As reported in The Lancet by Simron Singh, MD, MPH, FRCPC, and colleagues, primary results of the international, multicenter, randomized phase III NETTER-2 study have shown significantly improved progression-free survival with the addition of the radioligand lutetium-177 dotatate (Lu-177 dotatate) to standard first-line therapy for patients with untreated, high-grade gastroenteropancreatic neuroendocrine tumors.

“Lu-177 dotatate should be considered a new standard of care,” the investigators remarked.

Simron Singh, MD, MPH, FRCPC

Study Details

In NETTER-2, a total of 226 newly diagnosed patients with advanced, somatostatin receptor–positive, well-differentiated grade 2 or 3 (Ki67 index ≥ 10% and ≤ 55%) gastroenteropancreatic neuroendocrine tumors were randomly assigned 2:1 to receive either Lu-177 dotatate plus standard-dose (30 mg) octreotide every 8 weeks or high-dose (60 mg) octreotide alone every 4 weeks. They were stratified by neuroendocrine tumor grade (2 vs 3) and origin (pancreas vs other).

The primary endpoint of the trial was progression-free survival. The investigators identified the objective response rate and time to deterioration in quality-of-life scores for global health status, diarrhea, fatigue, and pain as key secondary endpoints.

Progression-Free Survival

At a median follow-up of 23.2 months, progression-free survival events were reported in 36% of the patients treated with Lu-177 dotatate and in 61% of those who did not receive radioligand-based therapy. The median duration of progression-free survival was 22.8 vs 8.5 months, respectively. Treatment with Lu-177 dotatate resulted in an approximate 72% reduction in the risk of disease progression or death (stratified hazard ratio = 0.276, P < .0001), with a reportedly consistent benefit across all prespecified subgroups.

The objective response rate was found to be significantly higher with vs without Lu-177 dotatate (43.0% vs 9.3%, stratified odds ratio = 7.81, P < .0001); complete responses were documented in 5% and 0% of patients, respectively. The time to deterioration of quality of life did not appear to significantly differ between the arms.

Adverse Events

No new safety concerns were observed. During the treatment period, any-grade adverse events were documented in 93% of the patients treated with Lu-177 dotatate and in 95% of those who did not receive radioligand-based therapy, with the most common being nausea (27% vs 18%), diarrhea (26% vs 34%), and abdominal pain (18% vs 27%). The investigators reported no deaths related to the study drugs.

A total of 35% and 27% of the patients treated with and without Lu-177 dotatate, respectively, experienced an adverse event of grade 3 or higher. Adverse events of special interest of grade 3 or higher included leukopenia, anemia, and thrombocytopenia; each affected fewer than three patients in either arm. Additionally, one case of myelodysplastic syndrome was reported with Lu-177 dotatate.

The NETTER-2 study will continue to collect additional safety and overall survival data for a long-term follow-up of 3 years. Patients in the study also have the option to participate in an optional crossover or retreatment phase after experiencing disease progression, subject to meeting specific protocol criteria.

The investigators concluded: “Our results will help to fill the evidence gap that has been highlighted in treatment guidelines. The significant improvement in progression-free survival and response with Lu-177 dotatate plus long-acting octreotide compared with somatostatin analogues alone was observed across tumor site and grade and will have clinical practice–changing implications.” 

Dr. Singh, of the University of Toronto, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Advanced Accelerator Applications, a Novartis company. For full disclosures of the study authors, visit thelancet.com.