Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial

Abstract

Objective: The aim of this study was to evaluate efficacy and safety of everolimus in patients with pancreatic neuroendocrine tumors (pNET) by prior chemotherapy use in the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3).

Methods: Patients with advanced, progressive, low- or intermediate-grade pNET were prospectively stratified by prior chemotherapy use and World Health Organization performance status and were randomly assigned (1:1) to everolimus 10 mg/d (n = 207) or placebo (n = 203).

Results: Of the 410 patients, 204 (50%) were naive to chemotherapy (chemonaive). Baseline characteristics were similar for patients with or without prior chemotherapy. Everolimus significantly prolonged median progression-free survival regardless of prior chemotherapy use (prior chemotherapy: 11.0 vs 3.2 months; hazard ratio, 0.34; 95% confidence interval, 0.25-0.48; P < 0.0001) (chemonaive: 11.4 vs 5.4 months; hazard ratio, 0.42; 95% confidence interval, 0.29-0.60; P < 0.0001). Stable disease was the best overall response in 73% of everolimus-treated patients (151/207). The most common drug-related adverse events included stomatitis (60%-69%), rash (47%-50%), and diarrhea (34%).

Conclusions: As more treatment options become available, it is important to consider the goals of treatment and to identify patients who would potentially benefit from a specific therapy. Findings from this planned subgroup analysis suggest the potential for first-line use of everolimus in patients with advanced pNET.

Trial registration: ClinicalTrials.gov NCT00510068.

FIGURE 1

Progression-free survival assessed by local investigators for both treatment arms (everolimus and placebo) in the patients who received prior chemotherapy (A) and did not receive prior chemotherapy (B).

FIGURE 2

Progression-free survival review by the central adjudication committee for both treatment arms (everolimus and placebo) in the patients who received prior chemotherapy (A) and did not receive prior chemotherapy (B).

FIGURE 3

Percentage change from baseline in size of target lesion (waterfall plot) for both treatment arms (everolimus and placebo) in the patients who received prior chemotherapy (A) and did not receive prior chemotherapy (B). A, Data for 11 patients with lesions that could be evaluated in the everolimus arm and 24 in the placebo arm were not included in the analysis for the following reasons: 6 in the everolimus arm (6.1%) and 16 in the placebo arm (17.0%) showed a change in the available target lesion that contradicted the overall response of PD. One patient in the everolimus arm (1.0%) showed a change in the available target lesion, but the overall response was UNK. The change in the target lesion could not be assessed in 4 patients in the everolimus arm (4.0%) and 8 in the placebo arm (8.5%). B, For the chemonaive patients, data for 19 patients with lesions that could be evaluated in the everolimus arm and 18 in the placebo arm were not included in the analysis for the following reasons: 8 in the everolimus arm (8.7%) and 12 in the placebo arm (12.6%) showed a change in the available target lesion that contradicted the overall response of PD. The change in the target lesion could not be assessed in 11 patients in the everolimus arm (12.0%) and 6 in the placebo arm (6.3%). PD, progressive disease; UNK, unknown.