Vienna, Austria—Patients with advanced neuroendocrine tumors (NETs) have 2 promising new treatment options, according to separate phase 3 studies presented as late-breakers at the 2015 European Cancer Congress.
The NETTER-1 trial evaluated the radiopharmaceutical agent 177Lu-DOTATATE in NETs confined to the midgut, and RADIANT-4 evaluated the mTOR inhibitor everolimus (Afinitor) in patients with advanced, nonfunctional, gastrointestinal or lung NETs. Both studies showed significantly prolonged progression-free survival (PFS), and data suggest that an overall survival (OS) benefit could emerge.
Everolimus is FDA approved for locally advanced, metastatic, or unresectable progressive NETs of pancreatic origin; 177Lu-DOTATATE is an investigational agent in the United States.
“We truly have just heard 2 practice-changing presentations,” commented Christoph Zielinski, MD, of the Medical University of Vienna, Austria.
177Lu-DOTATATE in Midgut NETs
Patients with advanced midgut NETs have few therapeutic options after progression with first-line somatostatin analog therapy, according to Philippe Ruszniewski, MD, Hôpital Beaujon, Clichy, France, who presented the results of NETTER-1. 177Lu-DOTATATE consists of a lutetium radionuclide chelated to a peptide that targets somatostatin receptors, which are overexpressed in approximately 80% of NETs. Upon binding to the receptors, cytotoxic high-energy electrons are released into cancer cells.
NETTER-1 enrolled 229 patients recruited from 36 sites in Europe and the United States with somatostatin receptor–positive, well-differentiated midgut NETs (functioning or not) that progressed with octreotide LAR 30 mg. The ileum was the primary tumor site in 75% of the patients, and 84% had liver metastases.
Patients in the experimental arm were randomized to receive 4 administrations of 177Lu-DOTATATE every 8 weeks plus octreotide 30 mg (not the LAR formulation); patients in the control arm received octreotide LAR 60 mg every 4 weeks. Follow-up was 5 years.
The study met the primary end point of PFS. The median PFS was 8.4 months with octreotide LAR and not yet reached with 177Lu-DOTATATE. The difference represented almost an 80% reduction in the hazard for progression or death with the radiopharmaceutical.
The interim analysis also suggests increased OS in the experimental arm, but this needs to be confirmed.
Deaths reported thus far were 13 in the 177Lu-DOTATATE arm compared with 22 in the octreotide LAR group.
Response rates were 3% with octreotide LAR alone compared with 19% for 177Lu-DOTATATE (P <.004).
Serious adverse events were reported in 26% of patients in the experimental arm and in 24% of those in the control arm, with 9% and 1%, respectively, considered related to treatment.
Everolimus in Multiple Sites
RADIANT-4 demonstrated a significant 52% reduction in the risk for disease progression or death with everolimus, said James C. Yao, MD, Deputy Chair, Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston.
Patients with anatomically diverse NETs had a nearly 3-fold increase in median PFS with everolimus—11.0 months versus 3.9 months with placebo.
“Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of NETs, including those arising from the pancreas, lung, and gastrointestinal tract,” Dr Yao said.
RADIANT-4 evaluated everolimus versus placebo in 302 patients with progressive, well-differentiated, advanced NETs of gastrointestinal or lung origin. Patients were required to have stopped receiving somatostatin analogs for 4 weeks before enrollment and to have no active symptoms of carcinoid syndrome. They were randomized 2:1 to everolimus 10 mg or to placebo daily.
The PFS was reduced by 52% with everolimus over placebo (P <.001), and by 61% by investigator assessment.
“Local radiology review confirmed the significant progression-free survival benefit, a change of 8.5 months,” Dr Yao reported.
“The curves were durable, and remained separated more than 18 months,” he said, adding that the benefit was observed in all sites of origin. Hazard ratios were most impressive in patients with the worst prognosis and among patients with a liver tumor burden >25%.
Although the response rates were just 2% with everolimus and 1% with placebo, disease control rates were 82.4% and 64.9%, respectively.
“Disease control is important for these patients,” Dr Yao noted.
Preliminary analysis showed a 36% improvement in OS with everolimus versus placebo, although this did not meet the prespecified criteria for significance.
Adverse events were consistent with the known safety profile.