Summary Basis of Decision for Lenvima

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.