The FDA has issued a complete response letter (CRL) to Advanced Accelerator Applications informing the company that its new drug application for Lutathera (177Lutetium DOTA-octreotate) as a treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) would need to be resubmitted.
The CRL, which follows a discipline review letter (DRL) issued in November, requests 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.
“We are pleased that the CRL reiterates the issues previously raised by the DRL, and does not contain any other significant requirements,” Stefano Buono, CEO of Advanced Accelerator Applications, said in a statement. “Receiving the DRL in advance of the CRL was helpful, as we are already working on revising the datasets, and will incorporate the requested supplemental information into our resubmission.”
In June 2016, the FDA had granted a priority review designation to the peptide receptor radionuclide therapy Lutathera based on 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 had been scheduled to make its final decision by December 28, 2016.
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.
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 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 8.4 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.
The ORR with Lutathera was 18% versus 3% with octreotide (P
= .0008). There was 1 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.
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%).
Lutathera consists of the somatostatin analog octreotide connected with the beta and gamma emitting radiopharmaceutical 177Lutetium (177Lu). The 2 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 1 to 3 years.
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).