Pembrolizumab and Peptide Receptor Radionuclide Therapy for Patients with Metastatic Well-Differentiated Neuroendocrine Tumors

Abstract

Purpose: Objective responses to peptide receptor radionuclide therapy (PRRT) for pre-treated patients with well-differentiated neuroendocrine tumors (WD-NET) and Ki-67 index >10% may not be durable. Response rate to single agent immune checkpoint inhibitors for patients with WD-NET is low. Targeted radiation using PRRT may potentiate anti-tumor immune response. This study evaluated safety and efficacy of the combination of PRRT and the PD-1 inhibitor pembrolizumab in high-risk WD-NET. Patients and Methods: In a single arm prospective pilot study, adult patients with WHO grade 2 or 3 well-differentiated (Ki-67 index >10%) somatostatin receptor avid metastatic NET of any primary site received concurrent pembrolizumab and 177Lu-DOTATATE PRRT. Primary endpoint was objective response rate (ORR) by RECIST v.1.1. Secondary endpoints were progression free survival (PFS), overall survival, and safety. Results: A total of 26 patients were enrolled, including 20 patients with grade 3 NET. Median PFS was 13.3 months (range 2.1-33.4 months). ORR was 35%. Median overall survival was 24.1 months (range 4.4 to 52.3 months). Severe adverse events (SAE) occurred in 14 (54%) patients. The most common immune-related AEs were grade 1 or 2 hepatitis (n=7), grade 2 hypothyroidism (n=5), and diabetes mellitus (n=4). Clinical responses were associated with higher baseline frequencies of proliferating CD8+ T cells and lower frequencies of CD14+ myeloid-derived suppressor cells in the peripheral blood. Conclusions: Added benefit of CPI to PRRT for patients with high risk WD-NET remains unclear. SAE rate was higher than expected for PRRT alone.