Yao 2016 — RADIANT-4 Trial

Citation: Yao JC, Fazio N, Singh S, et al; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977. doi:10.1016/S0140-6736(15)00817-X.

Study design

• International, multicentre (97 centres, 25 countries), randomised, double-blind, placebo- controlled, phase 3 trial (RADIANT-4; NCT01524783). 302 patients randomised 2:1 (205 everolimus / 97 placebo), April 2012–August 2013.
• Population: advanced, progressive, well-differentiated (grade 1 or 2), non-functional NETs of lung or gastrointestinal origin — explicitly excludes pancreatic NETs (covered separately by the earlier RADIANT-3 trial) and excludes carcinoid-syndrome/functioning tumours (covered by RADIANT-2). Primary tumour sites: lung (31%/28%), ileum (23%/25%), rectum (12%/16%), unknown primary (11%/13%), jejunum, stomach, duodenum, colon, and others.
• Intervention: oral everolimus 10 mg/day vs placebo, both with best supportive care.
• Primary endpoint: PFS by central radiology review.
• A planned interim overall-survival analysis is reported.

Key findings

• Median PFS: 11.0 months (95% CI 9.2–13.3) with everolimus vs 3.9 months (95% CI 3.6–7.4) with placebo; HR 0.48 (95% CI 0.35–0.67); p<0.00001 — a 52% reduction in the risk of progression or death. Investigator-assessed PFS was similar in direction (14.0 vs 5.5 months; HR 0.39).
• 12-month PFS rate (central review): 44% (everolimus) vs 28% (placebo).
• Interim overall-survival analysis: HR 0.64 (95% CI 0.40–1.05); one-sided p=0.037 — favoured everolimus numerically but did not cross the prespecified O’Brien-Fleming stopping boundary for statistical significance at this interim look (boundary p=0.0002); data were not mature enough to estimate median OS in either group. Treat as a trend, not a confirmed survival benefit.
• Objective response: 2% (everolimus, all partial responses) vs 1% (placebo); disease stabilisation was the dominant benefit — 81% vs 64% had stable disease as best response, and 64% vs 26% had some degree of tumour shrinkage.
• Treatment benefit was consistent across primary tumour origin (lung, GI, unknown primary) and other prespecified subgroups.
• Grade 3-4 drug-related adverse events (everolimus vs placebo): stomatitis 9% vs 0%, diarrhoea 7% vs 2%, infections 7% vs 0%, anaemia 4% vs 1%, fatigue 3% vs 1%, hyperglycaemia 3% vs 0%. Non-infectious pneumonitis occurred in 16% of everolimus patients (mostly grade 1-2; grade 3 in 1%, no grade 4).

Limitations

• Excludes pancreatic and functioning/carcinoid-syndrome NETs — evaluated separately in the earlier RADIANT-3 and RADIANT-2 trials (neither of which is independently ingested in this wiki), so everolimus’s role in those populations is not covered by this source.
• The overall-survival analysis reported is an interim, not final, analysis, and did not reach statistical significance — the survival benefit remains a plausible trend rather than an established finding as of this publication.
• Substantial dose modification burden: median relative dose intensity 0.9, with dose reductions or temporary interruptions in 67% of everolimus-arm patients (vs 30% placebo) — reflects real-world tolerability challenges alongside the efficacy signal.

Relevance

Closes the primary-literature gap flagged in Small Bowel Neuroendocrine Tumors (NETs)‘s Open items for everolimus/RADIANT-4 — the page’s existing textbook-sourced narrative (“progression-free survival improvement from 3.9 to 11 months with everolimus”) is confirmed precisely accurate against this primary source (median PFS 3.9 vs 11.0 months). RADIANT-4 establishes everolimus as an antineoplastic option for advanced non-functional lung/GI NETs specifically (distinct from pancreatic NETs), complementing Rinke 2009 - PROMID Trial and Caplin 2014 - CLARINET Trial (first-line SSA evidence, midgut/ enteropancreatic) and Strosberg 2017 - NETTER-1 Trial (PRRT, midgut-specific second-line option) as the wiki’s fourth primary-literature NET trial.