Table 18: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving TECENTRIQ in IMbrave150
Adverse Reaction
Vascular Disorders Hypertension
TECENTRIQ in combination with Bevacizumab (n = 329)
All Grades2 (%)
30
26 18
Grades 3–42 (%)
15
General Disorders and Administration Site Conditions Fatigue/asthenia1 Pyrexia
2 0
Renal and Urinary Disorders Proteinuria
Investigations Weight Decreased
20 11
Skin and Subcutaneous Tissue Disorders Pruritus Rash
19 12
Gastrointestinal Disorders Diarrhea
Constipation
Abdominal Pain Nausea Vomiting
19 13 12 12 10
Metabolism and Nutrition Disorders Decreased Appetite
Epistaxis
1 Includes fatigue and asthenia 2 Graded per NCI CTCAE v4.0
Table 19: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with HCC Receiving TECENTRIQ in IMbrave150
1 Laboratory Abnormality
Chemistry Increased AST
Increased Alkaline Phosphatase
Increased ALT
Decreased Albumin Decreased Sodium Increased Glucose Decreased Calcium
Decreased Phosphorus Increased Potassium Hypomagnesemia
Hematology Decreased Platelet
Decreased Lymphocytes Decreased Hemoglobin Increased Bilirubin Decreased Leukocyte Decreased Neutrophil
TECENTRIQ in combination with Bevacizumab (n=329)
All Grades1 (%)
86
Grades 3–41 (%)
16 8
Sorafenib (n=156)
All Grades1 (%)
90
70476 62
60 54 48 30 26 23
68 62 58 57 32 23
1.5 13 9
0.3 4.7 1.9
7 13
3.1 8
3.4 2.3
70 54 49 43 35 58 16
63 58 62 59 29 16
measurement available: TECENTRIQ plus bevacizumab (222-323) and sorafenib (90-153) 1
Grades 3–41 (%)
16
4.6 4.6
0.7 9
4.6 1.3 16 2
220220
4.6 11
3.9 14
1.3 1.1
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory Graded per NCI CTCAE v4.0
Melanoma The safety of TECENTRIQ, administered with cobimetinib and vemurafenib was evaluated in IMspire150, a double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma [see Clinical Studies (14.5)]. Patients received TECENTRIQ with cobimetinib and vemurafenib (N=230) or placebo with cobimetinib and vemurafenib (n=281). Among the 230 patients who received TECENTRIQ administered with cobimetinib and vemurafenib, the median duration of exposure to TECENTRIQ was 9.2 months (range: 0-30 months) to cobimetinib was 10.0 months (range: 1-31 months) and to vemurafenib was 9.8 months (range: 1-31 months). Fatal adverse reactions occurred in 3% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. Adverse reactions leading to death were hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest. Serious adverse reactions occurred in 45% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) serious adverse reactions were hepatotoxicity (7%), pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%). Adverse reactions leading to discontinuation of TECENTRIQ occurred in 21% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) adverse reactions leading to TECENTRIQ discontinuation were increased ALT (2.2%) and pneumonitis (2.6%). Adverse reactions leading to interruption of TECENTRIQ occurred in 68% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) adverse reactions leading to TECENTRIQ interruption were pyrexia (14%), increased ALT (13%), hyperthyroidism (10%), increased
Laboratory Abnormality
Hematology Decreased Lymphocytes Decreased Hemoglobin Decreased Platelet
Decreased Neutrophils
Chemistry Increased Creatine Kinase Increased AST Increased ALT
Increased Triacylglycerol Lipase
18
Respiratory, Thoracic and Mediastinal Disorders Cough
12 10
Injury, Poisoning and Procedural Complications Infusion-Related Reaction
11 3 0
0 0
1.8 0 0 0 0
1.2
0 0
2.4
Sorafenib (n=156)
All Grades2 (%)
24
32 10
7 10
10 17
49 14 17 16 8
24 10 4.5 0
Grades 3–42 (%)
12
6 0
0.6 0 0 2.6
5 0 0 0 0
3.8
0 0
0 Adverse Reaction
AST (10%), increased lipase (9%), increased amylase (7%), pneumonitis (5%), increased CPK (4.3%), diarrhea (3.5%), pneumonia (3.5%), asthenia (3%), rash (3%), influenza (3%), arthralgia (2.6%), fatigue (2.2%), dyspnea (2.2%), cough (2.2%), peripheral edema (2.2%), uveitis (2.2%), bronchitis (2.2%), hypothyroidism (2.2%), and respiratory tract infection (2.2%). Tables 20 and 21 summarize the incidence of adverse reactions and laboratory abnormalities in Study IMspire150.
Table 20: Adverse Reactions Occurring in ≥10% of Patients on the TECENTRIQ plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4 TECENTRIQ in IMspire150)
TECENTRIQ in combination with Cobimetinib and Vemurafenib
(n=230)
All Grades (%)
Skin and Subcutaneous Tissue Disorders Rash1
Pruritus Photosensitivity reaction
75 26 21
51 49 26
Grade 3–4 (%)
27 <1 <1
General Disorders and Administration Site Conditions Fatigue2 Pyrexia3 Edema4
3
1.7 <1
Gastrointestinal Disorders Hepatotoxicity5 Nausea
Stomatitis6
Endocrine Disorders Hypothyroidism8 Hyperthyroidism
50 30 23
Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain7
62
22 18
Injury, Poisoning and Procedural Complications Infusion-related reaction9
10
Respiratory, Thoracic and Mediastinal Disorders Pneumonitis10
12
Vascular Disorders Hypertension11
generalised and rash morbilliform 2Includes fatigue, asthenia and malaise 3Includes pyrexia and hyperpyrexia
4 5 17
21 <1 1.3
4.3 0 <1 2.6 1.3 10
Placebo with Cobimetinib and Vemurafenib
(n=281)
All Grades (%)
72 17 25
45 35 21
36 32 15
48
10 8
8 6 18
Grade 3–4 (%)
23 <1 3.2
1.8 2.1 0
13
2.5 <1
3.2
0 0
<1 <1 7
Includes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysaesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme,
rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative
Includes edema peripheral, lymphoedema, oedema, face oedema, eyelid oedema, periorbital oedema, lip oedema and generalised oedema
Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasaemia, bilirubin conjugated increased, hepatocellular
hepatitis fulminant and liver function test abnormal injury, hyperbilirubinaemia, liver function test increased, hepatic
6Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 7
8Includes hypothyroidism and blood thyroid stimulating hormone increased 9Includes infusion related reaction and hypersensitivity 10Includes pneumonitis and interstitial lung disease
11Includes hypertension, blood pressure increased, hypertensive crisis
Clinically important adverse reactions in < 10% of patients who received TECENTRIQ plus cobimetinib and vemurafenib were:
Cardiac Disorders: Arrhythmias, ejection fraction decreased, electrocardiogram QT prolonged Eye Disorders: Uveitis Gastrointestinal disorders: Pancreatitis Infections and infestations: Pneumonia, urinary tract infection Metabolism and nutrition disorders: Hyperglycemia Nervous system Disorders: Dizziness, dysgeusia, syncope Respiratory, thoracic and mediastinal disorders: Dyspnea, oropharyngeal pain Skin and Subcutaneous Tissue Disorders: Vitiligo Table 21: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients
failure,
Includes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness and non-cardiac chest pain
Receiving TECENTRIQ Plus Cobimetinib and Vemurafenib Arm or the Placebo Plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4) in IMspire150
TECENTRIQ in combination with Cobimetinib and Vemurafenib
(n=230)
All Grades (%)
80 77 34 26
88 80 79
75
Grade 3–4 (%)
24
2.6 1.3 2.2
22 13 18
46
Placebo with Cobimetinib and Vemurafenib
(n=281)
All Grades (%)
72 72 24 19
81 68 62
62
Grade 3–4 (%)
17
2.2 0.4 1.5
18 6
12 35
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