Lenvima Adverse Reactions

The incidence rates of treatment-emergent adverse events observed in clinical studies are presented in the respective tables listed as follows.
Table 3: DTC monotherapy; Table 4: RCC combination with pembrolizumab; Table 6: RCC combination with everolimus; Table 7: HCC monotherapy; Table 8: EC combination with pembrolizumab; Table 10: Postmarketing adverse drug reactions, monotherapy.
Events are included as Adverse Drug Reactions (ADRs) based on the incidence rates of treatment emergent adverse events (TEAEs) in the placebo-controlled DTC study together with events from other indications assessed in the context of TEAE incidence rates across study treatment arms, the known pharmacology of lenvatinib and the underlying indication.
Thyroid Cancer: The safety of lenvatinib was evaluated in 392 patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) randomized to receive lenvatinib 24 mg once daily (n=261) or placebo (n=131).
Table 3 presents the incidence rates of treatment-emergent adverse events observed in the double-blind phase of the DTC study. All adverse events occurring with a treatment difference of at least 5% over placebo are included in the Table. Clinically significant events (CSEs) that were observed more frequently than placebo are also included based on an assessment of the known pharmacology of lenvatinib and class effects. (See Tables 3a and 3b.)

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RCC 1L Combination With Pembrolizumab: The safety of lenvatinib was evaluated in Study 307, in which patients with advanced renal cell carcinoma (RCC) were randomized (1:1:1) to lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks(n=352), lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily(n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340).
The median duration of study treatment was 17.0 months (range 2 days to 39.1 months). The median duration of exposure to lenvatinib was 16.1 months (range 2 days to 39.1 months).
Tables 4 and 5 summarize treatment emergent adverse events and laboratory abnormalities, respectively, in patients receiving lenvatinib in combination with pembrolizumab in Study 307. (See Tables 4 and 5.)

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RCC 2L Combination With Everolimus: A multicenter, randomized, open-label, trial was conducted to determine the safety and efficacy of lenvatinib administered alone or in combination with everolimus in subjects with unresectable, advanced or metastatic RCC. The study consisted of a Phase 1b dose finding and a Phase 2 portion.
The Phase 2 portion enrolled a total of 153 patients with advanced or metastatic renal cell carcinoma(RCC) following 1 prior VEGF-targeted treatment who were randomized to receive the combination of 18 mg lenvatinib plus 5 mg everolimus (n=51), lenvatinib 24 mg (n=52) or everolimus 10 mg(n=50) once daily).
Table 6 presents the incidence rates of treatment-emergent adverse events observed in the RCC study.
All adverse events occurring with a frequency of at least 10% all Grades or 3% Grade 3 or 4. (See Table 6.)

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HCC: A multicenter, randomized, open-label study was conducted to determine the safety and efficacy of lenvatinib compared to sorafenib in subjects with unresectable hepatocellular carcinoma (HCC). Subjects were randomized 1:1 to lenvatinib (12 mg [≥ 60 kg BW] or lenvatinib 8 mg [<60 kg BW]) orally, once daily, or sorafenib 400 mg orally, twice daily.
Table 7 presents the incidence rates of treatment emergent adverse events observed in the HCC study and includes all adverse events occurring with a frequency of at least 10% and of at least 3% ≥ CTCAE Grade 3. (See Table 7.)

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EC 2L Combination With Pembrolizumab: The safety of lenvatinib in combination with pembrolizumab was investigated in Study 309, a multicenter, open-label, randomized (1:1), active-controlled trial in 827 patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received lenvatinib 20 mg orally once daily with pembrolizumab 200 mg intravenously every 3 weeks (n=406) or treatment of investigator's choice (n=388), consisting of 60 mg/m2 doxorubicin every 3 weeks or 80 mg/m2 paclitaxel given weekly, 3 weeks on/1 week off.
The median duration of study treatment was 7.6 months (range 1 day to 26.8 months). The median duration of exposure to lenvatinib was 6.9 months (range 1 day to 26.8 months).
Tables 8 and 9 summarize treatment emergent adverse events and laboratory abnormalities, respectively, in patients receiving lenvatinib in combination with pembrolizumab in Study 30. (See Table 8 and 9.)

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Postmarketing adverse drug reactions: The incidence of adverse events observed in lenvatinib monotherapy datasets for reactions identified from post marketing use of lenvatinib are provided in Table 10. (See Table 10.)

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The following are considered to be Adverse Drug Reactions (ADRs) for lenvatinib: Blood and Lymphatic System Disorders: Lymphopenia, Thrombocytopenia, Leukopenia, Neutropenia.
Cardiac Disorders: Cardiac failure, QT interval prolongation.
Endocrine Disorders: Hypothyroidism.
Gastrointestinal Disorders: Abdominal pain, Amylase increased^*, Constipation, Diarrhea, Dry mouth, Dyspepsia, Flatulence, Gastrointestinal perforation and fistula, Lipase increased^*, Nausea, Oral pain, Pancreatitis^*, Stomatitis, Vomiting.
General Disorders and Administration Site Conditions: Asthenia, Edema peripheral, Fatigue, Malaise, Impaired Wound Healing^*.
Hepatobiliary Disorders: Cholecystitis^*, Hepatotoxicity, Hepatic failure^‡, Hepatic encephalopathy^‡.
Infections and Infestations: Urinary tract infection.
Investigations: Weight decreased.
Metabolism and Nutrition Disorders: Decreased appetite, Dehydration, Hypercholesterolemia, Hypocalcemia, Hypokalemia, Hypomagnesemia.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, Back pain, Musculoskeletal pain, Myalgia, Pain in extremity, Osteonecrosis of the jaw^*.
Nervous System Disorders: Dizziness, Dysgeusia, Headache, Reversible posterior leukoencephalopathy syndrome.
Psychiatric Disorders: Insomnia.
Renal and Urinary Disorders: Nephrotic syndrome^*, Proteinuria, Renal failure^‡, Renal impairment.
Respiratory, Thoracic and Mediastinal Disorders: Cough, Dysphonia, Pneumothorax^*‡, Pulmonary embolism^‡.
Skin and Subcutaneous Tissue Disorders: Alopecia, Hyperkeratosis, Palmar-plantar erythrodysesthesia syndrome, Rash.
Vascular Disorders: Arterial thromboembolic events^‡, Hemorrhage^‡, Hypertension, Hypotension, Aortic Dissection^‡*.
^‡ Includes fatal events.
^* Identified from post-marketing of lenvatinib.