Efficacy and Safety of First-Line Everolimus Therapy Alone or in Combination with Octreotide in Gastroenteropancreatic Neuroendocrine Tumors. A Hellenic Cooperative Oncology Group (HeCOG) Study

Abstract

The purpose of this study was to explore the efficacy and safety of everolimus administered as a first-line treatment in newly diagnosed patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP NETs). This phase II, multicenter, single-arm study included patients with well-differentiated GEP NETs and a Ki67 < 20%. Everolimus, at 10 mg/day, was administered until disease progression; 18 patients (72%) concomitantly received octreotide long-acting release (LAR), at 30 mg/month. The primary endpoint was the 15-month progression-free survival (PFS) rate. Twenty-five patients (grade 1: 11 patients, grade 2: 14 patients) were enrolled between August 2012 and October 2015. At a median follow-up of 58.1 months, the median PFS was 14.6 months, while the 15-month PFS rate was 48%; median overall survival had not been reached yet. Normal baseline chromogranin A (<4 nmol/l) confirmed a longer PFS (HR = 0.25, 95% CI 0.08–0.77, p = 0.016). Seven patients (28%) achieved an objective response (one complete response and six partial responses) in a median of 2.6 months. Twenty-three grade 3–4 events were recorded (14 patients). No fatal reactions occurred. This prospective phase II study unravels the notable activity of everolimus as a first-line treatment in patients with GEP NETS and contributes valuable information about the high activity of the combination of everolimus and octreotide LAR in this setting. Clinical trial information: NCT01648465.

Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies

“…In terms of biomarkers predictive for everolimus’s effectiveness, an exploratory analysis of the Phase 3 RADIANT-3 trial showed that patients with elevated basal levels of chromogranin A (CgA), neuron specific enolase (NSE), placental growth factor, and soluble vascular endothelial growth factor-1 (VEGFR1) had significantly shorter OS [ 90 ]. The predictive value of these biomarkers in response to everolimus treatment is also reported in a sub-analysis of the Phase 2 RADIANT-1 study, which showed that baseline levels of CgA and NSE, as well as their early biochemical response, are independent predictors for PFS and OS [ 228 , 233 ]. In addition, a pooled analysis of RADIANT-3/4 reported that markers of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-To-monocyte ratio ( LMR), are predictive of PFS [ 234 ].…”

Targeted Cancer Therapy: What’s New in the Field of Neuroendocrine Neoplasms?

“…Mechanisms of innate and acquired resistance to mTOR inhibition include the activation of several compensatory signaling pathways, upstream activation of PI3K/AKT signaling, the occurrence of FKBP12 or mTOR mutations, epigenetic alterations, compensatory metabolism rewiring or the stimulation of autophagy [ 66 , 67 ]. To try to overcome resistance, different everolimus-based combinations have been explored, particularly with SSAs and antiangiogenic agents [ 62 , 63 , 65 , 68 , 69 , 70 , 71 , 72 , 73 ]. Randomized trials do not suggest a clear benefit in terms of efficacy for these combinations ( Table 1 ) , whereas some safety concerns were raised for some of these combinations.…”