[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

Author(s): Simron Singh, MD1; Daniel Halperin, MD2; Sten Myrehaug, MD1; Ken Herrmann, MD3,4; Prof Marianne Pavel, MD5; Pamela L Kunz, MD6; Beth Chasen, MD2; Salvatore Tafuto, MD7; Secondo Lastoria, MD8; Jaume Capdevila, MD9; Amparo García-Burillo, MD9; Do-Youn Oh, MD10; Changhoon Yoo, MD11; Thorvardur R Halfdanarson, MD12; Stephen Falk, MD13; Ilya Folitar, MD14; Yufen Zhang, PhD15; Paola Aimone, MD14; Wouter W de Herder, MD16; Diego Ferone, MD17
Source: DOI:https://doi.org/10.1016/S0140-6736(24)00701-3

Dr. Maen Hussein's Thoughts

PFS was 22 months vs. 8 months for the control group, this may become the new standard of care.

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 [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.

FUNDING

Advanced Accelerator Applications, a Novartis Company.

Author Affiliations

1University of Toronto, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; 2MD Anderson Cancer Center, Houston, TX, USA; 3Department of Nuclear Medicine, University of Duisburg-Essen, and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; 4National Center for Tumor Diseases (NCT), NCT West, Heidelberg, Germany; 5Department of Medicine 1, Uniklinikum Erlangen, and Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 6Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT, USA; 7Sarcoma and Rare Tumors Unit, Istituto Nazionale Tumori IRCCS, Fondazione G. Pascale, Naples, Italy; 8Division of Nuclear Medicine, Istituto Nazionale Tumori IRCCS, Fondazione G Pascale, Naples, Italy; 9Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 10Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea; 11Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 12Mayo Clinic, Rochester, MN, USA; 13Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, UK; 14Novartis Pharma AG, Basel, Switzerland; 15Novartis Pharmaceuticals Corp, East Hanover, NJ, USA; 16Erasmus MC and Erasmus MC Cancer Institute, Rotterdam, Netherlands; 17Endocrinology, IRCCS Policlinico San Martino and DiMI, University of Genova, Genoa, Italy

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