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 (%) |
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| 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 | 2 | 19 | 5 |
| 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 |
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| 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 (%) |
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| 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 |
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