[177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial.

BACKGROUND: In the phase 3 NETTER-2 study, first-line [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) significantly improved progression-free survival in patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Median progression-free survival was 22·8 months (95% CI 19·4-not estimable [NE]) with 177Lu-DOTATATE vs 8·5 months (7·7-13·8) in the control arm. Here, we report subgroup analyses, including preplanned assessments of efficacy by NET grade (G) and site of origin; further post-hoc analyses are reported in the main text. METHODS: In this open-label, parallel-group study, patients from nine countries were randomised 2:1 to receive four cycles of 177Lu-DOTATATE plus octreotide long-acting repeatable (LAR) 30 mg every 8 weeks then octreotide LAR 30 mg every 4 weeks, or high-dose octreotide LAR 60 mg every 4 weeks. The primary endpoint (progression-free survival) was previously reported. Tumours were assessed at baseline, week 16, week 24, then every 12 weeks until disease progression or death. Preplanned subgroup analyses used blinded independent centrally reviewed data. The study is registered with ClinicalTrials.gov, NCT03972488, and is completed. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, 261 patients were screened; 35 were excluded due to screen failure, and 226 were randomised. 177Lu-DOTATATE (n = 151) reduced risk of disease progression/death vs control (n = 75) regardless of NET grade/origin (hazard ratio [95% CI]: G2 NET 0·31 [0·18-0·53]; G3 NET 0·27 [0·14-0·49]; pancreatic NET 0·34 [0·20-0·56]; gastrointestinal NET 0·23 [0·12-0·46]). Median progression-free survival in months (95% CI) with 177Lu-DOTATATE was: G2 NET 29·0 (21·8-NE); G3 NET 22·2 (13·9-27·8); pancreatic NET 19·4 (16·6-24·9); gastrointestinal NET NE (22·6-NE). 177Lu-DOTATATE improved objective response rate vs control regardless of NET grade/origin. INTERPRETATION: These findings support the use of first-line 177Lu-DOTATATE for patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive GEP-NETs, and for whom chemotherapy is not considered the most appropriate treatment option, regardless of NET grade (2/3) or origin (pancreas/gastrointestinal). FUNDING: Advanced Accelerator Applications, a Novartis Company.