Summary Basis of Decision for Lenvima

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Lenvima is located below.

Recent Activity for Lenvima

SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Lenvima

Date SBD issued: 2016-02-09

The following information relates to the new drug submission for Lenvima.

Lenvatinib (as lenvatinib mesylate), 4 mg and 10 mg, capsules, oral

Drug Identification Number (DIN):

    Eisai Ltd.

    New Drug Submission Control Number: 180877

    On December 22, 2015, Health Canada issued a Notice of Compliance to Eisai Limited for the drug product Lenvima

    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 Lenvima is favourable for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

    1 What was approved?

    Lenvima, an antineoplastic agent, was authorized for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

    Of 261 patients who received Lenvima in a pivotal Phase III study, 118 (45.2%) were ≥65 years of age and 29 (11.1%) were ≥75 years of age. Patients 75 years or older had a higher incidence of fatal adverse events. Compared with patients younger than 65, patients who were 75 years or older were also more likely to experience (in descending order of frequency) Grade 3-4 hypertension, proteinuria, decreased appetite, and dehydration.

    The safety and efficacy of Lenvima in children and adolescents <18 years have not been established. Lenvima should not be used in children younger than 2 years of age because of safety concerns identified in animal studies.

    Lenvima is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Lenvima was approved for use under the conditions stated in the Lenvima Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

    Lenvima (4 mg and 10 mg lenvatinib, as lenvatinib mesylate) is presented as capsules. In addition to the medicinal ingredient, lenvatinib mesylate, the capsule contains black iron oxide, calcium carbonate, ferric oxide red, ferric oxide yellow, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, mannitol, microcrystalline cellulose, potassium hydroxide, propylene glycol, shellac, talc, and titanium dioxide.

    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 Lenvima Product Monograph, approved by Health Canada and available through the Drug Product Database.

    2 Why was Lenvima approved?

    Health Canada considers that the benefit/risk profile of Lenvima is favourable for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RR-DTC).

    Thyroid cancer is a rare disease but the incidence is increasing more rapidly than any other cancer worldwide. In Canada, thyroid cancer is the most common cancer in the 15-29 year old age group. Differentiated thyroid cancer (DTC) accounts for approximately 90% to 95% of thyroid cancers. The initial management of DTC is surgery, commonly followed by thyroxine therapy and radioactive iodine (RAI) treatment for higher risk cases. The disease reoccurs within 5 years in approximately 10% of DTC patients and one third of them will become RAI-refractory. Radioactive iodine-refractory DTC (RR-DTC) is an aggressive disease with a median overall survival of 2.5 to 3.5 years.

    Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of both physiologic and pathologic angiogenesis, with increased expression being associated with a poor prognosis in many human tumor types. Elevated levels of VEGF have been found in thyroid tumors, and the intensity of VEGF expression in papillary thyroid cancer has been correlated with a higher risk of metastasis and shorter disease-free survival.

    Lenvatinib, the medicinal ingredient of Lenvima, is a multiple receptor tyrosine kinase (RTK) inhibitor. Lenvatinib selectively inhibits the kinase activities of VEGF receptors VEGFR1, VEGFR2, and VEGFR3 in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, FGFR2, FGFR3, and FGFR4; the platelet derived growth factor (PDGF) receptor PDGFRα KIT; and RET.

    Lenvima has been shown to be efficacious in patients with RR-DTC. In a Phase III pivotal study, Lenvima extended progression-free survival (PFS) by 14.7 months compared to placebo [18.3 versus (vs.) 3.6 months, respectively, p<0.001]. The hazard ratio for disease progression or death was 0.21; 99% confidence interval, 0.14 to 0.31, p<0.001. These results are considered clinically relevant and are statistically significant. The median overall survival (OS) was not reached in either group. The PFS data from Phase II studies were consistent with the results of the pivotal study.

    The proportion of patients who had a treatment-emergent adverse event (TEAE) of any grade was higher with Lenvima compared to placebo (97% vs. 60%) as was the incidence of Grade ≥3 adverse events (AEs) (76% vs. 10%) and serious AEs (31% vs. 6%). In the pivotal study, the Lenvima daily dose (24 mg) was modified in 89.7% of the patients (interrupted in 85.3%, reduced in 78.2%) due to TEAEs so that the median daily dose of Lenvima was 16.2 mg. The implemented dose reduction algorithm resulted in decreasing the rate of TEAEs. Currently, the Lenvima Product Monograph provides recommendations for dosing and dose adjustments to manage Lenvima-related AEs.

    The following warnings have been included in a Serious Warnings and Precautions box in the Lenvima Product Monograph: hypertension, arterial thromboembolism, hepatotoxicity/hepatic failure, renal failure and impairment, hemorrhage, and posterior reversible encephalopathy. There is explicit information in the Lenvima Product Monograph about the most common, severe and serious AEs reported in the clinical studies, including appropriate recommendations for the monitoring and management. The safety findings from 10 clinical studies with Lenvima were supported by the findings from non-clinical studies and are adequately labelled to mitigate risks of lenvatinib-related toxicity.

    A Risk Management Plan (RMP) for Lenvima was submitted by Eisai Limited 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.

    Health Canada reviewed the Look-alike Sound-alike Report submitted by Eisai Limited and accepted the proprietary name for the drug product.

    Overall, the therapeutic benefits seen in the pivotal study are positive and the benefits of Lenvima therapy are considered to outweigh the potential risks for the treatment of patients with incurable and fatal RR-DTC. Lenvima has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Lenvima 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 Lenvima?

    Submission Milestones: Lenvima

    Submission MilestoneDate

    The Canadian regulatory decision on the non-clinical and clinical review of Lenvima was based on a critical assessment of the Canadian data package. The foreign reviews completed by United States Food and Drug Administration (FDA) were used as an added reference.

    For additional information about the drug submission process, refer to Management of Drug Submissions Guidance.

    4 What follow-up measures will the company take?

    Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

    Although not a condition of market authorization, Eisai Limited committed to provide Health Canada the following post-authorization study reports upon study completion, as the results of these studies may impact the benefit-risk assessment of Lenvima.

    • Study E7080-A001-109: An Open-Label Phase I Study to Assess the Effect of Lenvatinib (E7080) on the Pharmacokinetics of Midazolam, a CYP3A4 substrate, in Subjects with Advanced Solid Tumors. Expected completion date: March, 2018.
    • Study E7080-G000-211: A Multicentre, Randomized, Double-blind Phase II Trial of Lenvatinib (E7080) in Subjects with 131I Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 20 mg or 14 mg Daily Will Provide Comparable Efficacy to a 24-mg Starting Dose, But Have a Better Safety Profile. Expected completion date: July, 2020.
    • Study E7080-A001-010: A Multicentre Study In Healthy Subjects As Well As Subjects With Either Hepatic Or Renal Impairment To Obtain Plasma To Assess In Vitro Lenvatinib Protein Binding. Expected completion date: not determined yet.

    6 What other information is available about drugs?

    Up to date information on drug products can be found at the following links:

    7 What was the scientific rationale for Health Canada's decision?
    7.1 Clinical basis for decision

    Clinical Pharmacology

    Lenvatinib, the active ingredient in Lenvima, is an oral, multiple receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors VEGFR1, VEGFR2, and VEGFR3; in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, FGFR2, FGFR3, and FGFR4; the platelet derived growth factor (PDGF) receptor PDGFRα KIT; and RET. Lenvatinib signals pathways to block cell proliferation and tumor angiogenesis. It also interacts with VEGFR2 with a novel binding mode compared to other VEGF/VEGFR-targeted therapies.

    Eisai Limited has provided sufficient Lenvima pharmacokinetic (PK) data. Studies evaluating Lenvima PK parameters in patients with renal and hepatic impairment have been conducted. Based on the data, a dose adjustment is recommended for patients with severe renal and hepatic impairment. Also, geriatric patients should be monitored due to their reduced tolerability of the drug. Drug-drug-interaction (DDI) studies have been performed in vitro and in vivo showing there are no significant DDIs expected with Lenvima use, although it is noted there is an ongoing midazolam study (Study E7080-A001-109) that will be provided once completed.

    For further details, please refer to the Lenvima Product Monograph, approved by Health Canada and available through the Drug Product Database.

    Clinical Efficacy

    The clinical efficacy of Lenvima was primarily evaluated in one Phase III, multicentre, randomized, double-blind, placebo-controlled pivotal study conducted in 392 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) with radiographic evidence of disease progression within 12 months (+1 month window) prior to randomization. Randomization was stratified by geographic region (Europe, North America, and Other), prior VEGF/VEGFR-targeted therapy (patients may have received 0 or 1 prior VEGF/VEGFR-targeted therapy), and age (≤65 years or >65 years). Patients were randomized (2:1) to receive a 24 mg daily dose of Lenvima [number of patients (n) = 261] or placebo (n = 131) until confirmation of disease progression or unacceptable toxicity occurred.

    The Lenvima and placebo groups were similar with respect to age, gender, ECOG (Eastern Cooperative Oncology Group) performance status, and the percentage of patients with thyroid-stimulating hormone (TSH) levels of ≤0.5 mU/L. Other characteristics included hypotension, diabetes, proteinuria, renal impairment, hepatic impairment, race, and weight. The disease characteristics for RR-DTC patients were well-balanced between the two treatment groups [Lenvima versus (vs.) placebo]: 64.8% vs. 68.7% had papillary thyroid cancer; 35.2% vs. 31.3% had follicular thyroid cancer and 14.9% vs. 14.5% Hürthle cell carcinoma. All but 4 patients in the Lenvima group had metastatic disease. These 4 patients had locally advanced disease that met inclusion criteria. The most frequently reported sites of metastatic disease (Lenvima vs. placebo) were: lung (86.6% vs. 94.7%), lymph node (52.9% vs. 48.9%) and bone (39.8% vs. 36.6%). The majority of patients had metastases in multiple organs: 74.7% (195/261) in the Lenvima group vs. 74.0% (97/131) in the placebo group. The type and frequency of metastatic disease were similar between the two treatment groups. All patients had prior antithyroid surgery; 96.9% vs. 96.1% had prior radioactive iodine therapy, 50.2% vs. 53.4% had radiotherapy, 10.7% vs. 9.9%. had chemotherapy and 25.3% vs. 20.6% had prior VEGF/VEGFR-targeted therapy including sorafenib (77.3% vs. 77.8%). All patients had pathologically confirmed metastatic progressive RR-DTC. Overall, the two treatment groups were well-balanced with respect to baseline characteristics reflective of the target population for the specified indication. Two Phase II studies in patients with thyroid cancer supported the pivotal Phase III study. In each of the three studies, patients with RR-DTC received the Lenvima starting dosage of 24 mg once daily.

    In the pivotal Phase III study, the primary efficacy endpoint was progression-free survival (PFS) as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary efficacy endpoints included overall response rate and overall survival (OS). Patients in the placebo arm could receive Lenvima treatment after confirmed disease progression.

    Patients who received Lenvima had a median PFS of 18.3 months compared to 3.6 months for those who received placebo (p<0.001). The significant PFS prolongation was observed across all pre-specified subgroups. These results are considered clinically relevant and statistically significant. Among patients who achieved a complete or partial response, 70.4% achieved the response on or within 30 days of treatment with the 24 mg dose of Lenvima. Following independent review confirmation of disease progression, 109 (83%) patients randomly assigned to placebo crossed-over to open-label Lenvima.

    The objective response rate in the Lenvima group was 64.8% (4 complete responses) and 1.5% in the placebo group (0 complete responses) (p <0.001). There was a trend towards improved OS among patients treated with Lenvima. The hazard ratio for OS adjusted for crossover was 0.62 [95% confidence interval (CI): 0.40 to 1.00; p = 0.05]; the unadjusted for crossover hazard ratio was 0.73, 95% CI: 0.50 to 1.07, p = 0.10. Both approaches did not show a statistically significant improvement in OS. The median duration of treatment was 16.1 months in the Lenvima group and 3.9 months in the placebo group.

    For more information, refer to the Lenvima Product Monograph, approved by Health Canada and available through the Drug Product Database.

    Clinical Safety

    The clinical safety of Lenvima in RR-DTC patients was evaluated in the pivotal Phase III study described in the Clinical Efficacy section. In this study, patients with RR-DTC were randomized (2:1) to receive Lenvima (n = 261) or placebo (n = 131). The two treatment groups were well-balanced with respect to demographic and baseline characteristics. Among 261 patients who were randomized to receive Lenvima, the median age was 64 years, 52% were female, 80% were Caucasian, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity. The median treatment duration was 16.1 months for Lenvima and 3.9 months for placebo. The starting dose of Lenvima was 24 mg daily. Patients could have stepwise dose reductions to 20 mg (first reduction), 14 mg (second dose reduction), or 10 mg (third dose reduction) on an individual basis as needed for adverse events. Once the dose was reduced, it could not be increased later.

    Almost all patients treated with Lenvima (99.6%) and 90.1% of patients treated with placebo had at least one treatment-emergent adverse event (TEAE) of any grade. The most common adverse reactions observed in Lenvima-treated patients (≥30%) and at an incidence at least 5% higher than that for placebo (Lenvima vs. placebo): were hypertension (73% vs. 16%), diarrhea (67% vs. 17%), decreased appetite (54% vs. 18%), decreased weight (51% vs. 14%), nausea (47% vs. 25%), fatigue (42% vs. 24%), stomatitis (41% vs. 8%), headache (38% vs. 12%), vomiting (36% vs. 14%); proteinuria (34% vs. 3%); Palmar-plantar erythrodysesthesia (32% vs. 1%); and dysphonia (31% vs. 5%). The incidence of Grade ≥3 TEAEs was also higher in the Lenvima group than in placebo group (75.9% vs. 9.9%). The most commonly reported (≥5%) Grade 3 or 4 TEAEs were hypertension (44%), weight decreased (13%), fatigue (11%), proteinuria (11%), diarrhea (9%), decreased appetite (7%), arthralgia/myalgia (5%), and stomatitis (5%).

    Adverse reactions led to dose reductions in 68% of patients receiving Lenvima and 5% of patients receiving placebo. A total of 18% of patients discontinued Lenvima and 5% of patients discontinued placebo because of adverse reactions. The most common adverse reactions (≥10%) resulting in dose reductions of Lenvima were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%). The most common adverse reactions (≥1%) resulting in discontinuation of Lenvima were hypertension (1%) and asthenia (1%). Clinically significant serious adverse reactions were hypertension (3.4%), renal failure and impairment (3.4%), pulmonary embolism (1.9%), cardiac failure (0.7%), intracranial tumor haemorrhage (0.7%), posterior reversible encephalopathy (0.4%), hepatic failure (0.4%), arterial thromboembolisms [cerebrovascular accident (0.8%), transient ischaemic attack (0.4%), and myocardial infarction (1.1%)], gastrointestinal perforation (0.8%) and fistula (0.4%). Fatal adverse events (AEs) included myocardial infarction, cardiorespiratory arrest, intracranial tumor, haemorrhage, haemorrhagic stroke, pulmonary embolism, hepatic failure, and renal failure.

    Review of safety data obtained from 1,108 patients treated with Lenvima in clinical studies identified the following clinically significant AEs: hypertension, cardiac dysfunction, arterial thromboembolism, hepatotoxicity, renal failure and impairment, proteinuria, hemorrhage, QT interval prolongation, impairment of thyroid stimulating hormone suppression, gastrointestinal perforation and fistula, posterior reversible encephalopathy syndrome, and palmar-plantar erythrodysesthesia.

    Based on the pivotal Phase III study, the risk of major AEs can be managed with close monitoring, precautions and appropriate dose modifications. The Lenvima Product Monograph has explicit information about the most common, severe and serious AEs reported in clinical studies with Lenvima, including appropriate recommendations for their monitoring and management.

    Approximately 90% of patients treated with Lenvima in the pivotal study required a dose modification due to toxicity. In the pivotal study, the starting dose of Lenvima at 24 mg daily demonstrated clinically relevant and statistically significant improvement in PFS. The Lenvima Product Monograph is well-labelled to provide prescribers with the information they need for dose modification and management of toxicity. Additional efficacy data for three starting doses (24 mg, 20 mg and 14 mg) will be provided by the currently ongoing Phase III Study E7080-G000-211. Upon completion the benefit-risk of Lenvima at these doses will be re-evaluated.

    For more information, refer to the Lenvima Product Monograph, approved by Health Canada and available through the Drug Product Database.

    7.2 Non-Clinical Basis for Decision

    The review of the non-clinical studies suggests that Lenvima would likely be associated with diarrhea, weight loss, decreased appetite and other gastrointestinal toxicity as well as hepatic, renal, pancreatic, and hematologic toxicity. Additionally, toxic effects may be noted in the adrenal glands and pituitary as well as in reproductive organs. Lenvima was embryotoxic and teratogenic when administered to rats and rabbits and was excreted in rat milk. The clinically relevant findings are described in the corresponding parts of the Lenvima Product Monograph, including warnings for pregnant and nursing females and pediatric patients. The non-clinical safety studies characterized the toxicological profile of Lenvima adequately and support the market authorization in adult patients with radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). In view of the intended use of Lenvima, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

    For more information, refer to the Lenvima Product Monograph, approved by Health Canada and available through the Drug Product Database.

    7.3 Quality Basis for Decision

    The Chemistry and Manufacturing information submitted for Lenvima has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life of 36 months when stored at 15-30°C is considered acceptable.

    Proposed limits of drug-related impurities are considered adequately qualified; that is (i.e.) within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies.

    All sites involved in production are compliant with Good Manufacturing Practices.

    All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

    The excipients used in the drug product formulation are not of animal or human origin.