December 2015, Vol. 4, No. 6

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Encouraging New Options for Neuroendocrine Tumors

European Cancer Congress

Christoph_Zielinski98pxPatients 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, while RADIANT-4 evaluated the mTOR inhibitor everolimus in patients with advanced, nonfunctional, gastrointestinal, and lung NETs. Both studies showed significantly prolonged progression-free survival (PFS), and the data suggest that an overall survival (OS) benefit could emerge over longer follow-up.

James,Yao98pxEverolimus is approved by the FDA for locally advanced, metastatic, or unresectable progressive NETs of pancreatic origin, whereas 177Lu-DOTATATE is investigational in the United States and is used in Europe but has not been formally studied.

“We truly have just heard 2 practice-changing presentations,” said press briefing moderator Christoph Zielinsky, MD, of the Medical University of Vienna, Austria.

177Lu-DOTATATE in Midgut NETs

Patients with advanced midgut NETs have few therapeutic options after progression on first-line somatostatin analog therapy, according to Philippe Ruszniewski, MD, Professor of Gastroenterology at the University of Paris VII, Beaujon Hospital, France, who presented the results from NETTER-1.

177Lu-DOTATATE consists of a lutetium radionuclide chelated to a peptide that targets somatostatin receptors, which are overexpressed in about 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 15 centers in the United States with somatostatin receptor–positive, well-differentiated midgut NETs (functioning or not) that progressed on octre­otide LAR 30 mg. The ileum was the primary tumor site in 75% of patients, and 84% had liver metastases.

Patients in the experimental arm received 4 doses over 8 weeks plus 30 mg of octreotide LAR every 28 days. Patients in the octreotide LAR–alone group received 60 mg of the drug every 4 weeks. Follow-up was 5 years.

The study met the primary end point of PFS.

Median PFS was 8.4 months with octreotide LAR and not yet reached with 177Lu-DOTATATE. The difference represented an almost 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 in the final analysis.

Deaths reported thus far were 13 in the 177Lu-DOTATATE arm compared with 22 in the octreotide LAR group (P <.0186); however, the difference did not meet the prespecified level of statistical significance for this analysis.

Response rates were 3% with octreotide LAR alone compared with 19% for 177Lu-DOTATATE (P <.0004).

Serious adverse events were reported in 26% of patients in the experimental arm and 24% in the control arm, with 9% and 1%, respectively, considered related to treatment.

Everolimus in Multiple Sites

RADIANT-4 demonstrated a statistically significant 52% reduction in the risk of progression or death with everolimus among patients with a variety of NETs, said James Yao, MD, Deputy Chairman in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, Houston.

Patients with anatomically diverse NETs had a nearly 3-fold increase in median PFS with everolimus: 11.0 versus 3.9 months with placebo (P <.00001).

“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,” Yao said.

RADIANT-4 evaluated everolimus versus placebo in 302 patients with progressive, well-differentiated, nonfunctional, advanced NETs of gastrointestinal or lung origin (about 25% were midgut). Patients were required to have stopped 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 placebo daily.

When PFS, the primary end point, was assessed, a reduction in the risk of progression or death of 52% was seen with everolimus over placebo (P <.00001), and by 61% by investigator assessment (P <.00001).

“Local radiology review confirmed the significant progression-free survival benefit, a change of 8.5 months,” 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 (HRs) were most impressive in patients with the worst prognosis, ie, those whose tumors originated in the lung, stomach, rectum, and colon (except cecum) (HR, 0.43), and among patients with a liver tumor burden >25% (HR, 0.18).

While 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,” he noted.

Survival results will be analyzed in 2016.

Adverse events with everolimus were consistent with the known safety profile.

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