Adverse Drug Reactions (RCC + Everolimus)

The incidence rates of treatment-emergent adverse events observed in clinical studies for RCC in combination with everolimus are presented in the table 6 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 2L Combination With Everolimus

A multicenter, randomized, open-label, trial was conducted to determine the safety and efficacy of lenvatinib administered alone or in combination with everolimus in subjects with unresectable, advanced or metastatic RCC. The study consisted of a Phase 1b dose finding and a Phase 2 portion.

The Phase 2 portion enrolled a total of 153 patients with advanced or metastatic renal cell carcinoma (RCC) following 1 prior VEGF-targeted treatment who were randomized to receive the combination of 18 mg lenvatinib plus 5 mg everolimus (n=51), lenvatinib 24 mg (n=52) or everolimus 10 mg (n=50) once daily).

Table 6 presents the incidence rates of treatment-emergent adverse events observed in the RCC study.

All adverse events occurring with a frequency of at least 10% all Grades or 3% Grade 3 or 4.

Table 6 Treatment-Emergent Adverse Events with Frequency >10 All Grades or >3% Grade 3 and 4 by System Organ Class and Preferred Term Safety Analysis in Study 205 (RCC)
System Organ Class
Preferred Term
Lenvatinib 18 mg
+
Everolimus 5 mg
(N=51)
Lenvatinib 24 mg
(N=52)
Everolimus 10 mg
(N=50)
All Grades
(%)
Grades ≥3
(%)
All Grades
(%)
Grades ≥3
(%)
All Grades
(%)
Grades ≥3
(%)
Blood and Lymphatic System Disorders
Anemia 17.6 7.8 7.7 1.9 26 12.012
Thrombocytopenia 1 9.8 5.9 1.9 0 8 0
Endocrine Disorders
Hypothyroidism 23.5 0 36.5 1.9 2 0
Gastrointestinal Disorders
Abdominal pain 2 39.2 3.9 32.7 3.8 8 0
Constipation 11.8 0 36.5 0 18 0
Diarrhea 84.3 19.6 71.2 11.5 34 2
Dyspepsia 11.8 0 11.5 1.9 12 0
Nausea 43.1 5.9 61.5 7.7 16 0
Oral inflammation 2 39.2 0 26.9 1.9 50 4
Oral pain 2 17.6 0 13.5 0 4 0
Vomiting 47.1 7.8 38.5 3.8 12 0
General Disorders and Administration Site Conditions
Asthenia 25.5 3.9 15.4 1.9 6 2
Fatigue 51 11.8 40.4 7.7 32 0
General physical health deterioration 3.9 3.9 0 0 0 0
Edema peripheral 29.4 0 17.3 0 18 0
Pyrexia 21.6 2 9.6 0 10 2
Infections and Infestations
Nasopharyngitis 11.8 0 7.7 0 12 0
Investigations
Blood thyroid stimulating hormone increased 13.7 0 3.8 0 2 0
Lipase Increased 7.8 3.9 11.5 7.7 6 4
Weight decreased 31.4 2 50 5.8 8 0
Metabolism and Nutrition Disorders
Decreased appetite 52.9 5.9 57.7 3.8 18 0
Dehydration 9.8 5.9 1.9 0 2 0
Hypercholesterolaemia 5 35.3 2 11.5 1.9 16 0
Hyperglycemia 15.7 0 5.8 0 24 10
Hypertriglyceridemia 35.3 9.8 13.5 3.8 24 8
Hypocalcaemia 7.8 3.9 5.8 0 4 0
Hypokalemia 13.7 3.9 1.9 1.9 2 0
Musculoskeletal and Connective Tissue Disorders
Arthralgia 29.4 0 25 0 14 0
Back pain 21.6 3.9 21.2 0 14 0
Musculoskeletal chest pain 17.6 2 15.4 3.8 4 0
Pain in extremity 11.8 0 11.5 1.9 6 0
Nervous System Disorders
Headache 17.6 2 26.9 5.8 10 2
Psychiatric Disorders
Confusional state 3.9 3.9 3.8 1.9 0 0
Insomnia 17.6 2 15.4 0 2 0
Renal and Urinary Disorders
Proteinuria 23.5 3.9 30.8 19.2 14 2
Renal failure 6 5.9 5.9 9.6 5.8 2 2
Respiratory, Thoracic and Mediastinal Disorders
Cough 39.2 0 17.2 1.9 30 0
Dysphonia 19.6 0 36.5 0 4 0
Dyspnea 23.5 2 23.1 1.9 22 8
Skin and Subcutaneous Tissue Disorders
Pruritus 13.7 0 5.8 0 14 0
Rash 17.6 0 15.4 0 22 0
Vascular Disorders
Hemorrhagic events 7 33.3 5.9 28.8 1.9 28 2
Hypertension 8 41.2 13.7 48.1 17.3 10 2
1. Includes the following terms: thrombocytopenia, platelet count decreased
2. Includes the following terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain
upper, abdominal tenderness, epigastric discomfort, gastrointestinal pain
3. Includes the following terms: aphthous stomatitis, stomatitis, glossitis, mouth ulceration, mucosal inflammation
4. Includes the following terms: oral pain, glossodynia, oropharyngeal pain
5. Includes the following terms: hypercholesterolemia, blood cholesterol increased
6. Includes the following terms: acute prerenal failure, renal failure, renal failure acute, renal tubular necrosis
7. Includes the following terms: bone contusion, cerebral hemorrhage, contusion, diarrhea hemorrhagic, ecchymosis,
epistaxis, eye contusion, eyelid hematoma, gastric hemorrhage, gastrointestinal hemorrhage, gingival
bleeding, hemarthrosis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhagic disorder,
lip hemorrhage, periorbital contusion, petechiae, renal hematoma, scrotal hematocoele
8. Includes the following terms: hypertension, hypertensive crisis, blood pressure diastolic increased, blood
pressure increased, blood pressure systolic increased