UPDATE – June 5th 2024.

[¹⁷⁷Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2–3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study

Summary

There are currently no standard first-line treatment options for patients with higher grade 2–3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [¹⁷⁷Lu]Lu-DOTA-TATE (¹⁷⁷Lu-Dotatate) treatment.

Methods

NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous ¹⁷⁷Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (¹⁷⁷Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting.

Findings

Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the ¹⁷⁷Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7–13·8) in the control group and 22·8 months (19·4–not estimated) in the ¹⁷⁷Lu-Dotatate group (stratified hazard ratio 0·276 [0·182–0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the ¹⁷⁷Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period.

Interpretation

First-line ¹⁷⁷Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. ¹⁷⁷Lu-Dotatate should be considered a new standard of care in first-line therapy in this population.

[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2–3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study – The Lancet

Published:June 05, 2024DOI:https://doi.org/10.1016/S0140-6736(24)00701-3

• Simron Singh, MD 
• Daniel Halperin, MD
• Sten Myrehaug, MD
• Ken Herrmann, MD
• Prof Marianne Pavel, MD
• Pamela L Kunz, MD
• Beth Chasen, MD
• Salvatore Tafuto, MD
• Secondo Lastoria, MD
• Jaume Capdevila, MD
• Amparo García-Burillo, MD
• Do-Youn Oh, MD
• Changhoon Yoo, MD
• Thorvardur R Halfdanarson, MD
• Stephen Falk, MD
• Ilya Folitar, MD
• Yufen Zhang, PhD
• Paola Aimone, MD
• Wouter W de Herder, MD
• Diego Ferone, MD
  
  on behalf ofall the NETTER-2 Trial Investigators

Note:  Reference behind a paywall/institutional access. However, observations from NET Specialists on X (formerly twitter):

Dr Julie Hallet – Unprecedented response 43%.

Dr Thor Halfdanarson – upfront PRRT for G2 (Ki67 10% or more) and G3 NETs. Much higher ORR than in the lower grade NETTER-1 siNET population and much longer PFS than on the control arm of high dose octreotide LAR.

Author’s notes:

You may be wondering where lanreotide users fit into this summary  My opinion is that this does not mean G2 (10%+) and G3 NETs cannot get PRRT. The clinical trial sponsor for Lutathera is also the manufacturer of Sandostatin LAR thus why that somatostatin anlogue was used  If concerned consult your specialist.