Lenvatinib

1 INDICATIONS AND USAGE LENVIMA is a kinase inhibitor that is indicated: Differentiated Thyroid Cancer (DTC) For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). ( 1.1 ) Renal Cell Carcinoma (RCC) In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC). ( 1.2 ) In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. ( 1.2 ) Hepatocellular Carcinoma (HCC) For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). ( 1.3 ) Endometrial Carcinoma (EC) In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. ( 1.4 , 2.1 ) 1.1 Differentiated Thyroid Cancer LENVIMA is indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 1.2 Renal Cell Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). LENVIMA, in combination with everolimus, is indicated for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy. 1.3 Hepatocellular Carcinoma LENVIMA is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.4 Endometrial Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration ( 2.1 )] .

12.1 Mechanism of Action Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRA), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2 alpha (FRS2) phosphorylation. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro, and by decreases in tumor volume in mouse xenograft models of human renal cell cancer that were greater than those with either drug alone.

2 DOSAGE AND ADMINISTRATION Single Agent Therapy: DTC: The recommended dosage is 24 mg orally once daily. ( 2.3 ) HCC: The recommended dosage is based on actual body weight: 12 mg orally once daily for patients greater than or equal to 60 kg or 8 mg orally once daily for patients less than 60 kg. ( 2.5 ) Combination Therapy: EC: The recommended dosage is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. ( 2.6 ) RCC: The recommended dosage is: 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. ( 2.4 ) 18 mg orally once daily with everolimus 5 mg orally once daily. ( 2.4 ) Modify the recommended daily dose for certain patients with renal or hepatic impairment. ( 2.8 , 2.9 ) 2.1 Patient Selection For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MMR or MSI status in tumor specimens [see Clinical Studies ( 14.4 )]. Information on FDA-approved tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics . 2. 2 Important Dosage Information Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and Administration ( 2.8 , 2.9 )] . Take LENVIMA once daily, with or without food, at the same time each day [see Clinical Pharmacology ( 12.3 )] . If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration. 2. 3 Recommended Dos ag e for Differentiated Thyroid Cancer (DTC) The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity. 2. 4 Recommended Dosage for Renal Cell Carcinoma (RCC) F irst- L ine Treatment of Patients with Advanced RCC The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years. After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity. Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information. Previously Treated RCC The recommended dosage of LENVIMA is 18 mg in combination with 5 mg everolimus orally once daily until disease progression or until unacceptable toxicity. Refer to the everolimus prescribing information for recommended everolimus dosing information. 2. 5 Recommended Dosage for Hepatocellular Carcinoma (HCC) The recommended dosage of LENVIMA is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Take LENVIMA orally once daily until disease progression or until unacceptable toxicity. 2. 6 Recommended Dosage for Endometrial Carcinoma (EC) The recommended dosage of LENVIMA is 20 mg orally once daily, in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression. Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information. 2. 7 Dos age Modifications for Adverse Reactions Recommendations for LENVIMA dose interruption, reduction and discontinuation for adverse reactions are listed in Table 1. Table 2 lists the recommended dosage reductions of LENVIMA for adverse reactions. Table 1 : Recommended Dos ag e Modifications for LENVIMA for Adverse Reactions Adverse Reaction Severity a Dos ag e Modifications for LENVIMA Hypertension [see Warnings and Precautions ( 5.1 )] Grade 3 Withhold for Grade 3 that persists despite optimal antihypertensive therapy. Resume at reduced dose when hypertension is controlled at less than or equal to Grade 2. Grade 4 Permanently discontinue. Cardiac Dysfun

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Hypertension [see Warnings and Precautions ( 5.1 )] Cardiac Dysfunction [see Warnings and Precautions ( 5.2 )] Arterial Thromboembolic Events [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Renal Failure and Impairment [see Warnings and Precautions ( 5.5 )] Proteinuria [see Warnings and Precautions ( 5.6 )] Diarrhea [see Warnings and Precautions ( 5.7 )] Fistula Formation and Gastrointestinal Perforation [see Warnings and Precautions ( 5.8 )] QT Interval Prolongation [see Warnings and Precautions ( 5.9 )] Hypocalcemia [see Warnings and Precautions ( 5.10 )] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions ( 5.11 )] Hemorrhagic Events [see Warnings and Precautions ( 5.12 )] Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction [see Warnings and Precautions ( 5.13 )] Impaired Wound Healing [see Warnings and Precautions ( 5.14 )] Osteonecrosis of the Jaw (ONJ) [see Warnings and Precautions ( 5.15 )] In DTC, the most common adverse reactions (incidence ≥30%) for LENVIMA are hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. ( 6.1 ) In RCC: The most common adverse reactions (incidence ≥20%) for LENVIMA and pembrolizumab are fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, decreased weight, dysphonia, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, hemorrhagic events, vomiting, constipation, hepatotoxicity, headache, and acute kidney injury. ( 6.1 ) The most common adverse reactions (incidence ≥30%) for LENVIMA and everolimus are diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, hemorrhagic events, and proteinuria. ( 6.1 ) In HCC, the most common adverse reactions (incidence ≥20%) for LENVIMA are hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. ( 6.1 ) In EC, the most common adverse reactions (incidence ≥20%) for LENVIMA and pembrolizumab are hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, decreased weight, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-877-873-4724 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warnings and Precautions reflect exposure to LENVIMA as a single agent in 261 patients with DTC (SELECT) and 476 patients with HCC (REFLECT), LENVIMA with pembrolizumab in 406 patients with endometrial carcinoma (Study 309), LENVIMA with everolimus in 62 patients with RCC (Study 205), and LENVIMA with pembrolizumab in 352 patients with RCC (CLEAR). Safety data obtained in 1823 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions. Among the 1823 patients who received LENVIMA as a single agent, the median age was 61 years (20 to 89 years), the dose range was 0.2 mg to 32 mg daily, and the

5 WARNINGS AND PRECAUTIONS Hypertension : Control blood pressure prior to treatment and monitor during treatment. Withhold for Grade 3 hypertension despite optimal antihypertensive therapy. Discontinue for Grade 4 hypertension. ( 2.7 , 5.1 ) Cardiac Dysfunction : Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold or discontinue for Grade 3 cardiac dysfunction. Discontinue for Grade 4 cardiac dysfunction. ( 2.7 , 5.2 ) Arterial Thromboembolic Events : Discontinue following an arterial thromboembolic event. ( 2.7 , 5.3 ) Hepatotoxicity : Monitor liver function prior to treatment and periodically during treatment. Withhold or discontinue for Grade 3 or 4 hepatotoxicity. Discontinue for hepatic failure. ( 2.7 , 5.4 ) Renal Failure or Impairment : Withhold or discontinue for Grade 3 or 4 renal failure or impairment. ( 2.7 , 5.5 ) Proteinuria : Monitor for proteinuria prior to treatment and periodically during treatment. Withhold for 2 or more grams of proteinuria per 24 hours. Discontinue for nephrotic syndrome. ( 2.7 , 5.6 ) Diarrhea : May be severe and recurrent. Promptly initiate management for severe diarrhea. Withhold or discontinue based on severity. ( 2.7 , 5.7 ) Fistula Formation and Gastrointestinal Perforation : Discontinue in patients who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation. ( 2.7 , 5.8 ) QT Interval Prolongation : Monitor and correct electrolyte abnormalities. Withhold for QT interval greater than 500 ms or for 60 ms or greater increase in baseline QT interval. ( 2.7 , 5.9 ) Hypocalcemia : Monitor blood calcium levels at least monthly and replace calcium as necessary. Withhold or discontinue based on severity. ( 2.7 , 5.10 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : Withhold for RPLS until fully resolved or discontinue. ( 2.7 , 5.11 ) Hemorrha gic Events : Withhold or discontinue based on severity. ( 2.7 , 5.12 ) Impairment of Thyroid Stimulating Hormone Suppression /Thyroid Dysfunction : Monitor thyroid function prior to treatment and monthly during treatment. ( 5.13 ) Impaired Wound Healing : Withhold LENVIMA for at least 1 week before elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established. ( 5.14 ) Osteonecrosis of the Jaw : Consider preventive dentistry prior to treatment with LENVIMA. Avoid invasive dental procedures, if possible, particularly in patients at higher risk. ( 5.15 ) Embryo -F etal T oxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.16 , 8.1 , 8.3 ) 5.1 Hypertension Hypertension occurred in 73% of patients in SELECT (DTC) receiving LENVIMA 24 mg orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg or 12 mg orally once daily. The median time to onset of new or worsening hypertension was 16 days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Grade 4 hypertension occurred <1% in SELECT and Grade 4 hypertension was not reported in REFLECT. In patients receiving LENVIMA 18 mg orally once daily with everolimus in Study 205 (RCC), hypertension was reported in 42% of patients and the median time to onset of new or worsening hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients. Systolic blood pressure ≥160 mmHg occurred in 29% of patients and diastolic blood pressure ≥100 mmHg occurred in 21% [see Adverse Reactions ( 6.1 )] . Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiating LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permane

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable [see Clinical Pharmacology ( 12.3 )] . Death due to multiorgan dysfunction occurred in a patient who received a single dose of LENVIMA 120 mg orally.