Adverse Drug Reactions (HCC)

The incidence rates of treatment-emergent adverse events observed in clinical studies for HCC are presented in table 7 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.


A multicenter, randomized, open-label study was conducted to determine the safety and efficacy of lenvatinib compared to sorafenib in subjects with unresectable hepatocellular carcinoma (HCC). Subjects were randomized 1:1 to lenvatinib (12 mg [≥ 60 kg BW] or lenvatinib 8 mg [<60 kg BW]) orally, once daily, or sorafenib 400 mg orally, twice daily.

Table 7 presents the incidence rates of treatment emergent adverse events observed in the HCC study and includes all adverse events occurring with a frequency of at least 10% and of at least 3% ≥ CTCAE Grade 3.

Table 7 Treatment Emergent Adverse Events with Frequency ≥10% All Grades or Frequency ≥3% ≥Grade 3 by System Organ Class and Preferred Term in Study 304 (HCC)
System Organ Class Preferred Term HCC Randomized Safety Set Lenvatinib
(N=476)
n (%)
HCC Randomized Safety Set Sorafenib
(N=475)
n (%)
Any Grade Grade ≥3 Any Grade Grade ≥3
Blood and lymphatic system disorders
Thrombocytopenia 1 119 (25.0) 35 (7.4) 86 (18.1) 22 (4.6)
Leukopenia 2 58 (12.2) 13 (2.7) 35 (7.4) 9 (1.9)
Nuetropenia 3 56 (11.8) 21 (4.4) 18 (3.8) 8 (1.7)
Anemia 4 36 (7.6) 16 (3.4) 45 (9.5) 17 (3.6)
Endocrine Disorders
Hypothyroidism 78 (16.4) 0 8 (1.7) 0
Gastrointestinal Disorders
Diarrhoea 184 (38.7) 20 (4.2) 220 (46.3) 20 (4.2)
Abdominal pain 5 143 (30.0) 14 (2.9) 131 (27.6) 18 (3.8)
Nausea 93 (19.5) 4 (0.8) 68 (14.3) 4 (0.8)
Vomiting 77 (16.2) 6 (1.3) 36 (7.6) 5 (1.1)
Constipation 76 (16.0) 3 (0.6) 52 (10.9) 0
Ascites 68 (14.3) 18 (3.8) 44 (9.3) 14 (2.9)
Stomatitis 6 53 (11.1) 2 (0.4) 65 (13.7) 3 (0.6)
General Disorders and Administration Site Conditions
Fatigue 141 (29.6) 18 (3.8) 119 (25.1) 17 (3.6)
Pyrexia 69 (14.5) 0 63 (13.3) 1 (0.2)
Oedema peripheral 66 (13.9) 4 (0.8) 33 (6.9) 1 (0.2)
Asthenia 54 (11.3) 14 (2.9) 48 (10.1) 11 (2.3)
Hepatobiliary Disorders
Hyperbilirubinemia 7 82 (17.2) 37 (7.8) 75 (15.8) 28 (5.9)
Hypoalbunimia 8 57 (12.0) 5 (1.1) 47 (9.9) 2 (0.4)
Hepatic encephalopathy 9 40 (8.4) 26 (5.5) 13 (2.7) 9 (1.9)
Hepatic failure i0 17 (3.6) 17 (3.6) 12 (2.5) 12 (2.5)
Investigations
Weight decreased 147 (30.9) 36 (7.6) 106 (22.3) 14 (2.9)
Aspartate aminotransferase increased 65 (13.7) 24 (5.0) 80 (16.8) 38 (8.0)
Alanine aminotransferase increased 53 (11.1) 16 (3.4) 52 (10.9) 16 (3.4)
Gamma-glutamyltransferase
increased
37 (7.8) 26 (5.5) 26 (5.5) 19 (4.0)
Metabolism and Nutrition Disorders
Decreased appetite 162 (34.0) 22 (4.6) 127 (26.7) 6 (1.3)
Hyponatremia 11 27 (5.7) 23 (4.8) 10 (2.1) 10 (2.1)
Musculoskeletal and Connective Tissue Disorders
Back pain 50 (10.5) 1 (0.2) 331 (6.5) 5 (1.1)
Renal and Urinary Tract Disorders
Proteinuria 117 (24.6) 27 (5.7) 54 (11.4) 8 (1.7)
Respiratory and Mediastinal Disorders
Dysphonia 113 (23.7) 1 (0.2) 57 (12.0) 0
Skin and Subcutaneous Tissue Disorders
Palmar-plantar erythrodysaesthesia
syndrome
128 (26.9) 14 (2.9) 249 (52.4) 54 (11.4)
Vascular Disorders
Hypertension 12 212 (44.5) 112 (23.5) 147 (30.9) 69 (14.5))
Hemorrhagic events 13 117 (24.6) 24 (5.0) 76 (16.0) 22 (4.6)
1 Includes the terms: platelet count decreased, thrombocytopenia.
2 Includes the terms: leukopenia, white blood cell count decreased.
3 Includes the terms: neutropenia, neutrophil count decreased.
4 Includes the terms: anaemia, haemoglobin decreased.
5 Includes the terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, gastrointestinal pain.
6 Includes the terms: aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering, stomatitis.
7 Includes the terms: bilirubin conjugated increased, blood bilirubin increased, hyperbilirubinaemia, jaundice.
8 Includes the terms: blood albumin decreased, hypoalbuminaemia
9 Includes the terms: coma hepatic, encephalopathy, hepatic encephalopathy, metabolic encephalopathy.
10 Includes the terms: acute hepatic failure, chronic hepatic failure, hepatic failure.
11 Includes the terms: blood sodium decreased, hyponatraemia.
12 Includes the terms: blood pressure diastolic increased, blood pressure increased, hypertension, orthostatic hypertension.
13 Includes all terms reported to the MedDRA 19.1 Standard MedDRA Query Haemorrhage terms (excluding laboratory terms) (Narrow scope).