| General information |
| Database: | DB00723 |
| Objective: | Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in twophase 2 studies. They evaluated the agent in a prospective, randomized, phase 3 study. |
| Authors: | Yao JC, et al |
| Title: | Everolimus for advanced pancreatic neuroendocrine tumors. |
| Journal: | N Engl J Med. |
| Year: | 2011 |
| PMID: | 21306238 |
| Trial Design |
| Clinical Trial Id: | NCT00510068 |
| Agent: | everolimus
|
| Target: | Serine/threonineprotein kinase mTOR
|
| Cancer Type: | pancreatic cancer |
| Cancer Subtype: | advanced pancreatic neuroendocrine tumor |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | international, multicenter, doubleblind, phase III study |
| Key Patients Feature: | Patients were eligible to be included in the studyif were 18 years of age or older and had lowgrade or intermediategrade advanced (unresectable or metastatic) pancreatic neuroendocrine tumors and radiologic documentation of diseaseprogression (an unequivocal increase in the sizeof tumors) in the 12 months preceding randomization. Prior antineoplastic therapy was not anexclusion criterion. Other key eligibility criteria included the presence of measurable disease, as assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0 (see theSupplementary Appendix, available with the fulltext of this article at NEJM.org)21; a World HealthOrganization (WHO) performance status of 2 orless (with 0 indicating that the patient is fullyactive and able to carry on all predisease activitieswithout restriction; 1 indicating that the patientis restricted in physically strenuous activity but isambulatory and able to carry out work of a lightor sedentary nature, such as light housework oroffice work; and 2 indicating that the patient isambulatory and up and about more than 50% ofwaking hours and is capable of all selfcare butunable to carry out any work activities)22; adequatebone marrow, renal, and hepatic function; and adequately controlled lipid and glucose concentrations. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | 10 mg once daily (207 patients), or placebo (203 patients) |
| Treatment Info: | They randomly assigned pts to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. |
| Primary End Point: | progression free survival |
| Secondary End Point: | NA |
| Patients Number: | 410 |
| Trial Results |
| DLT_MTD: | Grade 3 or 4 events that were morefrequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia(5% vs. 2%) |
| Objective Response Rate: | The median progression free survival was 11.0 months with everolimus as comparedwith 4.6 months with placebo (hazard ratio for disease progression or death fromany cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001) |
| Median OS A vs. C: | the proportion of patients who were alive and progression free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. |
| Adverse Event(agent arm): | Drugrelated adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). |
| Conclusions: | Everolimus, as compared with placebo, significantly prolonged progression free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events.? |