Date: 2014-09-07
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 2014 Congress of the European Society for Medical Oncology (ESMO)
Company: Novartis (Switzerland)
Product: Afinitor® (everolimus)
Action
mechanism: Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation. Afinitor® (everolimus) is approved in more than 85 countries including the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin. It is also approved in more than 100 countries, including the United States and throughout the European Union, for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy.
Afinitor (everolimus) is approved in the European Union for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI). In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2-) breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.
Disease: pancreatic neuroendocrine tumors (pNET)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The core phase of the trial examined the efficacy and safety of everolimus plus BSC versus placebo plus BSC in 410 patients with advanced, low- or intermediate-grade pancreatic NET, also known as islet cell tumors. Patients who met the study entry criteria were randomized 1:1 to receive either everolimus 10 mg once-daily (n=207) or daily placebo (n=203) orally, both in conjunction with BSC. The primary endpoint was PFS, and the key secondary endpoints were OS and the safety and tolerability of everolimus.
Latest
news: * On September 27, 2014, Novartis presented final results on overall survival (OS) from a Phase III trial of Afinitor® (everolimus) tablets plus best supportive care (BSC) compared to placebo plus BSC in patients with well-differentiated advanced and progressive pancreatic neuroendocrine tumors (pNET). Overall survival was a secondary endpoint of the trial. The findings were presented at the European Society for Medical Oncology (ESMO) Congress, September 26-30, 2014 in Madrid, Spain, and are to be submitted to health authorities for inclusion in the Afinitor® prescribing information.
Results from the RADIANT-3 trial showed a median OS of 44.02 months (95% confidence interval [CI]: 35.61, 51.75) in the everolimus treatment arm and 37.68 months (95% CI: 29.14, 45.77) in the placebo arm. The 6.34 month difference between the two arms was not statistically significant (Hazard Ratio [HR] 0.94; 95% CI: 0.73, 1.20; p=0.300) . A high crossover of patients from placebo to everolimus (85%) likely contributed to the long median OS in the placebo arm of 37.68 months and may have confounded the ability to detect a difference in the OS results.
The safety profile was consistent with that observed for everolimus in advanced pancreatic NET and no unexpected or new safety concerns were identified at the time of this analysis, indicating that longer term treatment with everolimus continues to provide a positive benefit-risk ratio for patients. The most commonly reported (>=40%) adverse events (AEs) for everolimus compared to placebo during the core phase of the study were stomatitis (53.9% vs. 13.3%), rash (52.5% vs. 15.8%), diarrhea (48.0% vs. 23.6%) and fatigue (44.6% vs. 26.6%)[1]. The most common (>=40%) AEs reported with everolimus during this follow-up phase were stomatitis (46.7%), diarrhea (43.6%) and rash (40.0%).
The presentation at ESMO 2014 is an analysis of the mature OS results. Results from the primary analysis, which focused on the progression-free survival (PFS) endpoint in which Afinitor more than doubled median PFS vs. placebo, were previously published in the New England Journal of Medicine (NEJM; February 2011).
Patients on placebo whose disease progressed during the core phase were allowed to cross over to open-label everolimus. In addition, when all patients were unblinded at the end of the core phase, those initially assigned to placebo were offered to switch to open-label everolimus and those in the everolimus arm could transition to open-label everolimus. During the open label phase patients continued with treatment until disease progression was documented by the investigator. At this point, patients discontinued the study drug and entered the follow-up period to be monitored monthly for survival information. All patients initially randomized to placebo were included in the placebo arm results, even if they crossed over to everolimus therapy after progression or unblinding[1]. In total, 85% of patients in the placebo arm crossed over to everolimus during the course of the study[.
In the double-blind phase, serious adverse events (SAEs) were reported more often in the everolimus arm than in the placebo arm (41.2% vs. 25.6%). The most commonly reported SAEs (>=2% incidence) in the everolimus arm were pyrexia (3.9%), pneumonitis (3.4%), anemia (3.4%), abdominal pain (2.9%), dyspnea (2.9%), diarrhea (2.5%), pulmonary embolism (2.5%), asthenia (2.5%) and dehydration (2.5%). The frequency of AEs leading to study drug discontinuation during the double-blind period was higher for the everolimus treatment group (21.1%) compared to the placebo group (5.9%)[4]. In the open-label period, 23.6% of patients discontinued treatment due to AEs.
At the time of the final OS analysis there were 126 (60.9%) deaths in the everolimus arm and 130 (64.0%) deaths in the placebo arm[1]. While no statistically significant difference was evident in terms of OS, the median OS favored the everolimus arm, with a clinically meaningful improvement of 6.34 months over placebo, and supports the concept of starting treatment with everolimus early, once progression is detected[1]. The OS benefit is consistent with the statistically significant gain of 6.44 months in PFS (HR 0.35; 95% CI: 0.27-0.45; p<0.001) observed in the primary analysis.
