Lutetium Lu 177 Dotatate Approved by FDA

On the heels of an approval by the European Commission, the FDA greenlighted the radiopharmaceutical lutetium Lu 177 dotatate (Lutathera; Novartis, Advanced Accelerator Applications) to treat patients with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NET).

“In my opinion, this is a game changer for neuroendocrine tumor patients,” says Thorvardur Halfdanarson, MD, who treats patients with GEP-NETs at Mayo Clinic in Rochester, MN, and has seen a “huge, unmet need” for treatment options beyond somatostatin analogues, sunitinib (Sutent; Pfizer), and the mTOR inhibitor everolimus (Afinitor; Novartis). He adds that for the past 10 years, he has routinely referred patients abroad, mostly to Switzerland, where lutetium Lu 177 dotatate has been available on a compassionate-use basis.

Administered intravenously, lutetium Lu 177 dotatate consists of a radioisotope attached to a somatostatin analogue. The analogue binds to somatostatin type 2 receptor, which is highly expressed on the surface of neuroendocrine tumor cells. By localizing to the tumor cells, the agent allows a targeted increase in destructive beta radiation.

“This beta radiation has a tissue penetration range of roughly 2 mm and a long half-life, and so it's ideally suited to deliver radiation to tumors with relatively little collateral toxicity,” explains Jonathan Strosberg, MD, of Moffitt Cancer Center in Tampa, FL, who led the NETTER-1 phase III clinical trial.

In that trial, the results of which were the basis of the recent approvals, 116 patients with advanced midgut NETs treated with the drug had a response rate of 18% and a progression-free survival (PFS) rate of 65.2% at 20 months, compared with a response rate of 3% and a 20-month PFS rate of 10.8% in the control group.

NETTER-1 followed a large-scale retrospective study in the Netherlands where 1,214 patients treated with the drug had a PFS of 29 months and overall survival of 63 months.

“Until now it's been home-grown administration by hospitals manufacturing their own radiolabeled somatostatin analogues,” Strosberg explains. “What's been lacking is regulatory approval and, as importantly, high-quality data, and now we have both, so it's extremely exciting.”

Strosberg hopes FDA approval will make the treatment available to more patients within the United States who meet the indications. He adds that research is under way on other radiopharmaceuticals, including ones that use somatostatin receptor antagonists or a radioisotope that emits alpha instead of beta radiation.

Halfdanarson considers the FDA approval “surprisingly broad in a good way,” pointing out that it includes patients with foregut and hindgut GEP-NETs, who were excluded from the NETTER-1 trial, and does not specify tumor grade.

For him, the broad scope of the approval, combined with the fact that “the treatment is incredibly well tolerated and has few severe toxicities,” means that clinicians may soon use it in a variety of contexts.

“For those of us who have large neuroendocrine practices—for example at Mayo where we actively follow hundreds and hundreds of patients—this really is a major change for us,” he says. “Now we have to complete setting everything up here, and get ready to treat a large number of patients.” –Catherine Caruso