FDA Approves Lutathera for Gastroenteropancreatic Neuroendocrine Tumors

The FDA has approved Lutathera (lutetium Lu 177 dotate) for the treatment of patients with somatostatin receptor—positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

The approval is based on the phase 3 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 percent reduction in the risk of progression or death with Lutathera compared with octreotide.

"This is an important day for the pancreatic neuroendocrine — and the entire pancreatic cancer – community," said Lynn Matrisian, Ph.D., MBA, chief science officer at PanCAN. "Adding a new, and better, drug to the arsenal for the treatment of PNET patients can push us closer to our goal to double pancreatic cancer survival by 2020."

In NETTER-1, 229 patients with midgut NETs who progressed on standard-dose octreotide (30 mg) were randomized to Lutathera (116 patients) or high-dose octreotide (113 patients). Four doses of Lutathera were administered at 7.4 GBq every eight weeks in combination with octreotide at 30 mg for symptom control. In the control arm, patients received octreotide LAR at 60 mg every four weeks.

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

The primary endpoint of the study was progression-free survival (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 8.5 months in the high-dose octreotide arm.

The ORR with Lutathera was 13 percent versus 4 percent with octreotide. At the interim analysis of OS there was a 48 percent reduction in the risk of death seen with Lutathera versus octreotide.

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

The rates of the most common grade 3/4 AEs occurring at a higher frequency in the Lutathera group versus the high-dose octreotide arm were lymphopenia (44 percent); increased gamma-glutamyl transferase (20 percent); vomiting (7 percent); nausea and elevated AST (5 percent each); and increased ALT, hyperglycemia, and hypokalemia (4 percent each).

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 PFS ranged from one to three years.

The FDA had granted a priority review designation to a new drug application (NDA) for Lutathera in June 2016, and had been scheduled to make its final decision by December 28, 2016. However, on December 21, 2016, Advanced Accelerator Applications, the manufacturer of Lutathera, reported that the FDA had issued a complete response letter (CRL) informing the company that the NDA for Lutathera would need to be resubmitted.

The CRL, which followed a discipline review letter issued in November 2016, requested new subgroup data, a safety update, and that revisions be made to the previously submitted data. The letter did not request the initiation of additional studies of Lutathera.

"Here at PanCAN, we strongly recommend clinical trials at diagnosis and during every treatment decision," said Victoria Manax Rutson, M.D., chief medical officer at PanCAN. "We are grateful to the patients who participated in this trial, allowing a new treatment to be approved to extend survival and improve lives of people with pancreatic neuroendocrine tumors."