Supplementary Material for: Everolimus in Neuroendocrine Tumors of the Gastrointestinal Tract and Unknown Primary

<b><i>Purpose:</i></b> The RADIANT-4 randomized phase 3 study
demonstrated significant prolongation of median progression-free
survival (PFS) with everolimus compared to placebo (11.0 [95% CI
9.2-13.3] vs. 3.9 [95% CI 3.6-7.4] months) in patients with advanced,
progressive, nonfunctional gastrointestinal (GI) and lung neuroendocrine
tumors (NET). This analysis specifically evaluated NET patients with GI
and unknown primary origin. <b><i>Methods:</i></b> Patients in the
RADIANT-4 trial were randomized 2:1 to everolimus 10 mg/day or placebo.
The effect of everolimus on PFS was evaluated in patients with NET of
the GI tract or unknown primary site. <b><i>Results:</i></b> Of the 302
patients enrolled, 175 had GI NET (everolimus, 118; placebo, 57) and 36
had unknown primary (everolimus, 23; placebo, 13). In the GI subset, the
median PFS by central review was 13.1 months (95% CI 9.2-17.3) in the
everolimus arm versus 5.4 months (95% CI 3.6-9.3) in the placebo arm;
the hazard ratio (HR) was 0.56 (95% CI 0.37-0.84). In the unknown
primary patients, the median PFS was 13.6 months (95% CI 4.1-not
evaluable) for everolimus versus 7.5 months (95% CI 1.9-18.5) for
placebo; the HR was 0.60 (95% CI 0.24-1.51). Everolimus efficacy was
also demonstrated in both midgut and non-midgut populations; a 40-46%
reduction in the risk of progression or death was reported for patients
in the combined GI and unknown primary subgroup. Everolimus had a
benefit regardless of prior somatostatin analog therapy. <b><i>Conclusions:</i></b>
Everolimus showed a clinically meaningful PFS benefit in patients with
advanced progressive nonfunctional NET of GI and unknown primary,
consistent with the overall RADIANT-4 results, providing an effective
new standard treatment option in this patient population and filling an
unmet treatment need for these patients.