs; 6 SDs) and a median duration of response of 4.3 months. Six (10%) patients achieved SD or PR for >6 months and two for >1 year. Response rates were similar regardless of differentiation, Ki-67 expression, or primary localization. The median progression-free survival was 1.9 months, and the overall survival was 6.6 months. After a median follow-up of 3.6 years, only four (7%) patients were still alive; 1- and 2-year survival rates were 33% and 17%, respectively. Responders had a significantly longer overall survival of 30.2 months compared with 4.8 months in nonresponders. AVE was well tolerated, with few treatment-related grade 3/4 adverse events, and the quality of life remained stable during treatment. Conclusions: In patients with progressive high-grade NEN G3, AVE was well tolerated and provided disease control with significant clinical benefit in 15% of heavily pretreated patients.