RADIANT-4: Efficacy and safety of everolimus in advanced, nonfunctional neuroendocrine tumors (NET) of the lung or gastrointestinal (GI) tract

Aim/Background

Effective therapeutic options for advanced, nonfunctional NET of lung/GI origin are limited. RADIANT-4 evaluated the efficacy and safety of EVE in this NET population.

Methods

Patients (pts) with advanced, progressive, well-differentiated, nonfunctional lung/GI NET were randomized (2:1) to EVE (10 mg/d) or placebo (PBO), both with best supportive care. Pts were stratified by tumor origin, WHO performance status (PS), and prior SSA use. Primary endpoint was PFS (central review, modified RECIST 1.0). Secondary endpoints included OS, objective response rate (ORR), disease control rate (DCR), and safety.

Results

302 pts were randomized to EVE (205) or PBO (97); median age, 63 y; 53% females; G1/G2: 64%/35%; WHO PS: 0, 74% or 1, 26%; majority (76%) were Caucasian; most common primary tumor sites: lung (30%), ileum (24%). Both arms were similar with respect to prior SSA use (53% in EVE vs 56% in PBO), chemotherapy (26% vs 24%), radiotherapy including PRRT (22% vs 20%) and locoregional therapies (11% vs 10%). Median PFS by central review was 11.0 mo (95% CI, 9.2–13.3) in EVE and 3.9 mo (95% CI, 3.6–7.4) in PBO arm (HR, 0.48; 95% CI, 0.35–0.67; P < 0.001). Investigator-assessed PFS was consistent with central review. Subgroup analyses of PFS by stratification factors were consistent with primary efficacy analysis. ORR (all partial responses) was 2% (4 pts) in EVE vs 1% (1) in PBO. DCR was higher in EVE vs PBO (82% vs 65%). 9% in EVE vs 27% pts in PBO arm had progressive disease as best outcome. A pre-planned interim OS analysis favored everolimus arm (HR, 0.64; 95% CI, 0.40–1.05; P = 0.037; threshold P = 0.0002). AEs were mainly G1/2; most common G3/4 AEs (EVE vs PBO): diarrhea (9% vs 2%), stomatitis (7% vs 0), abdominal pain (5% in each), and anemia (5% vs 2%).

Conclusions

RADIANT-4, the first large, PBO-controlled, phase 3 study in pts with advanced, progressive, nonfunctional lung/GI NET, provided unequivocal evidence for the efficacy of EVE in this population. Everolimus showed statistically significant and clinically meaningful 7.1-month prolongation of PFS vs PBO. EVE was well tolerated and AEs were consistent with the known safety profile.

Clinical trial identification

NCT01524783

Disclosure

J.C. Yao: consulting or advisory role – Ipsen, Lexicon, Novartis; research funding to Institute – Novartis. S. Singh: honoraria – Novartis; consulting or advisory role – Novartis; research funding to Institute - Novartis; travel, accommodation, expenses – Novartis. E. Wolin: consulting or advisory role – Celgene, Ipsen, Novartis. M. Voi, L.B. Pacaud, J. Lincy, C. Sachs: employment – Novartis; Stock and other ownership interests – Novartis. J.W. Valle: honoraria – Novartis; consulting or advisory role – Novartis; Research Funding to Institute – Novartis. E. Van Cutsem: research funding to Institute – Novartis. Y. Shimada: research funding to Institute - Chugai Pharma, Lilly, Novartis, Taiho Pharmaceutical. D.-Y. Oh: no relationships to disclose.