Everolimus for advanced pancreatic neuroendocrine tumors

Abstract

Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.

Methods: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.

Results: The median progression-free survival was 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), representing a 65% reduction in the estimated risk of progression or death. Estimates of 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. Drug-related 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%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).

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. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Figure 1. Progression-free and Overall Survival

Kaplan–Meier curves are shown for progression-free survival as assessed by local investigators (Panel A) and by adjudicated central review (Panel B). A forest plot (Panel C) shows the effect of study treatment on progression-free survival in patient subgroups. Kaplan–Meier curves are also shown for overall survival (Panel D). NA denotes not available, and SSA somatostatin analogue.

Figure 2. Percentage Change from Baseline in Size of Target Lesion

The plot shows the best percentage change from baseline in the size of the target lesion (i.e., the best response in each patient) in the everolimus group (left) and the placebo group (right). Data on 30 patients with lesions that could be evaluated in the everolimus group and 42 in the placebo group were not included in the analysis for the following reasons: 14 in the everolimus group (7.3%) and 28 in the placebo group (14.8%) showed a change in the available target lesion that contradicted the overall response of progressive disease; 1 patient in the everolimus group (0.5%) showed a change in the available target lesion, but the overall response was unknown; and the change in the target lesion could not be assessed in 15 patients in the everolimus group (7.9%) and 14 in the placebo group (7.4%).