177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial
Mené en Europe et aux Etats-Unis sur 231 patients atteints d'une tumeur neuroendocrine de l'intestin moyen, cet essai de phase III compare l'efficacité, du point de vue de la survie globale, et la toxicité d'un traitement combinant le lutétium-177-dotatate et l'octréotide à action prolongée et un traitement par hautes doses d'octréotide à action prolongée
Background : The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results. Methods : This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eightcountries across Europe and the USA. Patients were 18 years and older with locallyadvanced or metastatic, well differentiated, somatostatin receptor-positive midgutneuroendocrine tumours (Karnofsky performance status score ≥60) and disease progressionon fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via aninteractive web-based response system to intravenous 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-actingoctreotide 30 mg (177Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (controlgroup). The primary endpoint of progression-free survival has been previously reported;here, we report the key secondary endpoint of overall survival in the intention-to-treatpopulation. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239. Findings : From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assignedfor treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months(range 0·4–95·0) in the 177Lu-Dotatate group and 76·5 months (0·1–92·3) in the control group. The secondary endpointof overall survival was not met: median overall survival was 48·0 months (95% CI 37·4–55·2)in the 177Lu-Dotatate group and 36·3 months (25·9–51·7) in the control group (HR 0·84 [95% CI0·60–1·17]; two-sided p=0·30). During long-term follow-up, treatment-related seriousadverse events of grade 3 or worse were recorded in three (3%) of 111 patients inthe 177Lu-Dotatate group, but no new treatment-related serious adverse events were reportedafter the safety analysis cutoff. Two (2%) of 111 patients given 177Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation(this person was the only the only reported 177Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome oracute myeloid leukaemia were reported during long-term follow-up. Interpretation : 177Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statisticalsignificance, the 11·7 month difference in median overall survival with 177Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up.
The Lancet Oncology , 2021