LENVIMA is indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 

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.

LENVIMA is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), 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 )].

For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MSI or MMR 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.

An FDA-approved test for the selection of patients who are not MSI-H is not currently available.

• 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.

The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity.

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.

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.

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.

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 Dysfunction [see Warnings and Precautions ( 5.2 )]	Grade 3	Withhold until improves to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction.
	Grade 4	Permanently discontinue.
Arterial Thromboembolic Event [see Warnings and Precautions ( 5.3 )]	Any Grade	Permanently discontinue.
Hepatotoxicity [see Warnings and Precautions ( 5.4 )]	Grade 3 or 4	Withhold until improves to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue depending on severity and persistence of hepatotoxicity. Permanently discontinue for hepatic failure.
Renal Failure or Impairment [see Warnings and Precautions ( 5.5 )]	Grade 3 or 4	Withhold until improves to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue depending on severity and persistence of renal impairment.
Proteinuria [see Warnings and Precautions ( 5.6 )]	2 g or greater proteinuria in 24 hours	Withhold until less than or equal to 2 grams of proteinuria per 24 hours. Resume at a reduced dose. Permanently discontinue for nephrotic syndrome.
Gastrointestinal Perforation [see Warnings and Precautions ( 5.8 )]	Any Grade	Permanently discontinue.
Fistula Formation [see Warnings and Precautions ( 5.8 )]	Grade 3 or 4	Permanently discontinue.
QT Prolongation [see Warnings and Precautions ( 5.9 )]	Greater than 500 ms or greater than 60 ms increase from baseline	Withhold until improves to less than or equal to 480 ms or baseline. Resume at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions ( 5.11 )]	Any Grade	Withhold until fully resolved. Resume at a reduced dose or discontinue depending on severity and persistence of neurologic symptoms.
Other Adverse Reactions [see Warnings and Precautions ( 5.7 , 5.10 , 5.12 )]	Persistent or intolerable Grade 2 or 3 adverse reaction Grade 4 laboratory abnormality	Withhold until improves to Grade 0 to 1 or baseline. Resume at reduced dose.
	Grade 4 adverse reaction	Permanently discontinue.
a.      a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Table 2: Recommended Dosage Reductions of LENVIMA for Adverse Reactions
Indication	First Dosage Reduction To	Second Dosage Reduction To	Third Dosage Reduction To
DTC	20 mg once daily	14 mg once daily	10 mg once daily
RCC	14 mg once daily	10 mg once daily	8 mg once daily
Endometrial Carcinoma	14 mg once daily	10 mg once daily	8 mg once daily
HCC
Actual weight 60 kg or greater	8 mg once daily	4 mg once daily	4 mg every other day
Actual weight less than 60 kg	4 mg once daily	4 mg every other day	Discontinue

Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Pembrolizumab

When administering LENVIMA in combination with pembrolizumab, modify the dosage of one or both drugs as appropriate. Withhold, dose reduce, or discontinue LENVIMA as shown in Table 1. Refer to pembrolizumab prescribing information for additional dose modification information.

Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Everolimus

When administering LENVIMA in combination with everolimus, withhold or reduce the LENVIMA dose first and then the everolimus dose for adverse reactions of both LENVIMA and everolimus. Refer to the everolimus prescribing information for additional dose modification information.

The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is [s ee Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.6 )]:

• Differentiated thyroid cancer: 14 mg orally once daily
  
• Renal cell carcinoma: 10 mg orally once daily
  
• Endometrial carcinoma: 10 mg orally once daily

The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is [s ee Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.7 ) ]:

• Differentiated thyroid cancer: 14 mg taken orally once daily
  
• Renal cell carcinoma: 10 mg taken orally once daily
  
• Endometrial carcinoma: 10 mg orally once daily

Administration

Oral: Capsule or Suspension

Capsule

• Swallow LENVIMA capsules whole at the same time each day with or without food [see Clinical Pharmacology ( 12.3 )]. Do not crush or chew the LENVIMA capsules.

Suspension

• Prepare [see Preparation below ] oral suspension with water or apple juice and administer at the same time each day with or without food [see Clinical Pharmacology ( 12.3 )].

Feeding Tube Administration

Suspension

• Prepare [see Preparation below ] suspension for feeding tube administration with water and administer at the same time each day with or without food [see Clinical Pharmacology ( 12.3 )].

Preparation of Suspension

• Place the required number of capsules, up to a maximum of 5, in a small container (approximately 20 mL capacity) or syringe (20 mL). Do not break or crush capsules.
  
• Add 3 mL of liquid to the container or syringe. Wait 10 minutes for the capsule shell (outer surface) to disintegrate, then stir or shake the mixture for 3 minutes until capsules are fully disintegrated and administer the entire contents.
  
• Next, add an additional 2 mL of liquid to the container or syringe using a second syringe or dropper, swirl or shake and administer. Repeat this step at least once and until there is no visible residue to ensure all of the medication is taken.
  
• If 6 capsules are required for a dose, follow these instructions using 3 capsules at a time.

If LENVIMA suspension is not used at the time of preparation, LENVIMA suspension may be stored in a refrigerator at 36ºF to 46ºF (2ºC to 8ºC) for a maximum of 24 hours in a covered container. If not administered within 24 hours, the suspension should be discarded.

Note: Compatibility has been confirmed for polypropylene syringes and for feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube) and at least 6 French diameter (silicone tube).

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 permanently discontinue LENVIMA based on severity [ see Dosage and Administration ( 2.7 ) ].

Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC or HCC, Grade 3 or higher cardiac dysfunction (including cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, cardiac failure, ventricular hypokinesia, or decrease in left or right ventricular ejection fraction of more than 20% from baseline) occurred in 3% of LENVIMA-treated patients. 

Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [ see Dosage and Administration ( 2.7 ) ].

Among patients receiving LENVIMA or LENVIMA with everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in Study 205 (RCC), 2% of patients in REFLECT (HCC) and 5% of patients in SELECT (DTC). Grade 3 to 5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials [see Adverse Reactions ( 6.1 )].

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue LENVIMA following an arterial thrombotic event [ see Dosage and Administration ( 2.7 ) ]. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. 

In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy, encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Grade 3 to 5 hepatic encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treated patients. Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Two percent of patients discontinued LENVIMA and 0.2% discontinued sorafenib due to hepatic encephalopathy and 1% of patients discontinued LENVIMA or sorafenib due to hepatic failure [see Adverse Reactions ( 6.1 )] .

Monitor liver function prior to initiating LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [ see Dosage and Administration ( 2.7 ) ].

Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment occurred in 14% of patients receiving LENVIMA in SELECT (DTC) and in 7% of patients receiving LENVIMA in REFLECT (HCC). Grade 3 to 5 renal failure or impairment occurred in 3% (DTC) and 2% (HCC) of patients, including 1 fatality in each study.

In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with everolimus, including Grade 3 in 10% of patients [see Adverse Reactions ( 6.1 )].

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA for renal failure or impairment based on severity [ see Dosage and Administration   ( 2.7 ) ]. 

Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6% in SELECT and REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in 31% of patients receiving LENVIMA with everolimus and 14% of patients receiving everolimus. Grade 3 proteinuria occurred in 8% of patients receiving LENVIMA with everolimus compared to 2% of patients receiving everolimus [see Adverse Reactions ( 6.1 )].

Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [ see   Dosage and Administration ( 2.7 ) ].

Of the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC), diarrhea occurred in 49% of patients, including Grade 3 in 6%.

In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, including Grade 3 in 19%. Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction [see Adverse Reactions ( 6.1 )].

Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [ see Dosage and Administration ( 2.7 ) ].

Of 799 patients treated with LENVIMA or LENVIMA with everolimus in SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), fistula or gastrointestinal perforation occurred in 2%. 

Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula [ see Dosage and Administration ( 2.7 ) ].

In SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In Study 205 (RCC), QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA with everolimus and QTc interval >500 ms occurred in 6%. In REFLECT (HCC), QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose of LENVIMA upon recovery based on severity [see Dosage and Administration   ( 2.7 )].

In SELECT (DTC), Grade 3 to 4 hypocalcemia occurred in 9% of patients receiving LENVIMA. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction. 

In Study 205 (RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients treated with LENVIMA with everolimus. In REFLECT (HCC), Grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients [see Adverse Reactions ( 6.1 )].

Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA depending on severity [ see Dosage and Administration   ( 2.7 ) ].

Across clinical studies of 1823 patients who received LENVIMA as a single agent [see Adverse Reaction s ( 6.1 )], reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 0.3%.

Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA depending on severity and persistence of neurologic symptoms [see Dosage and Administration ( 2.7 )].

Serious including fatal hemorrhagic events can occur with LENVIMA. Across SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), hemorrhagic events of any grade occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. 

In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receiving LENVIMA, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In Study 205, Grade 3 to 5 hemorrhage occurred in 8% of patients receiving LENVIMA with everolimus, including 1 fatal cerebral hemorrhage. In REFLECT, Grade 3 to 5 hemorrhage occurred in 5% of patients receiving LENVIMA, including 7 fatal hemorrhagic events [see Adverse Reactions ( 6.1 )].

Serious tumor related bleeds, including fatal hemorrhagic events, occurred in patients treated with LENVIMA in clinical trials and in the post-marketing setting. In post-marketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in other tumor types. The safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA based on the severity [see   Dosage and Administration   ( 2.7 ) ].

LENVIMA impairs exogenous thyroid suppression. In SELECT (DTC), 88% of all patients had a baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients.

Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving LENVIMA with everolimus in Study 205 (RCC) and in 21% of patients receiving LENVIMA in REFLECT (HCC). In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA in REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205 [see Adverse Reactions ( 6.1 )].

Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired wound healing has been reported in patients who received LENVIMA [see Adverse Reactions ( 6.2 )]. 

Withhold LENVIMA for at least 1 week prior to 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.

Osteonecrosis of the Jaw (ONJ) has been reported in patients receiving LENVIMA [see Adverse Reactions ( 6.1 )]. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices. Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) ]. 

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 median duration of exposure was 5.6 months.

The data below reflect exposure to LENVIMA in 1557 patients enrolled in randomized, active-controlled trials (REFLECT; Study 205; CLEAR; Study 309), and a randomized, placebo-controlled trial (SELECT). The median duration of exposure to LENVIMA across these five studies ranged from 6 to 16 months. The demographic and exposure data for each clinical trial population are described in the subsections below.

Differentiated Thyroid Cancer

The safety of LENVIMA was evaluated in SELECT, in which patients with radioactive iodine-refractory differentiated thyroid cancer were randomized (2:1) to LENVIMA (n=261) or placebo (n=131) [ see Clinical Studies ( 14.1 ) ]. The median treatment duration was 16.1 months for LENVIMA. Among 261 patients who received LENVIMA, median age was 64 years, 52% were females, 80% were White, 18% were Asian, and 2% were Black; and 4% were Hispanic/Latino. 

The most common adverse reactions observed in LENVIMA-treated patients (≥30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).

Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA; 18% of patients discontinued LENVIMA for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

Table 3 presents adverse reactions occurring at a higher rate in LENVIMA-treated patients than patients receiving placebo in the double-blind phase of the study.

Table  3 : Adverse Reactions Occurring in Patients with a Between-Group Difference of ≥5% in All Grades or ≥2% in Grades 3 and 4 in SELECT (DTC)
Adverse Reaction	LENVIMA 24   mg N=261		Placebo N=131
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3- 4 (%)
Vascular
Hypertensiona	73	44	16	4
Hypotension	9	2	2	0
Gastrointestinal
Diarrhea	67	9	17	0
Nausea	47	2	25	1
Stomatitisb	41	5	8	0
Vomiting	36	2	15	0
Abdominal painc	31	2	11	1
Constipation	29	0.4	15	1
Oral paind	25	1	2	0
Dry mouth	17	0.4	8	0
Dyspepsia	13	0.4	4	0
General
Fatiguee	67	11	35	4
Edema peripheral	21	0.4	8	0
Musculoskeletal and Connective Tissue
Arthralgia/Myalgiaf	62	5	28	3
Metabolism and Nutrition
Decreased appetite	54	7	18	1
Decreased weight	51	13	15	1
Dehydration	9	2	2	1
Nervous System
Headache	38	3	11	1
Dysgeusia	18	0	3	0
Dizziness	15	0.4	9	0
Renal and Urinary
Proteinuria	34	11	3	0
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia	32	3	1	0
Rashg	21	0.4	3	0
Alopecia	12	0	5	0
Hyperkeratosis	7	0	2	0
Respiratory, Thoracic and Mediastinal
Dysphonia	31	1	5	0
Cough	24	0	18	0
Epistaxis	12	0	1	0
Psychiatric
Insomnia	12	0	3	0
Infections
Urinary tract infection	11	1	5	0
Dental and oral infectionsh	10	1	1	0
Cardiac
Electrocardiogram QT prolonged	9	2	2	0
a.     Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b.     Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c.     Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain  d.     Includes oral pain, glossodynia, and oropharyngeal pain e.     Includes asthenia, fatigue, and malaise f.     Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia  g.     Includes macular rash, maculo-papular rash, generalized rash, and rash h.     Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection

Clinically important adverse reactions occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of <5% were pulmonary embolism (3%, including fatal reports vs 2%, respectively) and osteonecrosis of the jaw (0.4% vs 0%, respectively).

Laboratory abnormalities with a difference of ≥2% in Grade 3 – 4 events and at a higher incidence in the LENVIMA arm are presented in Table 4.

Table 4: Laboratory Abnormalities with a Difference of ≥2% in Grade 3 - 4 Events and at a Higher Incidence in the LENVIMA Arm a, b   in SELECT (DTC)
Laboratory A bnormality	LENVIMA 24   mg	Placebo
	Grades 3-4 (%)	Grades 3-4 (%)
Chemistry
Hypocalcemia	9	2
Hypokalemia	6	1
Increased aspartate aminotransferase (AST)	5	0
Increased alanine aminotransferase (ALT)	4	0
Increased lipase	4	1
Increased creatinine	3	0
Hematology
Thrombocytopenia	2	0
a.     With at least 1 grade increase from baseline b.     Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA (n = 253 to 258), Placebo (n = 129 to 131)

The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.

First-Line Treatment of Renal Cell Carcinoma in Combination with   P embrolizumab (CLEAR)

The safety of LENVIMA in combination with pembrolizumab was investigated in CLEAR [see Clinical Studies ( 14.2 )]. Patients received LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks (n=352), or LENVIMA 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 exposure to the combination therapy of LENVIMA and pembrolizumab was 17 months (range: 0.1 to 39).

Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage.

Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).

Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).

Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with LENVIMA and pembrolizumab in CLEAR.

Table 5 : Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC)
	LENVIMA 20 mg in combination with Pembrolizumab 200mg N=352		Sunitinib 50 mg N=340
Adverse Reactions	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
General
Fatiguea	63	9	56	8
Gastrointestinal
Diarrheab	62	10	50	6
Stomatitisc	43	2	43	2
Nausea	36	3	33	1
Abdominal paind	27	2	18	1
Vomiting	26	3	20	1
Constipation	25	1	19	0
Musculoskeletal and connective tissue
Musculoskeletal paine	58	4	41	3
Endocrine
Hypothyroidismf	57	1	32	0
Vascular
Hypertensiong	56	29	43	20
Hemorrhagic eventsh	27	5	26	4
Metabolism
Decreased appetitei	41	4	31	1
Skin and subcutaneous tissue
Rashj	37	5	17	1
Palmar-plantar erythrodysaesthesia syndromek	29	4	38	4
Respiratory, thoracic, and mediastinal
Dysphonia	30	0	4	0
Renal and urinary
Proteinurial	30	8	13	3
Acute kidney injurym	21	5	16	2
Investigations
Weight decreased	30	8	9	0
Hepatobiliary
Hepatotoxicityn	25	9	21	5
Nervous system
Headache	23	1	16	1
a.      Includes asthenia, fatigue, lethargy and malaise     b.      Includes diarrhea and gastroenteritis     c.      Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, and stomatitis     d.      Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, and upper abdominal pain     e.      Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and pain in jaw     f.       Includes hypothyroidism, increased blood thyroid stimulating hormone and secondary hypothyroidism     g.      Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, and labile blood pressure     h.      Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include: Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis, hematoma, hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage, increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, and upper gastrointestinal hemorrhage     i.      Includes decreased appetite and early satiety     j.      Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular     k.     Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome and plantar erythema     l.      Includes hemoglobinuria, nephrotic syndrome, and proteinuria     m.    Includes acute kidney injury, azotaemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininaemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic     n.     Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, and gamma-glutamyltransferase increased

Clinically relevant adverse reactions (<20%) that occurred in patients receiving LENVIMA/pembrolizumab were myocardial infarction (3%) and angina pectoris (1%).

Table 6: Laboratory Abnormalities in ≥20% (All Grades) of Patients on LENVIMA plus Pembrolizumab   in CLEAR (RCC)
	LENVIMA 20 mg in combination with Pembrolizumab 200 mg		Sunitinib 50 mg
Laboratory Abnormality a	All Grades % b	Grades 3-4 % b	All Grades % b	Grade 3-4 % b
Chemistry
Hypertriglyceridemia	80	15	71	15
Hypercholesterolemia	64	5	43	1
Increased lipase	61	34	59	28
Increased creatinine	61	5	61	2
Increased amylase	59	17	41	9
Increased aspartate aminotransferase (AST)	58	7	57	3
Hyperglycemia	55	7	48	3
Increased alanine aminotransferase (ALT)	52	7	49	4
Hyperkalemia	44	9	28	6
Hypoglycemia	44	2	27	1
Hyponatremia	41	12	28	9
Decreased albumin	34	0.3	22	0
Increased alkaline phosphatase	32	4	32	1
Hypocalcemia	30	2	22	1
Hypophosphatemia	29	7	50	8
Hypomagnesemia	25	2	15	3
Increased creatine phosphokinase	24	6	36	5
Hypermagnesemia	23	2	22	3
Hypercalcemia	21	1	11	1
Hematology
Lymphopenia	54	9	66	15
Thrombocytopenia	39	2	73	13
Anemia	38	3	66	8
Leukopenia	34	1	77	8
Neutropenia	31	4	72	16
a.     With at least 1 grade increase from baseline     b.     Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA/pembrolizumab (n= 343 to 349) and sunitinib (n= 329 to 335).

Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed in 3 patients on rechallenge in patients receiving LENVIMA and 10 patients receiving both LENVIMA and pembrolizumab.

Previously T reated Renal Cell Carcinoma in Combination with Everolimus (Study 205)

The safety of LENVIMA was evaluated in Study 205, in which patients with unresectable advanced or metastatic renal cell carcinoma (RCC) were randomized (1:1:1) to LENVIMA 18 mg orally once daily with everolimus 5 mg orally once daily (n=51), LENVIMA 24 mg orally once daily (n=52), or everolimus 10 mg orally once daily (n=50) [see Clinical Studies ( 14.2 ) ]. This data also includes patients on the dose escalation portion of the study who received LENVIMA with everolimus (n=11). The median treatment duration was 8.1 months for LENVIMA with everolimus. Among 62 patients who received LENVIMA with everolimus, the median age was 61 years, 71% were men, and 98% were White.

The most common adverse reactions observed in the LENVIMA with everolimus-treated group (≥30%) were, in order of decreasing frequency, 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. The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%).

Adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA with everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA with everolimus-treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%).

Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA with everolimus-treated group.

Table 7 presents the adverse reactions in >15% of patients in the LENVIMA with everolimus arm. Study 205 was not designed to demonstrate a statistically significant difference in adverse reaction rates for LENVIMA in combination with everolimus, as compared to everolimus for any specific adverse reaction listed in Table 7.

Table  7 : Adverse Reactions Occurring in >15% of Patients in the LENVIMA with Everolimus Arm in Study 205 (RCC)
	LENVIMA 18 mg with   Everolimus 5 mg N=62		Everolimus 10 mg N=50
Adverse Reactions	Grade 1-4 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
Endocrine
Hypothyroidism	24	0	2	0
Gastrointestinal
Diarrhea	81	19	34	2
Vomiting	48	7	12	0
Nausea	45	5	16	0
Stomatitis/Oral inflammationa	44	2	50	4
Abdominal painb	37	3	8	0
Oral painc	23	2	4	0
Dyspepsia/Gastro-esophageal reflux	21	0	12	0
Constipation	16	0	18	0
General
Fatigued	73	18	40	2
Peripheral edema	42	2	20	0
Pyrexia/Increased body temperature	21	2	10	2
Metabolism and Nutrition
Decreased appetite	53	5	18	0
Decreased weight	34	3	8	0
Musculoskeletal and Connective Tissue
Arthralgia/Myalgiae	55	5	32	0
Musculoskeletal chest pain	18	2	4	0
Nervous System
Headache	19	2	10	2
Psychiatric
Insomnia	16	2	2	0
Renal and Urinary
Proteinuria/Urine protein present	31	8	14	2
Renal failure eventf	18	10	12	2
Respiratory, Thoracic and Mediastinal
Cough	37	0	30	0
Dyspnea/Exertional dyspnea	35	5	28	8
Dysphonia	18	0	4	0
Skin and Subcutaneous Tissue
Rashg	35	0	40	0
Vascular
Hypertension/Increased blood pressure	42	13	10	2
Hemorrhagic eventsh	32	6	26	2
a       Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulceration b       Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain c       Includes gingival pain, glossodynia, and oropharyngeal pain d       Includes asthenia, fatigue, lethargy and malaise e       Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgia f       Includes blood creatinine increased, blood urea increased, creatinine renal clearance decreased, nephropathy toxic, renal failure, renal failure acute, and renal impairment g       Includes erythema, erythematous rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash, and septic rash h       Includes hemorrhagic diarrhea, epistaxis, gastric hemorrhage, hemarthrosis, hematoma, hematuria, hemoptysis, lip hemorrhage, renal hematoma, and scrotal hematocele

In Table 8, Grade 3-4 laboratory abnormalities occurring in ≥3% of patients in the LENVIMA with everolimus arm are presented.

Table  8 : Grade 3-4 Laboratory Abnormalities Occurring in ≥3% of Patients in the LENVIMA with Everolimus Arm a , b   in Study 205 (RCC)
Laboratory Abnormality	LENVIMA 18 mg with   Everolimus 5 mg	Everolimus 10 mg
	Grades 3-4 (%)	Grades 3-4 (%)
Chemistry
Hypertriglyceridemia	18	18
Increased lipase	13	12
Hypercholesterolemia	11	0
Hyponatremia	11	6
Hypophosphatemia	11	6
Hyperkalemia	6	2
Hypocalcemia	6	2
Hypokalemia	6	2
Increased aspartate aminotransferase (AST)	3	0
Increased alanine aminotransferase (ALT)	3	2
Increased alkaline phosphatase	3	0
Hyperglycemia	3	16
Increased creatine kinase	3	4
Hematology
Lymphopenia	10	20
Anemia	8	16
Thrombocytopenia	5	0
a.      With at least 1 grade increase from baseline     b.      Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA with Everolimus (n = 62), Everolimus (n = 50).

Hepatocellular Carcinoma

The safety of LENVIMA was evaluated in REFLECT, which randomized (1:1) patients with unresectable hepatocellular carcinoma (HCC) to LENVIMA (n=476) or sorafenib (n=475) [ see Clinical Studies ( 14.3 ) ]. The dose of LENVIMA was 12 mg orally once daily for patients with a baseline body weight of ≥60 kg and 8 mg orally once daily for patients with a baseline body weight of <60 kg. The dose of sorafenib was 400 mg orally twice daily. Duration of treatment was ≥6 months in 49% and 32% of patients in the LENVIMA and sorafenib groups, respectively. Among the 476 patients who received LENVIMA in REFLECT, the median age was 63 years, 85% were men, 28% were White and 70% were Asian. 

The most common adverse reactions observed in the LENVIMA-treated patients (≥20%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. 

The most common serious adverse reactions (≥2%) in LENVIMA-treated patients were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%).

Adverse reactions led to dose reduction or interruption in 62% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%).

Treatment discontinuation due to adverse reactions occurred in 20% of patients in the LENVIMA-treated group. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). 

Table 9 summarizes the adverse reactions that occurred in ≥10% of patients receiving LENVIMA in REFLECT. REFLECT was not designed to demonstrate a statistically significant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, for any specified adverse reaction listed in Table 9.

Table 9 : Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in REFLECT (HCC)
Adverse Reaction	LENVIMA 8 mg/12 mg N=476		Sorafenib 800 mg N=475
	Grade 1-4 (%)	Grade 3-4 (%)	Grade 1-4 (%)	Grade 3-4 (%)
Endocrine
Hypothyroidisma	21	0	3	0
Gastrointestinal
Diarrhea	39	4	46	4
Abdominal painb	30	3	28	4
Nausea	20	1	14	1
Vomiting	16	1	8	1
Constipation	16	1	11	0
Ascitesc	15	4	11	3
Stomatitisd	11	0.4	14	1
General
Fatiguee	44	7	36	6
Pyrexiaf	15	0	14	0.2
Peripheral edema	14	1	7	0.2
Metabolism and Nutrition
Decreased appetite	34	5	27	1
Decreased weight	31	8	22	3
Musculoskeletal and Connective Tissue
Arthralgia/Myalgiag	31	1	20	2
Nervous System
Headache	10	1	8	0
Renal and Urinary
Proteinuriah	26	6	12	2
Respiratory, Thoracic and Mediastinal
Dysphonia	24	0.2	12	0
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	27	3	52	11
Rashi	14	0	24	2