The molecular radiotherapy 177Lu-Dotatate (Lu-177) should be considered a new standard of care in the first-line treatment of advanced gastroenteropancreatic neuroendocrine tumours (GEP NETs), having significantly improved progression-free survival in a clinical trial regardless of tumour grade or origin, international researchers have reported.

Results of the Phase III NETTER-2 trial, sponsored by Novartis group Advanced Accelerator Applications, suggest that peptide receptor radionuclide therapy (PRRT) could help to fill a significant unmet clinical need, given that there are currently no standard first-line options for patients with higher grade 2-3 advanced disease.

The open-label, randomised trial included 226 patients with newly diagnosed, higher grade 2 and grade 3 somatostatin receptor-positive, advanced GEP NETs from nine countries in North America, Europe, and Asia.

Patients were randomly assigned to receive either four cycles of IV Lu-177 plus intramuscular octreotide 30mg long-acting repeatable (LAR), then octreotide 30mg LAR every four weeks (n=151 [67%]) or high-dose octreotide 60mg LAR every four weeks (control group; n=75; 33%).

Researchers assessed tumours at baseline, week 16 and week 24, followed by every 12 weeks until disease progression or death.

PFS benefit

Results showed a median progression-free survival of 8.5 months (95% CI 7·7–13·8) in the control group versus 22.8 months (19.4-not estimated) in the Lu-177 group (hazard ratio 0.276 [0.182–0·418]; p<0·0001).

Lu-177 plus octreotide 30 mg LAR slashed the risk of disease progression or death by around 72% versus high-dose octreotide 60 mg LAR, according to the paper published in The Lancet.

A subgroup analysis, presented at ESMO’s GI 2024 congress in Munich, also showed that median PFS was longer for the Lu-177 compared to high-dose octreotide control groups regardless of tumour grades (29 months versus 13.8 months for grade 2 and 22.2 months versus 5.6 months for grade 3) and tumour origin (19.4 months versus 8.5 months for pancreas and 29.0 versus 8.4 months for small intestine).

Tolerability was similar between the two treatment arms, with 93% of Lu-177 treated patients experiencing adverse events compared to 95% of the control group. No study drug-related deaths occurred, and no new safety concerns emerged.

The paper authors – which included representatives of Novartis and UK Consultant Clinical Oncologist Dr Stephen Falk, University Hospitals Bristol NHS Foundation Trust – noted that NETTER-2 is the first Phase III clinical trial to report data for radioligand therapy administered in the first-line setting to patients in any cancer population, as well as the first randomised story of any potential treatment for patients with grade 3 well-differentiated GEP NETs.

The treatment, they said, showed “consistent benefit” across all subgroups, and the population with grade 2–3 NETs had an objective response rate to Lu-177 plus octreotide 30mg LAR of 43%, “one of the highest reported in the literature”, compared to 9.3% for octreotide 60 mg LAR.

A new frontier

There were key limitations, including the study’s open-label design, which was necessary due to different treatment administration methods and the need for radiation-exposure precautions.

However, the findings show that radioligand therapy “is a promising new frontier in the treatment of cancers, which has previously been limited to surgery and systemic therapy”.

“The significant improvement in progression-free survival and response with 177Lu-Dotatate plus octreotide LAR compared with somatostatin analogues alone…will have clinical practice-changing implications in support of first-line radioligand therapy as standard of care for advanced higher grade 2 and grade 3, well-differentiated, gastroenteropancreatic NETs,” the authors concluded.