NETTER-2: Lu-177 Dotatate for Advanced Gastroenteropancreatic Neuroendocrine Tumors

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Results from the first phase III clinical trial evaluating radioligand therapy in the first-line setting demonstrated that treatment with lutetium Lu-177 dotatate significantly improved progression-free survival and objective response rates in patients with high-grade gastroenteropancreatic neuroendocrine tumors—potentially establishing a new standard of care. The research was presented by Simron Singh, MD, MPH, FRCPC, and colleagues at the 2024 ASCO Gastrointestinal Cancers Symposium (Abstract LBA588).

About NETTER-2

Most gastroenteropancreatic neuroendocrine tumors are advanced at the time of diagnosis. The incidence of grade 2 and grade 3 well-differentiated advanced gastroenteropancreatic neuroendocrine tumors varies across geographies, and the study authors estimate that approximately 20% to 30% of all gastroenteropancreatic neuroendocrine tumors may be classified as advanced grade 2 or grade 3.

“There is no established universal standard of care for these patients. Existing first-line treatment options for patients with high grade 2 or grade 3 well-differentiated gastroenteropancreatic neuroendocrine tumors are based on consensus guidelines with little supporting evidence. So far, no randomized phase III studies have investigated the most appropriate treatment strategy for higher grade 2 and grade 3 gastroenteropancreatic neuroendocrine tumors, highlighting the need for more robust data to guide clinical decision-making. This study will be practice-changing,” said lead study author Dr. Singh, of Odette Cancer Centre at Sunnybrook Health Sciences Centre.

In the phase III NETTER-2 trial, a total of 226 patients newly diagnosed with somatostatin receptor–positive high grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumors in the past 6 months were randomly assigned 2:1 to receive either Lu-177 dotatate plus octreotide (treatment arm) or octreotide alone (control arm). In the treatment arm, patients received four cycles of Lu-177 dotatate plus 30 mg of octreotide long-acting release at 8-weekly intervals. In the control arm, patients received 60 mg of octreotide long-acting release every 4 weeks.

Our study showed significant progression-free survival and unprecedented response rates, offering a new, safe treatment option in a field with no established standard of care.
— Simron Singh, MD, MPH, FRCPC

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Patients had a median age of 61 years; 53.5% were male and 46.5% were female; and 73.0% of patients were White, 15.0% were Asian, and 11.9% were of other races. Patients were stratified by grade (grade 2 or grade 3) and tumor origin (pancreas vs other location). The primary endpoint of the trial was progression-free survival; the secondary endpoint was objective response rate.

Radioligand therapy delivers radiation to cancer cells in a targeted and precise way, with a minimal effect on healthy cells. Lu-177 dotatate is a radioactive drug that binds to a protein called a somatostatin receptor and gives off radiation in an effort to destroy them. Octreotide is a synthetic version of somatostatin. According to the authors, approximately 90% of gastroenteropancreatic neuroendocrine tumors express the somatostatin receptor SSTR2.

Key Findings

A total of 151 patients were randomly assigned to the treatment arm, and 75 patients were randomly assigned to the control arm. Thirty-five percent of patients had grade 3 tumors; 54.4% of tumors were located in the pancreas and 29.2% of tumors were located in the small intestine.

Median progression-free survival was significantly extended in patients in the treatment arm when compared to patients in the control arm (22.8 months vs 8.5 months, respectively). Overall response rates were significantly higher in patients in the treatment arm when compared to patients in the control arm (43.0% vs 9.3%, respectively). Patients on the treatment arm had a 72.4% reduction in the risk of disease progression.

In the treatment arm, adverse events included grade 3/4 leukopenia, anemia, and thrombocytopenia, each affecting fewer than three patients. Additionally, one case of myelodysplastic syndrome was reported.

“Our study showed significant progression-free survival and unprecedented response rates, offering a new, safe treatment option in a field with no established standard of care,” said Dr. Singh.

Next Steps

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.

Disclosure: The study was funded by Advanced Accelerator Applications, a Novartis company.                                                                           

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