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177Lu-Dotatate improves PFS, response rate in advanced midgut neuroendocrine tumors
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177Lu-Dotatate conferred longer PFS and a significantly higher response rate than high-dose octreotide long-acting repeatable in patients with advanced midgut neuroendocrine tumors, according to results of the randomized, controlled, open-label, phase 3 NETTER-1 trial published in The New England Journal of Medicine.
“The truly striking improvement in PFS indicates that 177Lutetium (Lu)-Dotatate [Lutathera, Advanced Accelerator Applications] is a very promising therapy for patients with midgut neuroendocrine tumors progressing on somatostatin analog therapy,” Jonathan R. Strosberg, MD, associate professor at H. Lee Moffitt Cancer Center, told HemOnc Today. “There are few effective treatment options in this setting, and we are therefore hopeful that the drug will be approved for this indication.”
Neuroendocrine tumors of the midgut commonly metastasize to the liver, peritoneum and mesentery and are the most common type of malignant gastrointestinal neuroendocrine tumors. With a 5-year survival rate of less than 50%, first-line systemic therapy usually consists of a somatostatin analogue (octreotide) for control of both hormonal secretion and tumor growth. Second-line treatment has been limited to everolimus (Afinitor/Zortress, Novartis).
“Radiolabeled somatostatin analogs have been used for over a decade, primarily in Europe, for treatment of advanced, well-differentiated neuroendocrine tumors,” Strosberg said. “However, they have never been studied in a randomized prospective fashion, and therefore their impact on important outcomes such as PFS and OS was unknown. The NETTER-1 study was the first randomized, prospective study of a radiolabeled somatostatin analog — 177Lu-Dotatate. Given the fact that our team serves one of the largest neuroendocrine tumor populations in the country, we were very interested in participating in this key prospective phase 3 registrational study.”
From September 2012 through mid-January 2016, researchers evaluated the efficacy and safety of 177Lu-Dotatate (Lutathera, Advanced Accelerator Applications) compared with high-dose octreotide long-acting repeatable (LAR; Sandostatin, Novartis).
Researchers randomly assigned 229 patients from 41 sites (27 in Europe, 14 in the United States) with metastatic midgut neuroendocrine tumors to receive 7.4 GBq 177Lu-Dotatate every 8 weeks (n = 116) — which included four intravenous infusions, plus supportive care including 30 mg octreotide LAR administered intramuscularly — or a 60-mg intramuscular dose of octreotide LAR alone every 4 weeks (n = 113).
PFS served as the primary endpoint, and objective response rate, OS, safety and side effect profile served as secondary end points. An objective tumor assessment through CT or MRI was performed every 12 weeks after the date of randomization and safety was assessed at least every 2 to 12 weeks.
The estimated 20-month PFS was 65.2% (95% CI, 50-76.8) for patients in the 177Lu-Dotatate group vs. 10.8% (95% CI, 3.5-23) in the octreotide LAR group.
Median PFS was not reached in the 177Lu-Dotatate arm and was 8.4 months (95% CI, 5.8-9.1) in the octreotide LAR group (HR = 0.21; 95% CI, 0.13-0.33).
The response rate was 18% in the 177Lu-Dotatate group and 3% in the octreotide LAR group (P < 0.001).
At the time of the interim OS analysis, 14 deaths occurred in the 177Lu-Dotatate group and 26 occurred in the octreotide LAR group (P = 0.004).
In the 177Lu-Dotatate group, 1% of patients experienced grade 3 or grade 4 neutropenia, 2% experienced thrombocytopenia and 9% experienced lymphopenia. No patients in the control group experienced these events. There was no evidence of renal toxic effects in either arm.
“Early-phase data and institutional series suggest that 177Lu-Dotatate is effective across a range of somatostatin-receptor expressing neuroendocrine tumors,” Strosberg said. “Indeed, response rates seem to be higher in pancreatic neuroendocrine tumors compared to midgut neuroendocrine tumors. I anticipate future randomized clinical trials evaluating this radiopharmaceutical drug in patients with pancreatic neuroendocrine tumors and other nonmidgut neuroendocrine tumors, possibly comparing safety and efficacy to other systemic therapies, such as everolimus. Future combination trials, possibly with radiosensitizing drugs, will be of interest as well.”
- by Chuck Gormley
Disclosure: Advanced Accelerator Applications funded the study. Strosberg reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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