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Background: 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 [ 177 Lu]Lu-DOTA-TATE ( 177 Lu-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 177 Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks ( 177 Lu-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 177 Lu-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 177 Lu-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 177 Lu-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 177 Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177 Lu-Dotatate should be considered a new standard of care in first-line therapy in this population., Funding: Advanced Accelerator Applications, a Novartis Company., Competing Interests: Declaration of interests SS reports support for the present work from Novartis; grants or contracts from Novartis; consulting fees from Ipsen, Novartis, and Camurus; and meeting attendance support from Ipsen and Novartis. DH reports support for the present work from Novartis; grants or contracts from Novartis, ITM, RayzeBio, Thermo Fisher Scientific, Camurus, and Genentech/Roche; consulting fees from Novartis, TerSera, ITM, Crinetics, Amryt, Camurus, Chimeric Therapeutics, Harpoon Therapeutics, HarbourBioMed, Lantheus, Exelixis, and Ipsen; and participation on a data safety monitoring board for Alphamedix. SM reports advisory board participation for Novartis Oncology and Ipsen. KH reports payment for steering committee participation from Novartis; grants or contracts from Novartis and SOFIE Biosciences; consulting fees from Advanced Accelerator Applications (a Novartis company), Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, ITM, Janssen, Merck, Molecular Partners, NVision, Pfizer, POINT Biopharma, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, SOFIE Biosciences, Telix, Theragnostics, and Y-mAbs; honoraria from PeerVoice; meeting support from Janssen; advisory board participation for Fusion and GE Healthcare; and stock or stock options for SOFIE Biosciences, Pharma15, NVision, Convergent, Aktis Oncology, and AdvanCell. MP reports grants or contracts from Advanced Accelerator Applications (a Novartis company), Novartis, Ipsen, ITM, Camurus, and Boehringer Ingelheim; consulting fees from Advanced Accelerator Applications (a Novartis company), Novartis, Ipsen, Riemser, and HUTCHMED; honoraria from Ipsen, Advanced Accelerator Applications (a Novartis company), Novartis, Boehringer Ingelheim, MSD, Lilly, Recordati, Sanofi, and Serb; advisory board participation for Crinetics and Advanced Accelerator Applications (a Novartis company); and unpaid roles as ENETS committee member and President, on the ESMO education committee, and on the INCA advisory board. PLK reports grants or contracts from RayzeBio and Novartis; honoraria from Natera, ITM, BMS, and Foundation Medicine; steering committee participation (uncompensated) for RayzeBio and Exelixis; and advisory board participation and honoraria from Amgen, Genentech, Crinetics, HUTCHMED, and Ipsen. BC reports advisory board participation and honoraria from Advanced Accelerator Applications (a Novartis company). SL reports advisory board participation for Advanced Accelerator Applications (a Novartis company). JC reports grants or contracts from Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications (a Novartis company), Eisai, Amgen, and Bayer; and consulting fees and honoraria from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications (a Novartis company), Amgen, Sanofi, Lilly, Hutchinson Pharma, ITM, Advanz, Merck, Esteve, and Roche. AG-B reports consulting fees from Advanced Accelerator Applications (a Novartis company), Bayer, and Sanofi; and speaker fees and meeting support from Novartis. D-YO reports grants or contracts from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok; and advisory board participation for AstraZeneca, Novartis, Genentech/Roche, Merck, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, AbbVie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, and Idience. CY reports grants or contracts from Bayer, Ipsen, AstraZeneca, Boehringer Ingelheim, Servier, and Eisai; and honoraria from Bayer, Ipsen, MSD, Merck, Celgene, AstraZeneca, GSK, Eisai, Roche, Genentech, and Novartis. TRH reports consulting fees from TerSera; advisory board participation and research support from Camurus, ITM, Advanced Accelerator Applications (a Novartis company), Crinetics, and Perspective Therapeutics; research support from Thermo Fisher Scientific; and an unpaid role as President of NANETS. IF, YZ, and PA report employment by Novartis and stock or stock options for Novartis. WWdH reports consulting fees and honoraria from Ipsen, Novartis, and Advanced Accelerator Applications (a Novartis company); and consulting fees from ITM. DF reports grants or contracts from Camurus and Pfizer; honoraria from Novartis and Recordati Rare Diseases; and advisory board participation for Camurus, Ipsen, Novartis, Recordati Rare Diseases, and Pfizer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)