Midgut neuroendocrine tumors—the most common gastrointestinal neuroendocrine malignancy—metastasize primarily to the mesentery, peritoneum and liver. These tumors express high levels of somatostatin receptors, making somatostatin analog treatment the primary systemic therapy. There is currently no standard second-line systemic treatment, leaving patients who have progressive disease with few options.
Radiolabled somatostatin analogs, which allow for targeted delivery of radiation to somatostatin-receptor expressing tumors, have been evaluated in single-arm trials. Among the most promising has been Lutetium-177 (177Lu) Dotatate. 177Lu is a medium-energy beta emitting radionuclide with a maximum tissue penetration of 2mm. It also emits medium and low energy gamma radiation that can be used for imaging. In one large institutional registry, treatment with 177Lu-Dotatate resulted in 28% partial remissions, 2% complete remission, and 33-month median progression-free survival in a single group trial of 310 patients with gastroenteropancreatic neuroendocrine tumors. In order to evaluate this therapy in a randomized, prospective fashion, Moffitt physicians Jonathan Strosberg, MD, Ghassan El-Haddad, MD and their collaborators compared the safety and efficacy of 177Lu-Dotatate with high-dose octreotide in treatment of advanced, somatostatin-receptor positive neuroendocrine tumors of the midgut in the phase 3NETTER-1 trial. The results of the trial were recently published in the New England Journal of Medicine.
The NETTER-1 trial enrolled 229 patients with metastatic, well-differentiated neuroendocrine tumors of the mid-gut. 116 patients in the investigational arm received 177Lu-Dotatate every 8 weeks at a dose of 7.4 GBq, with four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] at a dose of 30 mg administered intramuscularly. The control group included 113 patients who received octreotide LAR alone at a dose of 60 mg every 4 weeks, administered intramuscularly. The investigators evaluated progression-free survival by blinded central radiology review, which was the primary endpoint, as well as overall survival, objective response rate, safety, and side-effect profile, which were all secondary end points.
The study demonstrated a clinically and statistically significant 79% improvement in progression free survival. At 20 months, the PFS rate was 65.2% on the investigational arm versus only 10.8% on the control arm. Moreover, 18% of patients in the 177Lu-Dotatate group responded to treatment compared to only 3% of the controls (P<0.001). A preliminary interim overall survival analysis showed promising results as well, with 26 deaths in the controls group compared to just 14 in the group that received 177Lu -Dotatate group (P=0.004). Additional survival analysis will be performed in the future. Although improved outcomes were associated with use of 177Lu -Dotatate, there were also more toxicities. 1%, 2%, and 9% of patients in this group experienced Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia, respectively, compared with no patients in the control group. However, there were no renal toxic effects found and the rates of grade 3 and 4 hematologic toxicities were tolerable. A renal-protective agent was administered concurrently in this study, and should be administered with 177Lu-Dotatate in this setting.
Looking forward, the authors have additional analysis planned, with final overall survival analysis in either 5 years following randomization of the last patient or after 158 patient deaths, whichever happens first. The reported results are exciting and promising for patients with advanced, somatostatin-receptor positive neuroendocrine tumors of the midgut, showing that 177Lu- Dotatate provides significantly better outcomes than high-dose octreotide LAR alone, and should be considered in this setting.
Video courtesy of The Healthcare Channel
About the Doctors
An associate professor at H. Lee Moffitt Cancer Center, Dr. Strosberg specializes in the management of gastrointestinal and neuroendocrine malignancies, leading the neuroendocrine tumor division at Moffitt. He serves on the board of directors of the North American Neuroendocrine Tumor Society (NANETS), on the neuroendocrine guidelines committee of the National Comprehensive Cancer Network (NCCN), on the neuroendocrine task force of the National Cancer Institute (NCI), and the neuroendocrine staging committee of the American Joint Committee on Cancer (AJCC).
Dr. El-Haddad is an assistant professor that specializes in nuclear medicine and interventional radiology, leading the Radionuclide Therapy Program at Moffitt. He serves on the board of directors of the American Board of Nuclear Medicine (ABNM), and Therapy Center of Excellence of the Society of Nuclear Medicine and Molecular Imaging (SNMMI). He is a member of the Neuroendocrine Tumor subcommittee of the Targeted Radionuclide Therapy outreach group of SNMMI. His research focuses on the development of novel targeted radiopharmaceutical therapies, and minimally invasive image-guided therapies such as tumor ablation and embolization.