Adverse Drug Reactions (RCC + Pembrolizumab)

The incidence rates of treatment-emergent adverse events observed in clinical studies for RCC in combination with permbrolizumab are presented in table 4 & 5 below.

Events are included as Adverse Drug Reactions (ADRs) based on the incidence rates of treatment emergent adverse events (TEAEs) in the placebo-controlled DTC study together with events from other indications assessed in the context of TEAE incidence rates across study treatment arms, the known pharmacology of lenvatinib and the underlying indication.


RCC 1L Combination With Pembrolizumab

The safety of lenvatinib was evaluated in Study 307, in which patients with advanced renal cell carcinoma (RCC) were randomized (1:1:1) to lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks (n=352), lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340).

The median duration of study treatment was 17.0 months (range 2 days to 39.1 months). The median duration of exposure to lenvatinib was 16.1 months (range 2 days to 39.1 months).

Tables 4 and 5 summarize treatment emergent adverse events and laboratory abnormalities, respectively, in patients receiving lenvatinib in combination with pembrolizumab in Study 307.

Table 4: Treatment Emergent Adverse Events with Frequency ≥10% All Grades or Frequency ≥3% Grade 3 and 4 by System Organ Class and Preferred Term in Study 307 (RCC)
System Organ Class Preferred Term Lenvatinib 20 mg in combination with
Pembrolizumab 200mg
N=352
n (%)
Sunitinib 50 mg
N=340
n (%)
All Grades a Grades 3-4 All Grades a Grades 3-4
General
Fatigue b 63 9 56 8
Pyrexia 15 1 13 0.3
Edema peripheral 12 0.3 10 0.3
Gastrointestinal
Diarrhea c 62 10 50 6
Stomatitis d 43 2 43 2
Nausea 36 3 33 1
Abdominal pain e 27 2 18 1
Vomiting 26 3 20 1
Constipation 25 1 19 0
Dyspepsia 11 0 16 0.3
Dry mouth 10 0 3 0
Musculoskeletal and connective tissue
Musculoskeletal pain f 58 4 41 3
Endocrine
Hypothroidism g 57 1 32 0
Vascular
Hypertension h 56 29 43 20
Hemorrhagic events i 27 5 26 4
Metabolism
Decreased appetite j 41 4 31 1
Hypertriglyceridaemia 12 5 12 6
Skin and Subcutaneous Tissue
Rash k 37 5 17 1
Palmar-plantar erythrodysesthesia syndrome l 29 4 38 4
Pruritus 15 0.3 8 0.3
Investigations
Weight decreased 30 8 9 0.3
Lipase increased 18 13 13 9
Amylase increased 18 9 8 3
Blood creatinine increased 14 1 10 1
Alanine aminotransferase increased 12 4 10 2
Aspartate aminotransferase increased 11 3 11 1
Respiratory, Thoracic and Mediastinal Disorders
Dysphonia 30 0 4 0
Cough 20 0 16 0.3
Dyspnea m 18 3 13 3
Renal and Urinary Disorders
Proteinuria n 30 8 13 3
Nervous System Disorders
Headache 23 1 16 1
Dysgeusia 12 0.3 28 0.3
Blood and lymphatic system disorders
Anemia 12 0.3 28 0.3
Infections and infestations
Nasopharyngitis 11 0.3 7 0
Psychiatric disorders
Insomnia 11 0 6 0
a Graded per NCI CTCAE v4.03
b Includes asthenia, fatigue, lethargy and malaise
c Includes diarrhea and gastroenteritis
d Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral
discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, and stomatitis
e Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal
rigidity, abdominal tenderness, and epigastric discomfort
f 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
g Includes increased blood thyroid stimulating hormone, hypothyroidism, and secondary hypothyroidism
h Includes blood pressure diastolic increased, blood pressure increased, essential hypertension, hypertension,
hypertensive crisis, labile blood pressure, and retinopathy hypertensive
i Includes 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, hematemesis, hematochezia, hematoma, hematuria, hemoptysis, hemorrhage
urinary tract, hemorrhoidal hemorrhage, hemothorax, 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, subarachnoid hemorrhage, subcutaneous hematoma, subdural
hematoma, thrombotic thrombocytopenic purpura, traumatic hematoma, tumor hemorrhage, and upper gastrointestinal
hemorrhage
j Includes decreased appetite and early satiety
k 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
l Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome and plantar erythema
m Includes dyspnea, and dyspnea exertional
n Includes hemoglobinuria, nephrotic syndrome, and proteinuria

 

Table 5: Laboratory Abnormalities in ≥10% (All Grades) or ≥3% (Grades 3-4) of Patients Receiving Lenvatinib plus Pembrolizumab in Study 307 (RCC)
Laboratory Abnormality a Lenvatinib 20 mg in combination with
Pembrolizumab 200mg
N=352
n (%)
Sunitinib 50 mg
N=340
n (%)
Any Grade (%) b, c Grade 3-4 (%) b Any Grade (%) b, c 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 58 7 57 3
Blood glucose increased 55 7 48 3
Increased alanine aminotransferase 52 7 49 4
Blood potassium increased 44 9 28 6
Blood glucose decreased 44 2 27 1
Hyponatremia 41 12 28 9
Blood albumin decreased 34 0.3 22 0
Alkaline phosphatase increased 32 4 32 1
Hypocalcemia 30 2 22 1
Blood phosphorus decreased 29 7 50 8
Blood magnesium decreased 25 2 15 3
Creatine phosphokinase increased 24 6 36 5
Hypermagnesemia 23 2 22 3
Blood calcium increased 21 1 11 1
Blood bilirubin increased 15 1 17 1
Hypokalemia 13 4 7 1
Blood sodium increased 10 0 10 0.3
Hematology
Lymphopenia 54 9 66 15
Platelet count decreased 39 2 73 13
Hemoglobin decreased 38 3 66 8
White blood cells decreased 34 1 77 8
Neutropenia 31 4 72 16
INR increased 17 3 9 1
Hemoglobin increased 16 0.3 7 0.3
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. Lenvatinib/pembrolizumab (n= 343 to 349) and sunitinib (n= 329 to 335).
c Graded per NCI CTCAE v4.03