Summary Basis of Decision for Lutathera
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Lutathera is located below.
Recent Activity for Lutathera
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
The following table describes post-authorization activity for Lutathera, a product which contains the medicinal ingredient lutetium (177Lu) oxodotreotide. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Updated: 2024-03-11
Drug Identification Number (DIN):
DIN 02484552 - 370 MBq/mL at calibration, lutetium (177Lu) oxodotreotide, solution, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
NDS # 282564 |
2024-01-05 |
Issued NOC 2024-02-28 |
Submission filed to transfer ownership of the drug product from Advanced Accelerator Applications USA, Inc. to Novartis Pharmaceuticals Canada Inc. An NOC was issued. |
|
SNDS # 276004 |
2023-06-06 |
Issued NOC 2023-11-17 |
Submission filed as a Level I – Supplement for labelling updates. As a result of the SNDS, modifications were made to the vial label, outer label, and package insert. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 267761 |
2022-09-09 |
Cancellation Letter Received 2022-12-14 |
Level II – Supplement (Safety) to update the PM with new safety information. A number of issues were identified with the submission during review. The submission was cancelled by the sponsor. |
|
SNDS # 257232 |
2021-10-04 |
Issued NOC 2022-09-09 |
Submission filed as a Level I – Supplement to update the PM with data from the final analysis of the NETTER-1 study. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued. |
|
SNDS # 263225 |
2022-04-08 |
Issued NOC 2022-07-18 |
Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
SNDS # 254350 |
2021-06-30 |
Issued NOC 2021-12-13 |
Submission filed as a Level I – Supplement to update the inner and outer labels. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 248433 |
2021-01-15 |
Issued NOC 2021-05-13 |
Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Dosage and Administration; Overdosage; Clinical Pharmacology; and Clinical Trials sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
NC # 249512 |
2021-02-18 |
Issued NOL 2021-04-22 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process and changes in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 240650 |
2020-06-12 |
Issued NOL 2020-09-21 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the batch size for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 233542 |
2019-11-15 |
Issued NOL 2020-02-24 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls for the materials used in the manufacture of the drug substance or the controls performed at critical steps in the process, and a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 233539 |
2019-11-19 |
Issued NOL 2020-02-24 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the batch size for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 228669 |
2019-06-14 |
Issued NOC 2020-01-28 |
Submission filed as a Level I – Supplement for the addition of a new drug substance and drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
Drug product (DIN 02484552) market notification |
Not applicable |
Date of first sale: 2019-12-10 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NC # 229865 |
2019-07-19 |
Issued NOL 2019-11-06 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the batch size for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NDS # 217184 |
2018-06-18 |
Issued NOC 2019-01-09 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Lutathera
Date SBD issued: 2019-05-29
The following information relates to the New Drug Submission for Lutathera.
Lutetium (177Lu) oxodotreotide
Drug Identification Number (DIN):
- DIN 02484552 - 370 MBq/mL at calibration, solution, intravenous administration
Advanced Accelerator Applications USA, Inc.
New Drug Submission Control Number: 217184
On January 9, 2019, Health Canada issued a Notice of Compliance to Advanced Accelerator Applications USA, Inc. for the therapeutic radiopharmaceutical Lutathera.
The market authorization was based on quality (chemistry and manufacturing), non clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Lutathera is favourable for the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults with progressive disease.
1 What was approved?
Lutathera, a therapeutic radiopharmaceutical, was authorized for the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults with progressive disease.
Dosing instructions for Lutathera include use of concomitant medications for renal protection and mitigation of nausea and vomiting. Provisions for patient monitoring and dose modifications are also provided in the Lutathera Product Monograph. This product should be administered under the supervision of a qualified health professional who is experienced in the use of therapeutic radiopharmaceuticals.
Data regarding the use of Lutathera in patients younger than 18 years of age have not been submitted to Health Canada. Consequently, Health Canada has not authorized an indication for pediatric use.
Of the 1,325 patients treated with Lutathera in clinical trials, 438 patients were 65 years of age and older. The proportion of patients with serious adverse events was similar to that of younger patients. However, since increased risk of toxicity has been described in elderly patients (aged 70 years and over), close monitoring is advisable in this population to allow for prompt dose modification.
Lutathera is contraindicated in patients with:
- severe renal impairment (creatinine clearance <30 mL/min)
- established or suspected pregnancy (when pregnancy has not been excluded)
- hypersensitivity to the active substance or to any of the excipients
Lutathera was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Lutathera (lutetium [177Lu] oxodotreotide, 370 MBq/mL at calibration) is presented as a solution. In addition to the medicinal ingredient, the solution contains sodium chloride 6.85 mg/mL, ascorbic acid 2.8 mg/mL, sodium acetate 0.66 mg/mL, sodium hydroxide 0.65 mg/mL, gentisic acid 0.63 mg/mL, acetic acid 0.48 mg/mL, and diethylene triamine pentaacetic acid 0.05 mg/mL.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Lutathera Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Lutathera approved?
Health Canada considers that the benefit-risk profile of Lutathera is favourable for the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults with progressive disease.
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) constitute a rare, heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. Well-differentiated carcinoid tumours overexpress somatostatin subtype 2 receptors, a common feature of all GEP-NETs.
Patients with early stage GEP-NETs are often asymptomatic or present with poorly defined symptoms. Consequently, at the time of confirmed diagnosis, a significant percentage of patients with GEP-NETs have hepatic metastases. Typically, the clinical management involves a multimodal approach including surgery and other means of cytoreductive treatment, embolization, chemoembolization, radiotherapy, and treatment with chemotherapy, interferons and somatostatin analogues. In the case of inoperable disease, neither chemotherapy nor external beam radiation therapy are considered effective. Accordingly, there are few treatment options, if any, with significant efficacy for patients with advanced disease, a population with an unmet medical need. Most products approved for the treatment of GEP-NETs have limited application because they are indicated for use in subpopulations of GEP-NET patients. The current standard-of-care options in Canada for systemic therapy of GEP-NETs are somatostatin analogues. Octreotide (long-acting release formulation) is authorized for symptomatic treatment and lanreotide is authorized for the treatment of unresectable, locally advanced or metastatic disease.
Lutathera (lutetium [177Lu] oxodotreotide) is a radiopharmaceutical agent developed for use in peptide receptor radionuclide therapy (PRRT). This therapy uses radiolabelled peptides as biological targeting vectors designed to deliver cytotoxic levels of radiation to cancer cells that overexpress specific receptors. The radiolabelled somatostatin analog (octreotate) preferentially binds to somatostatin receptors, thereby targeting GEP-NETs while limiting radiation exposure to non-tumour tissues. After binding to somatostatin subtype 2 receptors, Lutathera undergoes receptor-mediated internalization and intracellular retention, resulting in localized delivery of a cytotoxic radiation dose. Lutathera is the first PRRT agent authorized in Canada and provides a new treatment option to patients who have advanced progressive disease.
The market authorization of Lutathera for the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor-positive GEP-NETs in adults with progressive disease, was based on the results of NETTER-1, a pivotal, multicentre, randomized, controlled, Phase III clinical study, and the supportive data derived from ERASMUS, an investigator-sponsored, open-label, single-arm, Phase I/II clinical study.
In the pivotal NETTER-1 study, the primary efficacy endpoint was progression-free survival as determined by a blinded independent radiology committee according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. With a median follow-up of 10.5 months, the results of the progression-free survival analysis indicate a 79% reduction in the risk of disease progression or death in patients treated with Lutathera compared to patients treated with long-acting octreotide. The key secondary endpoints were overall response rate as assessed by an independent review committee, duration of response, and overall survival. Among the patients with an independent response assessment, the overall response rate and duration of response were substantially improved with Lutathera treatment. At a prespecified interim analysis of overall survival, there were 17 (14.7%) deaths in the Lutathera arm and 31 (27.4%) in the long-acting octreotide arm. The final analysis of overall survival will be conducted after 158 deaths have occurred or five years after the date of randomization of the last randomized patient, whichever occurs first.
The ERASMUS study provided limited evidence. However, based on the mechanism of action, the data are considered supportive of the efficacy of Lutathera in patients with foregut, midgut, and hindgut GEP-NETs, including bronchial and pancreatic NETs.
The safety profile of Lutathera is considered acceptable in the context of the treatment of unresectable or metastatic, progressive GEP-NETs. The most serious adverse drug reactions reported with the use of Lutathera were myelosuppression, secondary myelodysplastic syndrome, acute leukemia, and acute and chronic renal toxicity, all of which are related to radiotoxicity. The toxicities are manageable through close monitoring of hematologic, renal and hepatic functions, and dose modifications when appropriate. All safety risks are adequately described in the Lutathera Product Monograph with appropriate instructions for dose reduction, dose withholding, and treatment discontinuation. A Serious Warnings and Precautions Box in the Lutathera Product Monograph highlights the risks of acute and chronic renal toxicity, myelodysplastic syndrome, and acute leukemia. Furthermore, the use of Lutathera is contraindicated in patients with severe renal impairment. The adverse reactions related to the concomitant infusion of amino acids (intended to reduce the renal toxicity of Lutathera) including nausea and vomiting are described in the Lutathera Product Monograph with instructions on prophylactic administration of antiemetics.
Lutathera may be associated with an increased risk of developing secondary neoplasms. The risk of radiation exposure to medical personnel, family members and members of the public is considered to be low due to the limited tissue penetration of the beta emissions from lutetium (177Lu). Nevertheless, detailed instructions on Lutathera infusion and radiation safety precautions are included in the Lutathera Product Monograph.
A Risk Management Plan (RMP) for Lutathera was submitted by Advanced Accelerator Applications USA, Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
In addition, the sponsor has initiated an international post-authorization safety registry to assess the long-term safety of Lutathera for unresectable or metastatic, somatostatin receptor-positive GEP-NETs (with a follow-up period of up to 7 years).
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Lutathera Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
A Look alike Sound alike brand name assessment was performed and the proposed name Lutathera was accepted.
Overall, the therapeutic benefits of Lutathera are considered to outweigh the potential risks for the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Lutathera Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Lutathera?
The drug submission for Lutathera was reviewed under the Priority Review Policy. Lutathera demonstrated a significant increase in efficacy with an improved benefit-risk profile compared to existing therapies for unresectable or metastatic well-differentiated, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, a serious life-threatening condition that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Lutathera
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-11-29 |
| Request for priority status | |
| Filed: | 2018-01-24 |
| Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: | 2018-02-19 |
| Submission filed: | 2018-06-18 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-07-13 |
| Review | |
| Review of Risk Management Plan complete: | 2018-11-06 |
| Quality Evaluation complete: | 2019-01-04 |
| Clinical/Medical Evaluation complete: | 2019-01-08 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2019-01-08 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2019-01-09 |
The Canadian regulatory decision on the non-clinical and clinical review of Lutathera was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
The clinical pharmacology data support the use of Lutathera for the recommended indication.
Lutetium (177Lu) oxodotreotide, the medicinal ingredient in Lutathera, binds to somatostatin receptors with the highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor-expressing cells, including somatostatin receptor-positive malignant tumour cells, the compound is internalized. The beta emission from 177Lu induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighbouring cells.
A centrally assessed dosimetry, pharmacokinetics and electrocardiogram substudy was conducted in a subset of 20 patients enrolled in the Phase III NETTER-1 study, to define the pharmacokinetic profile of 177Lu oxodotreotide and to calculate whole body and organ radiation dosimetry, with particular focus on the absorbed radioactive dose to critical organs (kidneys and bone marrow). The majority of patients (15 out of 20) received four administrations of 177Lu oxodotreotide.
Time-activity curves for the whole body, source organs (the liver, spleen, kidneys and urinary bladder) and tumours were determined from whole-body planar scintigraphic images that were acquired for at least five time points in most patients. The time-activity curves and "residence times" (i.e., the time-integrated activity coefficients) were obtained in nine patients following the first administration and 11 patients following the second or third administration of 177Lu oxodotreotide.
The absorbed doses, with corrections applied for the individual masses of the source organs in each patient, were calculated with the Organ Level Internal Dose Assessment/Exponential Modeling (OLINDA/EXM, a personal computer software for internal dose assessment in nuclear medicine).
For determination of the absorbed doses to other, non-source organs of interest (such as the testes and ovaries), the output value calculated by OLINDA/EXM was based on the contribution of the surrounding uptaking tissues and the remainder of the body.
The mean absorbed doses calculated for four administrations of 7.4 GBq (maximum cumulative dose of 29.6 GBq) 177Lu oxodotreotide were 19.4 ± 8.9 Gy for the kidneys and 1.0 ± 0.8 Gy for the red marrow. The data appear to be comparable to those published in the literature. The absorbed dose to tumours was highly variable, with a mean value estimated at 240 ± 321 Gy for four administrations of 177Lu oxodotreotide.
Within four hours after administration, lutetium (177Lu) oxodotreotide is distributed to the kidneys, tumour lesions, liver and spleen, and in some patients, to the pituitary gland and thyroid. The co-administration of amino acids reduced the median radiation dose to the kidneys by 47% (34% to 59%) and increased the mean beta-phase blood clearance of lutetium (177Lu) oxodotreotide by 36%. The non-radioactive form of lutetium (177Lu) oxodotreotide, lutetium (175Lu) oxodotreotide, is 43% bound to human plasma proteins. Lutetium (177Lu) oxodotreotide is primarily eliminated through the kidneys with cumulative excretion of 58% within 24 hours and 65% within 48 hours after administration of Lutathera. Based on the half-life of lutetium (177Lu) and terminal half-life of lutetium (177Lu) oxodotreotide, more than 99% of the compound will be eliminated within 14 days after administration.
An intravenous amino acid solution containing L-lysine and L-arginine is administered before, during and after administration of Lutathera to decrease reabsorption of lutetium (177Lu) oxodotreotide through the proximal tubules and decrease the radiation dose to the kidneys.
For further details, please refer to the Lutathera Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Lutathera in the treatment of adult patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumours was evaluated in NETTER-1, a pivotal, randomized, multicentre, open-label, active-controlled, Phase III clinical study. Supportive efficacy data were derived from an investigator-sponsored Phase I/II clinical study, ERASMUS.
Key eligibility criteria for enrolment in the pivotal study included Ki67 index of ≤20%, Karnofsky performance status score of ≥60, confirmed presence of somatostatin receptors on all lesions, creatinine clearance of ≥50 mL/min, no prior treatment with peptide receptor radionuclide therapy, and no prior external radiation therapy to more than 25% of the bone marrow.
Two hundred and twenty-nine patients were randomized (1:1) to receive either Lutathera 7.4 GBq (200 mCi) every eight weeks for up to four administrations (with a maximum cumulative dose of 29.6 GBq) or high-dose long-acting octreotide (60 mg administered intramuscularly every four weeks). Patients in the Lutathera treatment arm also received long-acting octreotide 30 mg intramuscularly four to 24 hours after each dose of Lutathera and every four weeks after completion of Lutathera treatment until disease progression or until week 76 of the study.
The randomization of patients was stratified by tumour uptake score (Grade 2, 3 or 4) obtained on somatostatin receptor imaging with 111In‑DTPA0‑octreotide (OctreoScan) and by the length of time that patients had been on the most recent constant dose of octreotide prior to randomization (≤6 or >6 months).
Demographic and baseline disease characteristics of patients were balanced between the treatment arms. The median age was 64 years (28 to 87 years) and 51% were male patients. In 74% of patients the primary tumour site was the ileum, and 96% of patients had metastatic disease in the liver. The median Karnofsky performance score was 90 (60 to 100). Seventy-four percent of patients received a constant dose of octreotide for more than six months and 12% received prior treatment with everolimus. Sixty-nine percent of patients had Ki67 expression in ≤2% of tumour cells, 77% had chromogranin A >2 times the upper limit of normal, 65% had 5-hydroxyindoleacetic acid >2 times the upper limit of normal, and 65% had alkaline phosphatase ≤ the upper limit of normal.
The major efficacy outcome measure was progression-free survival as determined by a blinded independent radiology committee according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and with predefined endpoint. Additional efficacy outcome measures were overall survival, objective response rate, and duration of response.
At the time of the primary endpoint analysis, there were 27 events of centrally confirmed disease progressions or deaths in the Lutathera arm and 78 in the long-acting octreotide arm. The median follow-up was 10.5 months. The median progression-free survival was not reached in the Lutathera arm, whereas it was 8.5 months (95% confidence interval [CI]: 6.0, 9.1) in the long-acting octreotide arm. The corresponding hazard ratio was 0.21 (95% CI: 0.13, 0.32, p<0.0001), indicating a 79% reduction in the risk of disease progression or death in patients treated with Lutathera compared to patients treated with long-acting octreotide.
At a prespecified interim analysis of overall survival, 17 deaths had occurred among the patients treated with Lutathera arm and 31 among the patients treated with long-acting octreotide. Statistical significance was not demonstrated at this time. At the time of the updated analysis, there were 27 deaths in the Lutathera arm and 43 in the long-acting octreotide arm. The median overall survival was not reached in the Lutathera arm, whereas it was 27.4 months in the long-acting octreotide arm (hazard ratio of 0.52 [95% CI: 0.32, 0.84]). The final analysis of overall survival will be conducted after 158 deaths have occurred or five years after the last patient underwent randomization, whichever occurs first.
The objective response rate was 13% (7%, 19%) for the Lutathera arm and only 4% (0.1%, 7%) for the long-acting octreotide arm (p<0.0148).
Patients in the Lutathera arm had a higher median duration of response than patients in the long-acting octreotide arm: 5.8 months (0.03, 16.79) versus 1.9 months (0.03, 2.79).
The supportive study, ERASMUS, was an investigator-sponsored Phase I/II clinical study conducted at the Erasmus Medical Center in Rotterdam, the Netherlands. It evaluated the efficacy of Lutathera in 1,214 patients with somatostatin receptor-positive tumours, the majority of which were GEP-NETs. The study was a compassionate-use programme. Therefore, it had no prespecified protocol or statistical analysis plan and used different criteria for tumour assessment. A retrospective verification of the source data and statistical analyses were conducted by an independent clinical research organization. Given that a large number of patients (mostly non-residents of the Netherlands) were lost to follow-up, a subgroup of Dutch patients (number of patients [n] = 811) considered to have the most complete and accurate data was used for the efficacy analyses.
Among the 559 patients with GEP-NETs in the Dutch population, a subset of 360 patients had a baseline tumour assessment and long-term follow-up data. Therefore, these 360 patients constituted the Dutch GEP-NET population full analysis set. The 199 patients without a baseline tumour assessment were included in a sensitivity analysis as non-responders. In the Dutch GEP-NET population full analysis set, the median age was 60 years (30 to 85 years), 51% were male patients, 71% of patients had a baseline Karnofsky performance status score of ≥90, and 51% had tumour progression at baseline (the tumour status was unknown in 31% of patients). The tumour burden was moderate or extensive in 80% of the overall Dutch population.
The treatment regimen consisted of four intravenous administrations of Lutathera 200 mCi (7.4 GBq) at six- to 13-week intervals. Concomitant amino acids were given with each administration for renal protection.
The major efficacy outcome was the investigator-assessed objective response rate. The rate represents an aggregate of the best overall response in five subtypes of GEP-NETs; hence, it should be interpreted with caution. Out of the 360 patients, 183 had midgut NETs, 133 had pancreatic NETs, 19 had bronchial NETs, 13 had hindgut NETs, and 12 had foregut NETs.
One of the many limitations of the ERASMUS study was the use of different criteria for tumour response assessment. One hundred and forty-five patients (40%) were assessed as per the RECIST 1.1 criteria and 215 patients (60%) had tumour response assessments according to the modified Southwest Oncology Group (SWOG) criteria, which were retrospectively algorithmically converted to the RECIST 1.1 criteria (hereafter referred to as converted SWOG criteria).
In the Dutch GEP-NET population full analysis set, the objective response rate according to the RECIST 1.1. was 45.0% for all GEP-NETs, 33.3% for midgut NETs, 36.8% for bronchial NETs, 46.2% for hindgut NETs, 58.3% for foregut NETs, and 60.9% for pancreatic NETs.
The objective response rates computed for the subsets of patients assessed using the RECIST 1.1 criteria or converted SWOG criteria were similar (41% versus 47%, respectively). The median duration of response in 162 responders was 22.9 months. However, when computed based on the assessment criteria used, the duration of response is much longer in the subset of patients who were evaluated using RECIST 1.1 criteria compared to the subset of patients who were evaluated using the converted SWOG criteria (35 months versus 18.5 months, respectively).
In the sensitivity analyses performed on the Dutch GEP-NET population safety analysis set (n = 559), which considered patients without baseline tumour assessment as non-responders, the objective response rate was considerably lower at 29% (range: 21.9% to 40.9%) for GEP-NETs. However, the objective response rates observed in the sensitivity analyses are highly clinically relevant compared to the benefit described for other drugs currently available for the treatment of GEP-NETs. In addition, although the number of patients with foregut and hindgut GEP-NETs were small, the efficacy results were within the range of those in the more common midgut and pancreatic NETs.
The evidence of efficacy of Lutathera in the treatment of midgut NETs was primarily derived from the pivotal Phase III NETTER-1 study. The ERASMUS study provided limited additional evidence. However, based on the mechanism of action of Lutathera, this limited evidence is considered supportive of the efficacy of Lutathera in patients with well-differentiated somatostatin receptor-positive GEP-NETs, including the less common subtypes of NETs.
Indication
The New Drug Submission for Lutathera was filed by the sponsor with the following indication:
- Lutathera (lutetium [177Lu] oxodotreotide) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumours in adults.
To ensure safe and effective use of the product, Health Canada revised the proposed indication to reflect the patient population studied. Accordingly, Health Canada approved the following indication:
- Lutathera (lutetium [177Lu] oxodotreotide) is indicated for the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults with progressive disease.
For more information, refer to the Lutathera Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Lutathera was evaluated in the clinical studies NETTER-1 and ERASMUS (described in the Clinical Efficacy section). Safety analyses were performed both on individual study data and pooled data. However, the pooled analyses were limited, as the ERASMUS study recorded only serious adverse events and had a complete and long-term follow-up data collection only for the Dutch patient population. In addition, the differences in the follow-up time (median of 24 months in the NETTER-1 study and up to 12 years in the ERASMUS study) are to be considered in the assessment of delayed and long-term toxicities, such as nephrotoxicity and secondary malignancies.
Of the 111 patients in the NETTER-1 study who had received Lutathera, 79% received a cumulative dose of >600 mCi and 76% of patients received all four planned doses. In the ERASMUS study, 65.1% of the overall 811 Dutch patients included in the safety analysis set received a total cumulative dose of Lutathera of ≥800 mCi and 81.4% received >600 mCi.
In the NETTER-1 study, the most frequently observed (≥20%) adverse drug reactions in patients receiving Lutathera compared to controls were nausea (65% versus 12%), vomiting (53% versus 9%), fatigue (38% versus 26%), and decreased appetite (21% versus 11%). The most common Grade 3-4 adverse reactions occurring with a greater frequency in the Lutathera-treated patients included lymphopenia (44%), increased gamma-glutamyltransferase (20%), vomiting (7%), nausea and elevated aspartate transaminase (5% each), and increased alanine transaminase, hyperglycemia and hypokalemia (4% each). The most serious adverse events reported in patients treated with Lutathera were myelosuppression, secondary myelodysplastic syndrome and leukemia, renal toxicity, hepatotoxicity, and neuroendocrine hormonal crisis.
In the ERASMUS study, serious adverse events were identified through a post hoc review of the patients' medical charts. Except for laboratory toxicities, serious adverse events were not graded for their severity. Among the 811 Dutch patients included in the safety analysis set, 508 (62.6%) experienced a serious adverse event. Serious adverse events with the highest frequencies were pancytopenia (10.5%), abdominal pain (5.8%), diarrhea (6.4%), anemia (5.3%), death (5.1%), pyrexia (4.3%), vomiting (4.1%), nausea (3.6%), and thrombocytopenia (3.3%).
Adverse events of special interest, based on the mechanism of action of Lutathera, were those related to radiotoxicity. The most frequent adverse events of special interest in the NETTER-1 study were anemia (81%), thrombocytopenia (53%), and neutropenia (26%). Myelodysplastic syndrome was observed in 2.7% of patients who received Lutathera. Similarly, acute kidney injury was reported in 2.7% of Lutathera-treated patients. In the ERASMUS study, half of the patients in the safety analysis set had at least one serious adverse event of special interest. Serious adverse events of special interest that were experienced by ≥1.0% of patients in the Dutch population included: thrombocytopenia (15.9%), myelodysplastic syndrome (2.0%), leukopenia (4.9%), anemia (4.1%), hypotension (1.2%), cardiac failure (1.5%), myocardial infarction (1.1%), renal failure (1.0%), and renal impairment (1.2%). Other blood neoplasms reported (at incidence rates of 0.1-0.2%) were acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, and chronic myelomonocytic leukemia.
No treatment-related death was observed in the NETTER-1 study. In the dosimetry NETTER-1 substudy (described in the Clinical Pharmacology section), acute renal failure leading to death was reported in a 64-year-old female; however, the death was assessed as unrelated to treatment. The four cases of renal failure reported in the ERASMUS study are consistent with radiation nephropathy induced by peptide receptor radionuclide therapy. Radiation nephropathy develops gradually over months and years after treatment, leading to progressive loss of nephron function. Patients with baseline renal impairment, urinary tract obstruction, or predisposing risk factors such as diabetes or hypertension may be at greater risk of renal toxicity.
Radiotoxicity was also assessed in patients enrolled in the dosimetry NETTER-1 substudy, who were followed for a median of 12.5 months (range 0-33 months). Hematological toxicity was mild in the majority of patients. Two patients experienced a transient Grade 3 hematological toxicity affecting white blood cells during treatments, with partial recovery of the white blood cell counts in the follow-up period. Four patients experienced Grade 4 lymphopenia, confounded by Grade 2-3 lymphotoxicity observed at baseline and bone metastases. Mild (Grade 1) renal toxicity was observed in five patients during the treatment and four patients during the follow-up period. Although limited by the number of the patients and the duration of follow-up, there was statistically significant correlation between the red marrow dose and acute platelet toxicity, late hemoglobin toxicity, and late lymphocyte toxicity. The mean absorbed doses to red marrow in patients without platelet, hemoglobin, and lymphocyte toxicities were lower than in patients with Grade >1 platelet, hemoglobin, and lymphocyte toxicities (0.6 Gy, 0.7 Gy, 0.8 Gy versus 1.2 Gy, 1.1 Gy, 1.3 Gy, respectively).
Overall, Lutathera was well tolerated in the clinical studies. The safety profile of Lutathera is considered acceptable in the context of the treatment of unresectable or metastatic, progressive GEP-NETs. The toxicities related to Lutathera are manageable through careful monitoring of hematologic, renal, and hepatic functions, and dose modifications when appropriate. The identified safety risks are adequately described in the Lutathera Product Monograph with appropriate instructions for dose reduction, dose withholding, and treatment discontinuation. A Serious Warnings and Precautions Box in the Lutathera Product Monograph highlights the risks of acute and chronic renal toxicity, myelodysplastic syndrome, and acute leukemia.
For more information, refer to the Lutathera Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Lutetium (177Lu) oxodotreotide, the medicinal ingredient in Lutathera, is a 177Lu-labelled somatostatin analogue peptide conjugated with the metal chelating moiety 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).
Extensive in vitro and in vivo non-clinical pharmacology studies demonstrated that lutetium (177Lu) oxodotreotide binds with a very high affinity to the somatostatin subtype 2 receptors, which are commonly over-expressed in the majority of neuroendocrine tumours.
Safety pharmacology data and the results of the toxicology studies show that the compound has a favourable safety profile. The safety margin (calculated from no-observed-effect level [NOEL] or no-observed-adverse-effect level [NOAEL] versus the intended human dose) was 40 based on rat NOEL data and 400 based on dog NOAEL data from repeated toxicology studies. Evidence of minimal/moderate pancreatic acinar cell apoptosis detected in male and female rats was noted at about 170- and 700-fold the intended human dose.
No neurobehavioural effects, effects on the cardiac conduction times, central nervous system and respiratory function were observed in specific safety pharmacology studies, apart from a stimulatory effect on respiratory parameters only at higher doses. Genotoxicity studies showed that the compound does not induce mutation in a mouse lymphoma cell test and bacterial mutation assay. According to applicable guidelines, carcinogenicity and reproductive toxicology studies have not been conducted for 177Lu oxodotreotide, considering its short-term use and its indication for a life-threatening disease.
In vitro metabolism studies and plasma protein binding studies performed on non radioactive lutetium (175Lu) oxodotreotide showed an absence of significant inhibitory or induction effects on human cytochrome P450 (CYP450) enzymes, no potential P-glycoprotein (P-gp) specific interactions, absence of significant inhibitory effects on human transporters, and that lutetium (175Lu) oxodotreotide is not highly protein bound. These results indicate that the compound has a low risk for clinically relevant drug-drug interactions.
The peptide was demonstrated to be stable when tested in vitro (in either human serum or rat plasma) as well as when injected intravenously in healthy rats. No release of 177Lu from the DOTA moiety was observed.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Lutathera Product Monograph. In view of the intended use of Lutathera, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
Appropriate warnings and precautionary measures are in place in the Lutathera Product Monograph to address the identified safety concerns.
For more information, refer to the Lutathera Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Product
Lutathera is a ready-to-use radiopharmaceutical agent. The drug product is a sterile, preservative-free and clear, colourless to slightly yellow solution for intravenous use. It is supplied in a colourless Type I glass 30 mL single-dose vial containing 7.4 GBq (200 mCi) ± 10% of lutetium (177Lu) oxodotreotide at the time of injection. The solution volume in the vial is adjusted from 20.5 mL to 25 mL to provide a total of 7.4 GBq (200 mCi) of radioactivity.
The medicinal ingredient in Lutathera is lutetium (177Lu) oxodotreotide, a 177Lu-labelled somatostatin analogue peptide octreotate conjugated with the metal chelating moiety 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Lutetium (177Lu) oxodotreotide is also referred to as 177Lu DOTA0 Tyr3-Octreotate and 177Lu DOTATATE.
Lutetium (177Lu) is a radionuclide that decays to stable hafnium (177Hf) with a half-life of 6.647 days, by emitting beta radiation with a maximum energy of 0.498 MeV and gamma radiation of 0.208 MeV (11%) and 0.113 MeV (6.4%).
Extensive characterization studies of the drug substance have been performed by the sponsor. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The manufacturing process of the drug substance, lutetium (177Lu) oxodotreotide, incorporates two different batch sizes, 74 GBq ± 20% (2 Ci ± 20%) or 148 GBq ± 20% (4 Ci ± 20%), two suppliers of lutetium chloride (177LuCl3), two synthesis modules, and two manufacturing sites. The drug substance is manufactured using a chemical precursor oxodotreotide (DOTA0 Tyr3-Octreotate), a radioactive precursor 177LuCl3, and reaction buffer lyophilisate.
The synthesis of the drug substance is performed in a self-contained closed-system synthesis module, which is automated and remotely controlled by good manufacturing practices (GMP)-compliant software and automated monitoring and recording of the process parameters. Each production run of the synthesis module uses a single-use disposable kit cassette containing a fluid pathway (tubing), reactor vial, and sealed reagent vials. The synthesis module is protected from manual interventions during the production run. Once the synthesis is finished, the 177Lu oxodotreotide solution is pre-filtered into a 30 mL sterile vial (bulk drug substance) in a dispensing isolator (Grade A). The drug substance is not isolated, therefore the validation has been performed using in-process controls. The evaluation of the in-process controls has demonstrated that the drug substance manufacturing process provides consistency from batch to batch irrespective of the batch size, the synthesis module, or the manufacturing site.
The synthesis of the drug substance (177Lu oxodotreotide) and its formulation into the drug product (177Lu oxodotreotide 370 MBq/mL solution for infusion) are part of an automated continuous process which does not allow for isolation and testing of the drug substance due to its radioactive decay. The manufacturing process of the drug product starts when, inside a dispensing isolator, the drug substance is recovered in an intermediate vial following the first sterilizing filtration. The bulk drug substance is transferred into a 200 mL or 500 mL bottle depending on the drug substance batch size. The total radioactivity is verified. The volume of the formulation buffer to be added is adjusted in order to obtain the required radioactive concentration of 370 MBq/mL 177Lu oxodotreotide at the end of the production (i.e., at calibration time). The final sterilizing filtration occurs during the dispensing of the solution into 30 mL vials, with 20.5 to 25 mL per vial, depending on the calibration date. The filter used for the final sterilization is tested for integrity before the release of the batch.
A comparative analysis of results obtained from process validation batches produced by each manufacturing site demonstrated that the manufacturing sites produce batches with reproducible and comparable quality. The manufacturing site, the synthesis module, the batch size, and the supplier of lutetium chloride do not have any differential impact on the quality of the product.
The aseptic process was validated through three consecutive process simulations (media fills) with a maximum filling duration of 93 minutes and a filling volume between 200 mL and 400 mL. The media fills were performed at each manufacturing site taking into account worst-case situations (e.g., change of filling needle, introduction of vials in the dispensing isolator). In all cases, the vials of culture media did not show any microbial contamination.
The bioburden test is performed on a non-radioactive 175Lu oxodotreotide bulk solution every six months in order to monitor any microbiological deviation of the process. The method for the proposed bioburden test was appropriately validated. The bioburden test confirmed that there was no microbiological contamination from the raw materials or the drug substance process.
In addition, as part of the validation of the drug product manufacturing process, a complete validation of the sterilizing filter was performed with the following tests: bacterial viability study, bacterial challenge, compatibility study, adsorption study, product wet integrity test, and extractables test. All acceptance criteria for the tests were met. The aseptic liquid filtration with the sterile membrane filter produces a sterile effluent.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of lutetium (177Lu) oxodotreotide with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 72 hours for Lutathera, when stored at a temperature between 2ºC and 27ºC, is considered acceptable. The in-use shelf life for Lutathera drug product in saline is 4 hours when stored at room temperature.
The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.
On-site evaluation of the facilities involved in the manufacture and testing of Lutathera was not conducted as it is not required for radiopharmaceutical products.
Adventitious Agents Safety Evaluation
No materials of animal or human origin are used during the manufacture of the drug substance and the drug product.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| LUTATHERA | 02484552 | NOVARTIS PHARMACEUTICALS CANADA INC | LUTETIUM (177LU) OXODOTREOTIDE 370 MBq / ML |