Regulatory Decision Summary for Lutathera

The authorization of Lutathera in the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults with progressive disease, was based on the results of NETTER-1, a Phase III multi-centre, randomized controlled pivotal study, and on the supporting data from ERASMUS, an investigator sponsored Phase I/II, open label, single-arm clinical study. GEP-NETs are rare and most patients with have persistent progressive disease despite being on octreotide or other therapies; therefore this is a patient population with an unmet medical need.

The evidence of efficacy for Lutathera in the treatment of mid-gut NETs was demonstrated in the NETTER-1 study. The primary efficacy endpoint was progression free survival (PFS). With a median follow-up of 10.5 months, the results of the PFS analysis indicates a 79% reduction in the risk for a patient to progress or die under Lutathera compared to treatment with Octreotide LAR. The key secondary endpoints were overall response rate (ORR) as assessed by an independent review committee, duration of response (DOR), and overall survival (OS). Among the patients with an independent response assessment the ORR and DOR were substantially improved with Lutathera treatment. At a pre-specified interim analysis of overall survival (OS), there were 17 (14.7%) deaths in the Lutathera arm and 31 (27.4%) in the octreotide LAR arm. The ERASMUS study provided limited evidence; however, based on the mechanism of action, the data is supportive of the efficacy of Lutathera in patients with foregut, midgut, and hindgut GEP-NETs, including bronchial and pancreatic tumours.

The safety profile of Lutathera in this population is considered acceptable in the context of the treatment of unresectable or metastatic, progressive gastroenteropancreatic neuroendocrine tumors. The most serious adverse drug reactions reported with Lutathera use were myelosuppression, secondary myelodysplastic syndrome, acute leukemia, and acute and chronic renal toxicity, which are related to radiotoxicity. The toxicities are manageable through close monitoring of hematologic, renal and hepatic function, and dose modification when appropriate. All safety risks are adequately described in the Lutathera Product Monograph (PM) with appropriate instructions for dose reduction, discontinuation and dose holding. The adverse reactions related to the co-infusion of amino acids (to reduce renal toxicity of Lutathera) including nausea and vomiting are described in the PM with instructions on prophylactic antiemetic administration.

Given the substantial evidence of efficacy observed in a population of patients with a high unmet medical need, the risks are considered acceptable when Lutathera is administered under the conditions described in the product monograph (PM). Therefore, the overall benefit-risk assessment is favourable.

Overall the benefit/risk balance is considered favorable for the use of Lutathera in patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumor who have disease progression following octreotide therapy or chemotherapy.

The recommended Lutathera dose in adults is 7.4 GBq (200 mCi) as an intravenous infusion over 30 minutes every 8 weeks for a total of 4 doses.

Health Canada granted this application priority review in accordance with the priority review policy.