Activity and safety of avelumab in high-grade neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas progressive after chemotherapy (AveNEC trial)

Abstract Background: Neuroendocrine neoplasias 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. Methods: The phase II AVENEC study evaluated the effect of avelumab (AVE, 10 mg/kg IV Q2W) in 60 patients with well-differentiated high-grade neuroendocrine tumors (NET G3, N=22) or poorly differentiated neuroendocrine carcinomas (NEC, N=38) progressing after ≥ one prior chemotherapy (excluding Merkel cell and small-cell lung cancer). Results: The best overall response according to iRECIST was partial response (PR) in 3 (5%) and stable disease (SD) in 9 (15%) patients, with a disease control rate at 16 weeks of 15% (3 PR, 6 SD), and a median duration of response of 4.3 months. Six patients (10%) achieved SD or PR for > 6 months and two for > one year. Response rates were similar regardless of differentiation, Ki67 expression, or primary localization. The median progression-free survival (PFS) was 1.9 months and overall survival (OS) was 6.6 months. After a median follow-up of 3.6 years, only four (7%) patients were still alive. One- and two-year survival rates were 33% and 17%, respectively. Responders had significantly longer OS of 30.2 months compared to 4.8 months in non-responders. AVE was well tolerated, with few treatment-related grade 3/4 adverse events, and quality of life remained stable during treatment. Conclusions: In patients with progressive high-grade NEN G3, avelumab was well tolerated and provided disease control with significant clinical benefit in 15% of heavily pretreated patients.