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)]

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 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 Arma, b in SELECT (DTC)
Laboratory Abnormality	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 Pembrolizumab (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 Abnormalitya	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 Treated 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 Arma,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
Vascular
Hypertensionj	45	24	31	15
Hemorrhagic eventsk	23	4	15	4
a. Includes hypothyroidism, blood thyroid stimulating hormone increased. b. Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain c. Includes ascites and malignant ascites d. Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering, and stomatitis e. Includes asthenia, fatigue, lethargy and malaise f. Includes increased body temperature, pyrexia g. Includes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, and myalgia h. Includes proteinuria, increased urine protein, protein urine present i. Includes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash and rash j. Includes increased diastolic blood pressure, increased blood pressure, hypertension and orthostatic hypertension k. Includes all hemorrhage terms. Hemorrhage terms that occurred in 5 or more subjects in either treatment group include: epistaxis, hematuria, gingival bleeding, hemoptysis, esophageal varices hemorrhage, hemorrhoidal hemorrhage, mouth hemorrhage, rectal hemorrhage and upper gastrointestinal hemorrhage

In Table 10, Grade 3-4 laboratory abnormalities occurring in ≥2% of patients in the LENVIMA arm in REFLECT (HCC) are presented.

Table 10: Grade 3-4 Laboratory Abnormalities Occurring in ≥2% of Patients in the LENVIMA Arma,b in REFLECT (HCC)
Laboratory Abnormality	LENVIMA (%)	Sorafenib (%)
Chemistry
Increased GGT	17	20
Hyponatremia	15	9
Hyperbilirubinemia	13	10
Increased aspartate aminotransferase (AST)	12	18
Increased alanine aminotransferase (ALT)	8	9
Increased alkaline phosphatase	7	5
Increased lipase	6	17
Hypokalemia	3	4
Hyperkalemia	3	2
Decreased albumin	3	1
Increased creatinine	2	2
Hematology
Thrombocytopenia	10	8
Lymphopenia	8	9
Neutropenia	7	3
Anemia	4	5
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=278 to 470) and sorafenib (n=260 to 473)

Endometrial Carcinoma

The safety of LENVIMA in combination with pembrolizumab was investigated in Study 309, a multicenter, open-label, randomized (1:1), active-controlled trial in 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 [see Clinical Studies (14.4)]. Patients with endometrial carcinoma that are pMMR or not MSI-H received LENVIMA 20 mg orally once daily with pembrolizumab 200 mg intravenously every 3 weeks (n=342); or received doxorubicin or paclitaxel (n= 325).

For patients with pMMR or not MSI-H status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to LENVIMA was 6.7 months (range: 1 day to 26.8 months).

Fatal adverse reactions among these patients occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.

Serious adverse reactions occurred in 50% of these patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%).

Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of these patients. The most common (≥1 %) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%).

Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%).

Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).

Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in patients receiving LENVIMA in Study 309.

Table 11: Adverse Reactions in ≥20% of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC)
	Endometrial Carcinoma (pMMR or not MSI-H)
	LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342		Doxorubicin or Paclitaxel N=325
Adverse Reaction	All Gradesa (%)	Grades 3-4 (%)	All Gradesa (%)	Grades 3-4 (%)
Endocrine
Hypothyroidismb	67	0.9	0.9	0
Vascular
Hypertensionc	67	39	6	2.5
Hemorrhagic eventsd	25	2.6	15	0.9
General
Fatiguee	58	11	54	6
Gastrointestinal
Diarrheaf	55	8	20	2.8
Nausea	49	2.9	47	1.5
Vomiting	37	2.3	21	2.2
Stomatitisg	35	2.6	26	1.2
Abdominal painh	34	2.6	21	1.2
Constipation	27	0	25	0.6
Musculoskeletal and Connective Tissue
Musculoskeletal disordersi	53	5	27	0.6
Metabolism
Decreased appetitej	44	7	21	0
Investigations
Decreased weight	34	10	6	0.3
Renal and Urinary
Proteinuriak	29	6	3.4	0.3
Infections
Urinary tract infectionl	31	5	13	1.2
Nervous System
Headache	26	0.6	9	0.3
Respiratory, Thoracic and Mediastinal
Dysphonia	22	0	0.6	0
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesiam	23	2.9	0.9	0
Rashn	20	2.3	4.9	0
a. Graded per NCI CTCAE v4.03 b. Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, primary hypothyroidism, and secondary hypothyroidism c. Includes hypertension, blood pressure increased, hypertensive crisis, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, and blood pressure fluctuation d. Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, injection site hemorrhage, melena, purpura, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, coital bleeding, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, and vessel puncture site bruise e. Includes fatigue, asthenia, malaise, and lethargy f. Includes diarrhea and gastroenteritis g. Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, and tongue ulceration h. Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, and epigastric discomfort i. Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw j. Includes decreased appetite and early satiety k. Includes proteinuria, protein urine present, hemoglobinuria l. Includes urinary tract infection, cystitis, and pyelonephritis m. Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema, and skin reaction n. Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, and application site rash

Table 12: Laboratory Abnormalities Worsened from Baselinea Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC)
	Endometrial Carcinoma (pMMR or not MSI-H)
	LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342		Doxorubicin or Paclitaxel N=325
Laboratory Testb	All Gradesc (%)	Grades 3-4 (%)	All Gradesc (%)	Grades 3-4 (%)
Chemistry
Hypertriglyceridemia	70	6	45	1.7
Hypoalbuminemia	60	2.7	42	1.6
Increased aspartate aminotransferase	58	9	23	1.6
Hyperglycemia	58	8	45	4.4
Hypomagnesemia	46	0	27	1.3
Increased alanine aminotransferase	55	9	21	1.2
Hypercholesteremia	53	3.2	23	0.7
Hyponatremia	46	15	28	7
Increased alkaline phosphatase	43	4.7	18	0.9
Hypocalcemia	40	4.7	21	1.9
Increased lipase	36	14	13	3.9
Increased creatinine	35	4.7	18	1.9
Hypokalemia	34	10	24	5
Hypophosphatemia	26	8	17	3.2
Increased amylase	25	7	8	1
Hyperkalemia	23	2.4	12	1.2
Increased creatine kinase	19	3.7	7	0
Increased bilirubin	18	3.6	6	1.6
Hematology
Lymphopenia	51	18	66	23
Thrombocytopenia	50	8	30	4.7
Anemia	49	8	84	14
Leukopenia	43	3.5	83	43
Neutropenia	34	8	80	60
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 (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). c. Graded per NCI CTCAE v4.03

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of LENVIMA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal: pancreatitis, increased amylase

General: impaired wound healing

Hepatobiliary: cholecystitis

Renal and Urinary: nephrotic syndrome

Vascular: arterial (including aortic) aneurysms, dissections, and rupture