Type of information: Granting of a Market Authorisation in the US
Product name: Lutathera®
Compound: Lutetium-DOTA-Tyr-Octreotate/lutetium (177Lu) oxodotreotide
Therapeutic area: Cancer - Oncology
- peptide/radiopharmaceutical product. Lutathera®, is a radiolabeled somatostatin analog that selectively targets somatostatin receptors which are over-expressed in some tumor types. It acts like a Trojan horse, delivering Lu directly into the tumour cell. Lu is an instable particle that releases an electron which, as in radiotherapy, is capable of killing the tumors. It also releases a gamma ray, which exits the body and enables physicians to image and evaluate the progress of the treatment via a SPECT (Single Photon Emission Computed Tomography) camera. Lutathera® is an example of a theragnostic drug, since its efficacy can be evaluated and monitored using imaging at every therapeutic injection, without additional costs.
- It targets malignant cells which overexpress sst2 receptors and has a limited effect on neighbouring noncancerous cells.
Company: Advanced Accelerator Applications (France) now Novartis (Switzerland)
Disease: gastro entero pancreatic neuroendocrine tumors (GEP-NETs)
- • On January 26, 2018, Novartis announced that Advanced Accelerator Applications, a subsidiary of Novartis Groupe S.A., has received US FDA approval of its new drug application (NDA) for Lutathera® (lutetium Lu 177 dotatate*) for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults. The approval was based on a Phase 3 study (NETTER-1) which demonstrated a 79% reduction in the risk of disease progression or death within the Lutathera plus best standard of care arm (octreotide LAR 30mg every four weeks) compared to 60 mg of octreotide LAR alone (hazard ratio 0.21, 95% CI; 0.13-0.32; p<00.001). The most common Grade 3-4 adverse reactions occurring with a greater frequency among patients in the NETTER-1 study receiving Lutathera with octreotide compared to patients receiving high-dose octreotide include: lymphopenia (44%), increased gamma-glutamyl transferase (20%), vomiting (7%), nausea and elevated aspartate aminotransferase (5% each), and increased alanine aminotransferase, hyperglycemia and hypokalemia (4% each).
- • On July 20, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Lutathera®, a radiopharmaceutical medicinal product indicated for the treatment of well differentiated gastroenteropancreatic neuroendocrine tumours . Lutathera® will be available as a 370 MBq/ml solution for infusion. The benefits with Lutathera are its ability to improve progression-free survival compared with octreotide LAR, a somatostatin receptor agonist, in patients with well differentiated GEP-NET tumours. The most common side effects are nausea, vomiting, haematological toxicity (thrombocytopenia, lymphopenia, anaemia, pancytopenia), fatigue and decreased appetite. The full indication is: "Lutathera® is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours in adults." Lutathera® should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings and after evaluation of the patient by a qualified physician.
- The CHMP adopted its opinion based on results of a randomized pivotal Phase 3 study, NETTER-1 that
compared treatment using lutetium (177Lu) oxodotreotide with a double dose of Octreotide LAR in 229 patients with inoperable midgut NETs progressive under standard Octreotide LAR treatment and overexpressing somatostatin receptors, as well as efficacy and safety data from the Erasmus Phase 1/2 trial conducted in more than 1,200 patients with a wide range of NET indications including bronchial, pancreatic, foregut (excluding bronchial and pancreatic), midgut and hindgut.
- The NETTER-1 study met its primary endpoint by demonstrating that treatment with lutetium (177Lu)
oxodotreotide was associated with a statistically significant and clinically meaningful risk reduction of 79% in disease progression or death versus a treatment with a double dose of Octreotide LAR (hazard ratio 0.21, 95% CI: 0.13-0.33; p<0.001). The New Drug Application submission to the FDA is currently under review.
- • On December 21, 2016, Advanced Accelerator Applications announced that following the issuance of a previously disclosed Discipline Review Letter (DRL) in November, the FDA has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for Lutathera® for the treatment of gastroenteropancreatic neuroendocrine tumors in adults. Similar to the DRL, the CRL refers to issues with the format, traceability, uniformity, and completeness relating to the NETTER-1 and Erasmus clinical datasets, which are precluding FDA reviewers from performing the required independent analysis of these clinical studies. In addition, the CRL requests subgroup analyses for gender, age and racial subgroups, as well as other stratification factors and important disease characteristics. A safety update on clinical and non-clinical studies, which is already in process, was also requested in the CRL. Finally, the CRL noted that any observations made during inspections of manufacturing facilities supporting the NDA need to be resolved prior to approval of the NDA. No additional clinical studies were requested in the CRL and there were no comments at this time on other sections of the NDA submission.
- • On September 20, 2016, Advanced Accelerator Applications announced that the Accelerated Assessment timeline for the European Medicines Agency (EMA) review of the Marketing Authorization Application (MAA) for Lutathera® for the treatment of neuroendocrine tumors, has been modified to a standard review period due to additional clarifications requested by the EMA, as well as their request to inspect one of AAA’s contract research organizations (CRO).
• On June 27, 2016, Advanced Accelerator Applications announced that the FDA has accepted the company’s
New Drug Application (NDA) and granted Priority Review for Lutathera® currently under development for the treatment of gastro entero pancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults. The Prescription Drug User Fee Act (PDUFA) target action date is December 28, 2016.
The Lutathera NDA is based on the results of a randomized pivotal Phase 3 study, NETTER-1 that compared treatment using Lutathera with a double dose of Octreotide LAR in patients with inoperable midgut NETs progressive under Octreotide LAR treatment and overexpressing somatostatin receptors. The NETTER-1 study met its primary endpoint by demonstrating that treatment with Lutathera was associated with a statistically significant and clinically meaningful risk reduction of 79% in disease progression or death versus a treatment with a double dose of Octreotide LAR. Efficacy and safety data from a large Phase I-II trial conducted in more than 1,200 patients in NET indications is also part of the NDA.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2018-01-26
UE authorization: 2017-09-26
Favourable opinion UE: 2017-07-20
Favourable opinion USA:
Orphan status USA:
Orphan status UE: 2008-01-31
Pediatric exclusivit _USA:
Pediatric exclusivity UE: