FDA Grants Lutathera Priority Review for Neuroendocrine Tumors

Stefano Buono

The FDA has granted a priority review designation to Lutathera (177Lutetium DOTA-octreotate) as a treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), according to the developer of the peptide receptor radionuclide therapy (PRRT), Advanced Accelerator Applications.

UPDATE 1/26/2018: FDA Approves Lutathera for GEP-NETs

The application was based upon data from the phase III NETTER-1 trial, which compared Lutathera with high-dose octreotide LAR for patients with grade 1 or 2 metastatic midgut NETs. In this trial, there was a 79% reduction in the risk of progression or death with Lutathera compared with octreotide. The FDA is scheduled to make a decision on the PRRT by December 28, 2016, as part of the Prescription Drug User Fee Act (PDUFA).

“We are encouraged that the FDA has granted Priority Review for Lutathera as a potential treatment for GEP-NETs,” said Stefano Buono, chief executive officer of Advanced Accelerator Applications. “We believe this action emphasizes the need to improve the lives of these patients.”

Lutathera consists of the somatostatin analog octreotide connected with the beta and gamma emitting radiopharmaceutical 177Lutetium (177Lu). The two components are connected using the chelator DOTA. Lutathera represents a new generation of PRRT, and has been tested in several single-arm studies. In these trials, the median progression-free survival (PFS) ranged from 1 to 3 years.

Baseline characteristics were well balanced between the two arms. The mean age of patients in the investigational arm was 63 years (±9) and the mean BMI was 25 (±5). The primary tumor site was the ileum (74%) and the most common sites of metastasis were the liver (84%), lymph nodes (66%), and other locations (35%). All patients had somatostatin receptor-positive tumors, the majority of which were grade 4 on the Krenning scale (60%).

The primary endpoint of the study was PFS. Secondary endpoints focused on objective response rates (ORR), overall survival (OS), and safety.

Median PFS had not been reached in the Lutathera arm compared with 8.4 months in the high-dose octreotide arm (HR, 0.21; 95% CI, 0.13-0.33; P <.0001). The estimated median PFS was approximately 40 months with Lutathera, according to Jonathan R. Strosberg, MD, who presented an updated of the data at the 2016 ASCO Annual Meeting.

"Median PFS has not yet been reached in the Lutathera arm. Based on the Kaplan-Meier curve, we can estimate a median PFS that will be in excess of 3 years," said Strosberg, from the H. Lee Moffitt Cancer Center & Research Institute. "The treatment arm was favored for all baseline prognostic factors, including degree of somatostatin receptor expression."

The ORR with Lutathera was 18% versus 3% with octreotide (P = .0008). There was one complete response with Lutathera and 17 partial responses. The stable disease rate with Lutathera was 66% versus 62% with octreotide.

At the interim analysis of OS there was a 60% reduction in the risk of death seen with Lutathera versus octreotide (HR, 0.398; 95% CI, 0.21-0.77; P = .0043); however, the prespecified P value for statistical significance at the interim analysis was <.000085. Eighty-eight percent of patients in the Lutathera arm remained alive versus 77% in the octreotide group.

"This very strong signal needs to be confirmed at the final analysis," Strosberg said.

An adverse event (AE) of any grade was experienced by 96% of those in the Lutathera arm versus 86% of those in the octreotide group. Eighty-six percent and 31% of patients, in the Lutathera and octreotide groups, experienced treatment-related AEs, respectively. Treatment related serious AEs were experienced by 9% of patients treated with Lutathera versus 1% in the octreotide arm. Five patients discontinued the study due to Lutathera-related AEs.

The most common grade 3/4 AEs in the Lutathera group versus high-dose octreotide, respectively, were lymphopenia (9% vs 0%), vomiting (7% vs 0%), nausea (4% vs 2%), diarrhea (3% vs 2%), abdominal pain (3% vs 5%), fatigue (2% vs 2%), and thrombocytopenia (2% vs 0%). Grade 3/4 liver enzyme increases were seen in those treated with Lutathera that were not apparent in the high-dose octreotide arm, including AST increase (4% vs 0%), ALT increase (4% vs 0%), and bilirubin increase (2% vs 0%).

"The rates of grade 3 hepatotoxicity were exceptionally low with Lutathera. Although nephrotoxicity is a potential adverse event, there was really no evidence of observed nephrotoxicity in this timeframe, possibly secondary to the renal protective effective of the amino acid infusions," said Strosberg.

In early June 2016, the FDA approved a diagnostic tool for the detection of somatostatin receptor-positive NETs, known as Netspot. The kit includes a single-dose injection of gallium (Ga)-68 Dotatate, which binds to somatostatin receptors. The agent was approved under the FDA's priority review program.

Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: Efficacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE. J Clin Oncol. 2016;34 (suppl; abstr 4005).

In the phase III study, 229 patients with midgut NETs who progression on standard-dose octreotide (30 mg) were randomized to Lutathera (n = 116) or high-dose octreotide (n = 113). Four doses of Lutathera were administered at 7.4 GBq every 8 weeks in combination with octreotide at 30 mg for symptom control. In the control arm, patients received octreotide LAR at 60 mg every 4 weeks, which was the control arm recommended by the FDA and European Medicines Agency.