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.

Abstract

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 eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (177Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). 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-treat population. 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 assigned for 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 endpoint of 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% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177Lu-Dotatate group, but no new treatment-related serious adverse events were reported after 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 or acute 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 statistical significance, 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.

FUNDING:

Advanced Accelerator Applications, a Novartis company.

• Authors: Jonathan R Strosberg, Martyn E Caplin, Pamela L Kunz, Philippe B Ruszniewski, Lisa Bodei, Andrew Hendifar, Erik Mittra, Edward M Wolin, James C Yao, Marianne E Pavel, Enrique Grande, Eric Van Cutsem, Ettore Seregni, Hugo Duarte, Germo Gericke, Amy Bartalotta, Maurizio F Mariani, Arnaud Demange, Sakir Mutevelic, Eric P Krenning, NETTER-1 investigators
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 22 Issue 12 Pg. 1752-1763 (12 2021) ISSN: 1474-5488 [Electronic] England
• PMID: 34793718 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Hormonal
• Organometallic Compounds
• Radiopharmaceuticals
• lutetium Lu 177 dotatate
• Octreotide

Topics

• Aged
• Antineoplastic Agents, Hormonal (therapeutic use)
• Chemoradiotherapy (mortality)
• Digestive System Neoplasms (mortality, pathology, therapy)
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Humans
• Male
• Neuroendocrine Tumors (mortality, pathology, therapy)
• Octreotide (analogs & derivatives, therapeutic use)
• Organometallic Compounds (therapeutic use)
• Prognosis
• Radiopharmaceuticals (therapeutic use)
• Survival Rate