Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4

BACKGROUND: Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35–0.67; P<0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01524783. PATIENTS AND METHODS: Patients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported. RESULTS: A total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 {95% CI, 0.37–0.85}]; without SSA: 9.5 vs 3.7 months [0.57 {0.36–0.89}]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 {0.19–0.64}]; without chemotherapy: 11.2 vs 5.4 months [0.60 {0.42–0.86}]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 {0.24–0.94}]; without radiotherapy: 11 vs 5.1 months [0.59 {0.42–0.83}]) exposure. The most frequent drug-related adverse events included stomatitis (59%–65%), fatigue (27%–35%), and diarrhea (24%–34%) among the subgroups. CONCLUSION: These results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET.