Baseline demographics of patients from the randomized, placebo-controlled, double-blind, phase III RADIANT-4 study of everolimus in nonfunctional gastrointestinal (GI) or lung neuroendocrine tumors (NET).

Background: NET are malignant tumors arising from neuroendocrine cells throughout the body. Everolimus (EVE), a mammalian target of rapamycin inhibitor, is approved for the treatment of advanced, well-differentiated pancreatic NET. There is an unmet medical need in Gl and lung NET; targeted therapies, such as everolimus, are of particular interest. Methods:Patients with advanced nonfunctional NET of Gl or lung origin with progressive disease (PD) within the past 6 months were randomized (2:1) to EVE 10 mg/d or placebo, both with best supportive care. Concomitant use of somatostatin analogue (SSA) was not allowed during the study, except for control of emergent carcinoid symptoms not manageable by standard therapy. Patients were stratified based on tumor sites, prior SSA exposure, and WHO performance status (PS) at baseline. Primary end point was progression-free survival (PFS) as assessed by central radiology review using modified RECIST 1.0 criteria. Primary analysis is planned after 176 PFS events. Crossover to open label EVE after progression would not be allowed prior to the primary analysis. Overall survival was the key secondary end point. Results: Recruitment has been completed. Of 388 patients screened, 302 were randomized. Median age was 63 years, 53% were females, and majority of them (76.2%) were Caucasians. The most common tumor sites were lung (29.8%), ileum (23.5%), and rectum (13.2%). WHO PS was zero in 219 (72.5%) patients and 1 in 82 (27.2%) patients; 52% had received SSA prior to study entry. As of September 16, 2013, 173 (57.3%) patients remained on treatment, 127 (42.1%) discontinued treatment and 2 (0.7%) were not treated. PD (24.2%) and adverse events (10.6%) were the most common reasons for treatment discontinuation. Results of primary analysis are expected by early 2015. Conclusions: RADIANT-4 is the first phase Ill study to assess efficacy and safety of EVE in patients with nonfunctional NET of Gl or lung origin. Noncrossover design and prospective stratification of the population based on known prognostic factors should minimize confounding in the estimation of the treatment effect. Clinical trial information: NCT01524783

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