Lutetium-177-Dotatate (177Lu-Dotatate, Lutathera), in combination with octreotide, may change care for patients with newly diagnosed high-grade gastroenteropancreatic neuroendocrine tumors (NETs), according to data presented Friday, Jan. 19, at the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium (Abstract LBA588).
“Our study showed significant progression-free survival [PFS] and unprecedented response rates, offering a new, safe treatment option in a field with no established standard of care,” said study presenter Simron Singh, MD, MPH, from the Odette Cancer Centre at Sunnybrook Health Sciences Centre in Toronto, Canada.
Neuroendocrine neoplasms are classified into poorly differentiated neuroendocrine carcinomas and well-differentiated NETs, which are further subdivided into three grades on the basis of Ki67 staining. Grade 3 well-differentiated NETs are a relatively new classification, and the most appropriate first-line treatment strategy remains to be defined, as this subtype has been excluded from many clinical trials.
“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,” Dr. Singh said.
“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,” he continued. The current trial aims to fill that gap.
Radioligand therapy using the somatostatin analog 177Lu-Dotatate demonstrated improved outcomes for patients with somatostatin-receptor-positive grade 1 and 2 midgut NETs after progression on a somatostatin analog in the NETTER-1 trial.
The phase 3 NETTER-2 study enrolled 226 patients with newly diagnosed somatostatin receptor-positive high grade 2 or 3 (Ki67: 10%–55%) advanced gastroenteropancreatic NETs. Patients were randomly assigned in a 2:1 fashion to either initial treatment with 177Lu-Dotatate plus 30 mg long-acting-release (LAR) octreotide every eight weeks or high-dose octreotide LAR at 60 mg every four weeks. The study included an optional treatment extension phase, and crossover was allowed. The primary endpoint of the study was PFS.
Most tumors in the study originated in the pancreas or small intestine. Among patients treated with the combination, 34% had grade 3 tumors, as did 36% treated with the single agent. The median Ki67 index was 17% and 16%, respectively. Nearly all patients had liver metastases at baseline.
The median cumulative dose of 177Lu-Dotatate was 29.2 GBq, with 88% of patients receiving all four planned doses.
Median PFS was significantly prolonged in the 177Lu-Dotatate plus octreotide group, with a median PFS of 22.8 months vs 8.5 months in the high-dose octreotide group (stratified hazard ratio [HR] = 0.276; 95% confidence interval [CI], 0.182–0.418; P< .0001); representing a 72% reduction in the risk for disease progression or death in the experimental group. The PFS benefit was observed consistently across all prespecified subgroups.
The objective response rate was significantly higher with 177Lu-Dotatate/octreotide vs high-dose octreotide, at 43.0% and 9.3%, respectively (stratified odds ratio = 7.81; 95%CI, 3.32–18.4; P< .0001). Eight patients (5.3%) in the 177Lu-Dotatate/octreotide group had a complete response compared with zero patients in the control group. No difference in deterioration in quality of life was identified between the study groups.
Nausea (27%), diarrhea (26%), and abdominal pain (18%) were the most common any-grade adverse events. The most common grade three or higher adverse events in the 177Lu-Dotatate-containing group were decreased lymphocyte count (5.4%), increased gamma-glutamyl transferase (4.8%), small intestine obstruction (3.4%), and abdominal pain (2.7%). One patient (0.7%) treated with 177Lu-Dotatate/octreotide developed a secondary hematologic malignancy (myelodysplastic syndrome).
“Neither treatment was particularly toxic, which is nice,” said Jordan D. Berlin, MD, from Vanderbilt University Medical Center in Nashville, during the abstract discussion, “but it is still early, and we don’t know what the long-term hematologic toxicities will be.”
Overall survival was not mentioned during the presentation. Although there are still questions to be addressed, experts said that the study appears to have clinical implications.
“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 Cathy Eng, MD, from Vanderbilt Ingram Cancer Center.
The NETTER-2 study was supported by Advanced Accelerator Applications, a Novartis company.
Dr. Singh reported honoraria and a consulting or advisory role with Advanced Accelerator Applications/Novartis and IPSEN, as well as a family member employed with Sanofi.
Dr. Berlin reported a consulting or advisory role and research funding and/or other financial relationship with various companies.
Dr. Eng reported consulting or advisory role and/or research funding with various companies.