ASCO Perspective

“This first phase 3 study evaluating radioligand therapy in this context could redefine first-line treatments for patients with these complex tumors, filling a critical gap in evidence-based care for patients with advanced grade 2 and 3 gastroenteropancreatic neuroendocrine tumors,” said ASCO Expert Cathy Eng, MD.

Study at-a-Glance

ALEXANDRIA, Va. — Results from the first phase 3 clinical trial evaluating radioligand therapy in the first-line setting demonstrated that treatment with [¹⁷⁷Lu]Lu-DOTA-TATE 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 will be presented at the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, taking place January 18-20 in San Francisco, California.

About the Study

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 authors estimate that approximately 20-30% 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 3 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 Simron Singh, MD, MPH, FRCPC, Odette Cancer Centre at Sunnybrook Health Sciences Centre.

In the Phase 3 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 randomized in a 2:1 ratio to receive either [¹⁷⁷Lu]Lu-DOTA-TATE plus octreotide (treatment arm) or octreotide alone (control arm). In the treatment arm, patients received 4 cycles of [¹⁷⁷Lu]Lu-DOTA-TATE plus 30 milligrams octreotide long-acting release at 8-weekly intervals. In the control arm, patients received 60 milligrams of octreotide long-acting release every 4 weeks.

Patients were a median age of 61; 53.5% were males and 46.5% females; and 73.0% of patients were White, 15.0% Asian, and 11.9% were comprised of other races. Patients stratified by grade (grade 2 or grade 3) and tumor origin (pancreas vs. other) and the primary endpoint was progression-free survival (PFS). 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. [¹⁷⁷Lu]Lu-DOTA-TATE 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

• 151 patients were randomized to the treatment arm and 75 patients were randomized to the control arm.
• 35% 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 PFS 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 Singh.

Next Steps

The NETTER-2 study will continue to collect additional safety and overall survival data for a long-term follow-up of three 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 study was funded by Advanced Accelerator Applications, a Novartis company.                                                                           

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View author disclosures (Link will be added shortly)

View the News Planning Team disclosures https://old-prod.asco.org/sites/new-www.asco.org/files/content-files/about-asco/pdf/2024-asco-gi-npt-disclosures.pdf

ATTRIBUTION TO THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY GASTROINTESTINAL CANCERS SYMPOSIUM IS REQUESTED IN ALL COVERAGE.

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