LENVIMA SIDE EFFECTS

  • Generic Name: lenvatinib capsules
  • Brand Name: Lenvima
  • Drug Class: Antineoplastics, VEGF Inhibitor
Last updated on MDtodate: 10/7/2022

SIDE EFFECTS

The following adverse reactions are discussed elsewhere in the labeling:

  • Hypertension
  • Cardiac Dysfunction
  • Arterial Thromboembolic Events
  • Hepatotoxicity
  • Renal Failure and Impairment
  • Proteinuria
  • Diarrhea
  • Fistula Formation and Gastrointestinal Perforation
  • QT Interval Prolongation
  • Hypocalcemia
  • Reversible Posterior Leukoencephalopathy Syndrome
  • Hemorrhagic Events
  • Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction
  • Impaired Wound Healing
  • Osteonecrosis of the Jaw (ONJ)

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). 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 1 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 1: 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 2.

Table 2: 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. 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 3 and 4 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with LENVIMA and pembrolizumab in CLEAR.

Table 3: Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC)

Adverse Reactions LENVIMA 20 mg in combination with Pembrolizumab 200mg
N=352
Sunitinib 50 mg
N=340
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
Hypertensionh 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
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 gammaglutamyltransferase increased

 

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

Table 4: Laboratory Abnormalities in ≥20% (All Grades) of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC)

Laboratory Abnormalitya LENVIMA 20 mg in combination with Pembrolizumab 200 mg Sunitinib 50 mg
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). 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 5 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 5: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with Everolimus Arm in Study 205 (RCC)

Adverse Reactions LENVIMA 18 mg with Everolimus 5 mg
N=62
Everolimus 10 mg
N=50
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 6, Grade 3-4 laboratory abnormalities occurring in ≥3% of patients in the LENVIMA with everolimus arm are presented.

Table 6: 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). 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 7 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 7: 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 8, Grade 3-4 laboratory abnormalities occurring in ≥2% of patients in the LENVIMA arm in REFLECT (HCC) are presented.

Table 8: Grade 3-4 Laboratory Abnormalities Occurring in ≥2% of Patients in the LENVIMA Arma,b in REFLECT (HCC)

Laboratory Abnormality Lenvatinib (%) 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 . Patients with endometrial carcinoma that are not MSI-H or dMMR 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 not MSI-H or dMMR 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 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in patients receiving LENVIMA in Study 309.

Table 9: Adverse Reactions in ≥20% of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC)

Adverse Reaction LENVIMA 20 mg in combination with Pembrolizumab 200 mg
N=342
Doxorubicin or Paclitaxel
N=325
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 10: 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)

Laboratory Testb Endometrial Carcinoma (not MSI-H or dMMR)
LENVIMA 20 mg in combination with Pembrolizumab 200 mg
N=342
Doxorubicin or Paclitaxel
N=325
All Gradesc (%) Grades 3-4 (%) All Grades(%) 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 53 6 32 3.8
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 1.7
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 50 16 65 20
Thrombocytopenia 50 8 30 4.7
Anemia 49 8 84 14
Leukopenia 43 3.5 83 43
Neutropenia 31 6 76 58
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: 312 to 404 patients) and doxorubicin or paclitaxel (280 to 380).
c Graded per NCI CTCAE v4.03

 

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.

 

SRC: NLM .