A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial
Mené sur 160 patients atteints d'une tumeur neuroendocrine pancréatique bien différenciée, progressive et de stade avancé, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du pasiréotide, un analogue de la somatostatine de première génération, à l'évérolimus
Résumé en anglais
Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET (pNET).
Patients and methods: Patients were randomized 1:1 to receive a combination of everolimus (10 mg/d, orally) and pasireotide long-acting release (LAR; 60 mg/28 d, intramuscularly) or everolimus alone (10 mg/d, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate, disease control rate (DCR), and safety. Biomarker response was evaluated in an exploratory analysis.
Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm vs 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% vs 6.2% of patients in combination arm vs everolimus arm; however, overall DCR was similar (77.2% vs 82.7%, respectively). No significant improvement was observed in median OS. Adverse events were consistent with the known safety profile of both the drugs; Grade 3 or 4 fasting hyperglycemia was seen in 37% vs 11% of patients, respectively.
Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared to everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted
