Daily Oral Everolimus Activity in Patients with Metastatic Pancreatic Neuroendocrine Tumors after Failure of Cytotoxic Chemotherapy

Background: No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mTOR, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. Methods: This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs progressing on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/day [n = 115]; stratum 2: everolimus 10 mg/day plus octreotide long-acting release [LAR; n = 45]). Tumor assessments (RECIST) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results: By central radiology review, in stratum 1, there were 11 (9.6%) partial responses (PR), 78 (67.8%) stable disease (SD), and 16 (13.9%) progressive disease (PD); median progression-free survival (PFS) was 9.7 months. In stratum 2, there were 2 (4.4%) PR, 36 (80%) SD and 0 PD; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Co-administration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. Conclusion: Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by ORR and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy. Sponsor:This study was sponsored by Novartis Pharma AG, Basel, Switzerland.