TECENTRIQ SIDE EFFECTS
- Generic Name: atezolizumab injection
- Brand Name: Tecentriq
- Drug Class: PD-1PD-L1 Inhibitors
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as a single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and four open-label, single arm studies (PCD4989g, IMvigor210, BIRCH, FIR) which enrolled 524 patients with metastatic urothelial carcinoma, 1636 patients with metastatic NSCLC, and 456 patients with other tumor types. TECENTRIQ was administered at a dose of 1200 mg intravenously every 3 weeks in all studies except PCD4989g. Among the 2616 patients who received a single-agent TECENTRIQ, 36% were exposed for longer than 6 months and 20% were exposed for longer than 12 months. Using the dataset described for patients who received TECENTRIQ as a single-agent, the most common adverse reactions in ≥ 20% of patients were fatigue/asthenia (48%), decreased appetite (25%), nausea (24%), cough (22%), and dyspnea (22%).
In addition, the data reflect exposure to TECENTRIQ in combination with other antineoplastic drugs in 2421 patients with NSCLC (N = 2223) or SCLC (N = 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133. Among the 2421 patients, 53% were exposed to TECENTRIQ for longer than 6 months and 29% were exposed to TECENTRIQ for longer than 12 months. Among the 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with other antineoplastic drugs, the most commonadverse reactions in ≥20% of patients were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%) and decreased appetite (27%).
The data also reflect exposure to TECENTRIQ administered in combination with cobimetinib and vemurafenib in 230 patients enrolled in IMspire150. Among the 230 patients, 62% were exposed to TECENTRIQ for longer than 6 months and 42% were exposed to TECENTRIQ for longer than 12 months.
Urothelial Carcinoma
Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma
The safety of TECENTRIQ was evaluated in IMvigor210 (Cohort 1), a multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. Patients received TECENTRIQ 1200 mg intravenously every 3 weeks until either unacceptable toxicity or disease progression. The median duration of exposure was 15 weeks (0 to 87 weeks).
Five patients (4.2%) who were treated with TECENTRIQ experienced one of the following events which led to death: sepsis, cardiac arrest, myocardial infarction, respiratory failure, or respiratory distress. One additional patient (0.8%) was experiencing herpetic meningoencephalitis and disease progression at the time of death.
Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (≥ 2%) were diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure.
TECENTRIQ was discontinued for adverse reactions in 4.2% of patients. The adverse reactions leading to discontinuation were diarrhea/colitis (1.7%), fatigue (0.8%), hypersensitivity (0.8%), and dyspnea (0.8%).
Adverse reactions leading to interruption occurred in 35% of patients; the most common (≥ 1%) were intestinal obstruction, fatigue, diarrhea, urinary tract infection, infusion-related reaction, cough, abdominal pain, peripheral edema, pyrexia, respiratory tract infection, upper respiratory tract infection, creatinine increase, decreased appetite, hyponatremia, back pain, pruritus, and venous thromboembolism.
Tables 1 and 2 summarize the adverse reactions and Grades 3–4 selected laboratory abnormalities, respectively, in patients who received TECENTRIQ in IMvigor210 (Cohort 1).
Table 1: Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)
| Adverse Reaction | TECENTRIQ N = 119 |
|
| All Grades (%) |
Grades 3–4 (%) |
|
| General | ||
| Fatigue1 | 52 | 8 |
| Peripheral edema2 | 17 | 2 |
| Pyrexia | 14 | 0.8 |
| Gastrointestinal | ||
| Diarrhea3 | 24 | 5 |
| Nausea | 22 | 2 |
| Vomiting | 16 | 0.8 |
| Constipation | 15 | 2 |
| Abdominal pain4 | 15 | 0.8 |
| Metabolism and Nutrition | ||
| Decreased appetite5 | 24 | 3 |
| Musculoskeletal and Connective Tissue | ||
| Back/Neck pain | 18 | 3 |
| Arthralgia | 13 | 0 |
| Skin and Subcutaneous Tissue | ||
| Pruritus | 18 | 0.8 |
| Rash6 | 17 | 0.8 |
| Infections | ||
| Urinary tract infection7 | 17 | 5 |
| Respiratory, Thoracic, and Mediastinal | ||
| Cough8 | 14 | 0 |
| Dyspnea9 | 12 | 0 |
| 1 Includes fatigue, asthenia, lethargy, and malaise 2 Includes edema peripheral, scrotal edema, lymphedema, and edema 3 Includes diarrhea, colitis, frequent bowel movements, autoimmune colitis 4 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and flank pain 5 Includes decreased appetite and early satiety 6 Includes rash, dermatitis, dermatitis acneiform, rash maculo-papular, rash erythematous, rash pruritic, rash macular, and rash papular 7 Includes urinary tract infection, urinary tract infection bacterial, cystitis, and urosepsis 8 Includes cough and productive cough 9 Includes dyspnea and exertional dyspnea |
||
Table 2: Grades 3–4 Laboratory Abnormalities in ≥ 1% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)
| Laboratory Abnormality | Grades 3–4 (%) |
| Chemistry | |
| Hyponatremia | 15 |
| Hyperglycemia | 10 |
| Increased Alkaline Phosphatase | 7 |
| Increased Creatinine | 5 |
| Hypophosphatemia | 4 |
| Increased ALT | 4 |
| Increased AST | 4 |
| Hyperkalemia | 3 |
| Hypermagnesemia | 3 |
| Hyperbilirubinemia | 3 |
| Hematology | |
| Lymphopenia | 9 |
| Anemia | 7 |
| Graded per NCI CTCAE v4.0. | |
Non-Small Cell Lung Cancer (NSCLC)
IMpower110
The safety of TECENTRIQ was evaluated in IMpower110, a multicenter, international, randomized, open-label study in 549 chemotherapy-naïve patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations. Patients received TECENTRIQ 1200 mg every 3 weeks (n=286) or platinum-based chemotherapy consisting of carboplatin or cisplatin with either pemetrexed or gemcitabine (n=263) until disease progression or unacceptable toxicity. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells [TC] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 1% of the tumor area). The median duration of exposure to TECENTRIQ was 5.3 months (0 to 33 months).
Fatal adverse reactions occurred in 3.8% of patients receiving TECENTRIQ; these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infarction, and device occlusion (1 patient each).
Serious adverse reactions occurred in 28% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%).
TECENTRIQ was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (≥2 patients) leading to TECENTRIQ discontinuation were peripheral neuropathy and pneumonitis.
Adverse reactions leading to interruption of TECENTRIQ occurred in 26% of patients; the most common (>1%) were ALT increased (2.1%), AST increased (2.1%), pneumonitis (2.1%), pyrexia (1.4%), pneumonia (1.4%) and upper respiratory tract infection (1.4%).
Tables 3 and 4 summarize adverse reactions and selected laboratory abnormalities in patients receiving TECENTRIQ in IMpower110.
Table 3: Adverse Reactions Occurring in ≥10% of Patients with NSCLC Receiving TECENTRIQ in IMpower110
| Adverse Reaction | TECENTRIQ N = 286 |
Platinum -Based Chemotherapy N = 263 |
||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Gastrointestinal | ||||
| Nausea | 14 | 0.3 | 34 | 1.9 |
| Constipation | 12 | 1.0 | 22 | 0.8 |
| Diarrhea | 11 | 0 | 12 | 0.8 |
| General | ||||
| Fatigue/asthenia | 25 | 1.4 | 34 | 4.2 |
| Pyrexia | 14 | 0 | 9 | 0.4 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 15 | 0.7 | 19 | 0 |
| Respiratory, Thoracic and Mediastinal | ||||
| Dyspnea | 14 | 0.7 | 10 | 0 |
| Cough | 12 | 0.3 | 10 | 0 |
| Graded per NCI CTCAE v4.0 | ||||
Table 4: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower110
| Laboratory Abnormality | TECENTRIQ | Platinum-Based Chemotherapy | ||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Hematology | ||||
| Anemia | 69 | 1.8 | 94 | 20 |
| Lymphopenia | 47 | 9 | 59 | 17 |
| Chemistry | ||||
| Hypoalbuminemia | 48 | 0.4 | 39 | 2 |
| Increased alkaline phosphatase | 46 | 2.5 | 42 | 1.2 |
| Hyponatremia | 44 | 9 | 36 | 7 |
| Increased ALT | 38 | 3.2 | 32 | 0.8 |
| Increased AST | 36 | 3.2 | 32 | 0.8 |
| Hyperkalemia | 29 | 3.9 | 36 | 2.7 |
| Hypocalcemia | 24 | 1.4 | 24 | 2.7 |
| Increased blood creatinine | 24 | 0.7 | 33 | 1.5 |
| Hypophosphatemia | 23 | 3.6 | 21 | 2 |
| Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: TECENTRIQ (range: 278-281); platinum-based chemotherapy (range: 256-260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range. | ||||
IMpower150
The safety of TECENTRIQ with bevacizumab, paclitaxel and carboplatin was evaluated in IMpower150, a multicenter, international, randomized, open-label trial in which 393 chemotherapy-naïve patients with metastatic non-squamous NSCLC received TECENTRIQ 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC 6 mg/mL/min intravenously every 3 weeks for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg with bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 8.3 months in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin.
Fatal adverse reactions occurred in 6% of patients receiving TECENTRIQ; these included hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, death, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction and aortic dissection.
Serious adverse reactions occurred in 44%. The most frequent serious adverse reactions (>2%) were febrile neutropenia, pneumonia, diarrhea, and hemoptysis.
TECENTRIQ was discontinued due to adverse reactions in 15% of patients; the most common adverse reaction leading to discontinuation was pneumonitis (1.8%).
Adverse reactions leading to interruption of TECENTRIQ occurred in 48%; the most common (>1%) were neutropenia, thrombocytopenia, fatigue/asthenia, diarrhea, hypothyroidism, anemia, pneumonia, pyrexia, hyperthyroidism, febrile neutropenia, increased ALT, dyspnea, dehydration and proteinuria.
Tables 5 and 6 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin in IMpower150.
Table 5: Adverse Reactions Occurring in ≥15% of Patients with NSCLC Receiving TECENTRIQ in IMpower150
| Adverse Reaction | TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin N = 393 |
Bevacizumab, Paclitaxel and Carboplatin N = 394 |
||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Nervous System | ||||
| Neuropathy1 | 56 | 3 | 47 | 3 |
| Headache | 16 | 0.8 | 13 | 0 |
| General | ||||
| Fatigue/Asthenia | 50 | 6 | 46 | 6 |
| Pyrexia | 19 | 0.3 | 9 | 0.5 |
| Skin and Subcutaneous Tissue | ||||
| Alopecia | 48 | 0 | 46 | 0 |
| Rash2 | 23 | 2 | 10 | 0.3 |
| Musculoskeletal and Connective Tissue | ||||
| Myalgia/Pain3 | 42 | 3 | 34 | 2 |
| Arthralgia | 26 | 1 | 22 | 1 |
| Gastrointestinal | ||||
| Nausea | 39 | 4 | 32 | 2 |
| Diarrhea4 | 33 | 6 | 25 | 0.5 |
| Constipation | 30 | 0.3 | 23 | 0.3 |
| Vomiting | 19 | 2 | 18 | 1 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 29 | 4 | 21 | 0.8 |
| Vascular | ||||
| Hypertension | 25 | 9 | 22 | 8 |
| Respiratory | ||||
| Cough | 20 | 0.8 | 19 | 0.3 |
| Epistaxis | 17 | 1 | 22 | 0.3 |
| Renal | ||||
| Proteinuria5 | 16 | 3 | 15 | 3 |
| Graded per NCI CTCAE v4.0 1 Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paraesthesia, dysesthesia, polyneuropathy 2 Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform 3 Includes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain 4 Includes diarrhea, gastroenteritis, colitis, enterocolitis 5 Data based on Preferred Terms since laboratory data for proteinuria were not systematically collected |
||||
Table 6: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in IMpower150
| Laboratory Abnormality | TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin | Bevacizumab, Paclitaxel and Carboplatin | ||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Hematology | ||||
| Anemia | 83 | 10 | 83 | 9 |
| Neutropenia | 52 | 31 | 45 | 26 |
| Lymphopenia | 48 | 17 | 38 | 13 |
| Chemistry | ||||
| Hyperglycemia | 61 | 0 | 60 | 0 |
| Increased BUN | 52 | NA1 | 44 | NA1 |
| Hypomagnesemia | 42 | 2 | 36 | 1 |
| Hypoalbuminemia | 40 | 3 | 31 | 2 |
| Increased AST | 40 | 4 | 28 | 0.8 |
| Hyponatremia | 38 | 10 | 36 | 9 |
| Increased Alkaline Phosphatase | 37 | 2 | 32 | 1 |
| Increased ALT | 37 | 6 | 28 | 0.5 |
| Increased TSH | 30 | NA1 | 20 | NA1 |
| Hyperkalemia | 28 | 3 | 25 | 2 |
| Increased Creatinine | 28 | 1 | 19 | 2 |
| Hypocalcemia | 26 | 3 | 21 | 3 |
| Hypophosphatemia | 25 | 4 | 18 | 4 |
| Hypokalemia | 23 | 7 | 14 | 4 |
| Hyperphosphatemia | 25 | NA1 | 19 | NA1 |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with bevacizumab, paclitaxel, and carboplatin range: 337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0 1 NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities |
||||
IMpower130
The safety of TECENTRIQ with paclitaxel protein-bound and carboplatin was evaluated in IMpower130, a multicenter, international, randomized, open-label trial in which 473 chemotherapy-naïve patients with metastatic non-squamous NSCLC received TECENTRIQ 1200 mg and carboplatin AUC 6 mg/mL/min intravenously on Day 1 and paclitaxel protein-bound 100 mg/m2 intravenously on Day 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Among patients receiving TECENTRIQ, 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year.
Fatal adverse reactions occurred in 5.3% of patients receiving TECENTRIQ; these included pneumonia (1.1%), pulmonary embolism (0.8%), myocardial infarction (0.6%), cardiac arrest (0.4%), pneumonitis (0.4%) and sepsis, septic shock, staphylococcal sepsis, aspiration, respiratory distress, cardiorespiratory arrest, ventricular tachycardia, death (not otherwise specified), and hepatic cirrhosis (0.2% each).
Serious adverse reactions occurred in 51% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (≥2%) were pneumonia (6%), diarrhea (3%), lung infection (3%), pulmonary embolism (3%), chronic obstructive pulmonary disease exacerbation (2.5%), dyspnea (2.3%), and febrile neutropenia (1.9%).
TECENTRIQ was discontinued due to adverse reactions in 13% of patients; the most common adverse reactions leading to discontinuation were pneumonia (0.8%), pulmonary embolism (0.8%), fatigue (0.6%), dyspnea (0.6%), pneumonitis (0.6%), neutropenia (0.4%), nausea (0.4%), renal failure (0.4%), cardiac arrest (0.4%), and septic shock (0.4%).
Adverse reactions leading to interruption of TECENTRIQ occurred in 62% of patients; the most common (>1%) were neutropenia, thrombocytopenia, anemia, diarrhea, fatigue/asthenia, pneumonia, dyspnea, pneumonitis, pyrexia, nausea, acute kidney injury, vomiting, pulmonary embolism, arthralgia, infusion-related reaction, abdominal pain, chronic obstructive pulmonary disease exacerbation, dehydration, and hypokalemia.
Tables 7 and 8 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with paclitaxel protein-bound and carboplatin in IMpower130.
Table 7: Adverse Reactions Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in IMpower130
| Adverse Reaction | TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin N = 473 |
Paclitaxel Protein-Bound and Carboplatin N = 232 |
||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| General | ||||
| Fatigue/Asthenia | 61 | 11 | 60 | 8 |
| Gastrointestinal | ||||
| Nausea | 50 | 3.4 | 46 | 2.2 |
| Diarrhea1 | 43 | 6 | 32 | 6 |
| Constipation | 36 | 1.1 | 31 | 0 |
| Vomiting | 27 | 2.7 | 19 | 2.2 |
| Musculoskeletal and Connective Tissue | ||||
| Myalgia/Pain2 | 38 | 3 | 22 | 0.4 |
| Nervous System | ||||
| Neuropathy3 | 33 | 2.5 | 28 | 2.2 |
| Respiratory, Thoracic and Mediastinal | ||||
| Dyspnea4 | 32 | 4.9 | 25 | 1.3 |
| Cough | 27 | 0.6 | 17 | 0 |
| Skin and Subcutaneous Tissue | ||||
| Alopecia | 32 | 0 | 27 | 0 |
| Rash5 | 20 | 0.6 | 11 | 0.9 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 30 | 2.1 | 26 | 2.2 |
| Graded per NCI CTCAE v4.0 1 Includes diarrhea, colitis, and gastroenteritis 2 Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 3 Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 4 Includes dyspnea, dyspnea exertional and wheezing 5 Includes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular. |
||||
Table 8: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower130
| Laboratory Abnormality | TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin N = 473 |
Paclitaxel Protein-Bound and Carboplatin N = 232 |
||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Hematology | ||||
| Anemia | 92 | 33 | 87 | 25 |
| Neutropenia | 75 | 50 | 67 | 39 |
| Thrombocytopenia | 73 | 19 | 59 | 13 |
| Lymphopenia | 71 | 23 | 61 | 16 |
| Chemistry | ||||
| Hyperglycemia | 75 | 8 | 66 | 8 |
| Hypomagnesemia | 50 | 3.4 | 42 | 3.2 |
| Hyponatremia | 37 | 9 | 28 | 7 |
| Hypoalbuminemia | 35 | 1.3 | 31 | 0 |
| Increased ALT | 31 | 2.8 | 24 | 3.9 |
| Hypocalcemia | 31 | 2.6 | 27 | 1.8 |
| Hypophosphatemia | 29 | 6 | 20 | 3.2 |
| Increased AST | 28 | 2.2 | 24 | 1.8 |
| Increased TSH | 26 | NA1 | 5 | NA1 |
| Hypokalemia | 26 | 6 | 24 | 4.4 |
| Increased Alkaline Phosphatase | 25 | 2.6 | 22 | 1.3 |
| Increased Blood Creatinine | 23 | 2.8 | 16 | 0.4 |
| Hyperphosphatemia | 21 | NA1 | 13 | NA1 |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with paclitaxel protein-bound and carboplatin (range: 423 -467); paclitaxel protein-bound and carboplatin (range: 218 -229). Graded per NCI CTCAE v4.0. 1 NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities |
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Previously Treated Metastatic NSCLC
The safety of TECENTRIQ was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. A total of 609 patients received TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n=578) 75 mg/m2 intravenously every 3 weeks until unacceptable toxicity or disease progression. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids. The median duration of exposure was 3.4 months (0 to 26 months) in TECENTRIQ-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients.
The study population characteristics were: median age of 63 years (25 to 85 years), 46% age 65 years or older, 62% male, 71% White, 20% Asian, 68% former smoker, 16% current smoker, and 63% had ECOG performance status of 1.
Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure.
Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (>1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection.
TECENTRIQ was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to TECENTRIQ discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of TECENTRIQ occurred in 25% of patients; the most common (>1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain.
Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in OAK.
Table 9: Adverse Reactions Occurring in ≥10% of Patients with NSCLC Receiving TECENTRIQ in OAK
| Adverse Reaction | TECENTRIQ N = 609 |
Docetaxel N = 578 |
||
| All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
| General | ||||
| Fatigue/Asthenia1 | 44 | 4 | 53 | 6 |
| Pyrexia | 18 | <1 | 13 | <1 |
| Respiratory | ||||
| Cough2 | 26 | <1 | 21 | <1 |
| Dyspnea | 22 | 2.8 | 21 | 2.6 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 23 | <1 | 24 | 1.6 |
| Musculoskeletal | ||||
| Myalgia/Pain3 | 20 | 1.3 | 20 | <1 |
| Arthralgia | 12 | 0.5 | 10 | 0.2 |
| Gastrointestinal | ||||
| Nausea | 18 | <1 | 23 | <1 |
| Constipation | 18 | <1 | 14 | <1 |
| Diarrhea | 16 | <1 | 24 | 2 |
| Skin | ||||
| Rash4 | 12 | <1 | 10 | 0 |
| Graded per NCI CTCAE v4.0 1 Includes fatigue and asthenia 2 Includes cough and exertional cough 3 Includes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia 4 Includes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid |
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Table 10: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in OAK
| Laboratory Abnormality | TECENTRIQ | Docetaxel | ||
| All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
| Hematology | ||||
| Anemia | 67 | 3 | 82 | 7 |
| Lymphocytopenia | 49 | 14 | 60 | 21 |
| Chemistry | ||||
| Hypoalbuminemia | 48 | 4 | 50 | 3 |
| Hyponatremia | 42 | 7 | 31 | 6 |
| Increased Alkaline Phosphatase | 39 | 2 | 25 | 1 |
| Increased AST | 31 | 3 | 16 | 0.5 |
| Increased ALT | 27 | 3 | 14 | 0.5 |
| Hypophosphatemia | 27 | 5 | 23 | 4 |
| Hypomagnesemia | 26 | 1 | 21 | 1 |
| Increased Creatinine | 23 | 2 | 16 | 1 |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 546−585) and docetaxel (range: 532−560). Graded according to NCI CTCAE version 4.0 | ||||
Metastatic Triple Negative Breast Cancer (TNBC)
The safety of TECENTRIQ in combination with paclitaxel protein-bound was evaluated in IMpassion130, a multicenter, international, randomized, double-blinded placebo-controlled trial in patients with locally advanced or metastatic TNBC who have not received prior chemotherapy for metastatic disease. Patients received TECENTRIQ 840 mg (n=452) or placebo (n=438) intravenously followed by paclitaxel protein-bound (100 mg/m2) intravenously. For each 28 day cycle, TECENTRIQ was administered on days 1 and 15 and paclitaxel protein-bound was administered on days 1, 8, and 15 until disease progression or unacceptable toxicity. In the safety-evaluable population, the median duration of exposure to TECENTRIQ was 5.5 months (range: 0-32 months) and paclitaxel protein-bound was 5.1 months (range: 0-31.5 months) in the TECENTRIQ and paclitaxel protein-bound arm. The median duration of exposure to placebo was 5.1 months (range: 0-25.1 months) and paclitaxel protein-bound was 5.0 months (range: 0-23.7 months) in the placebo and paclitaxel protein-bound arm.
Fatal adverse reactions occurred in 1.3% of patients in the TECENTRIQ and paclitaxel protein-bound arm; these included septic shock, mucosal inflammation, auto-immune hepatitis, aspiration, pneumonia, pulmonary embolism.
Serious adverse reactions occurred in 23% of patients. The most frequent serious adverse reactions were pneumonia (2%), urinary tract infection (1%), dyspnea (1%), and pyrexia (1%).
Adverse reactions leading to discontinuation of TECENTRIQ occurred in 6% (29/452) of patients in the TECENTRIQ and paclitaxel protein-bound arm. The most common adverse reaction leading to TECENTRIQ discontinuation was peripheral neuropathy (<1%).
Adverse reactions leading to interruption of TECENTRIQ occurred in 31% of patients; the most common (≥ 2%) were neutropenia, neutrophil count decreased, hyperthyroidism, and pyrexia.
Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 13% (59/452) of patients in the TECENTRIQ and paclitaxel protein-bound arm.
Tables 11 and 12 summarize adverse reactions and selected laboratory abnormalities worsening from baseline in the TECENTRIQ treated patients.
Table 11: Adverse Reactions Occurring in ≥10% of Patients with TNBC in IMpassion130
| Adverse Reaction | TECENTRIQ with Paclitaxel Protein-Bound N = 452 |
Placebo with Paclitaxel Protein-Bound N = 438 |
||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Skin and Subcutaneous Tissue | ||||
| Alopecia | 56 | <1 | 58 | <1 |
| Rash | 17 | <1 | 16 | <1 |
| Pruritus | 14 | 0 | 10 | 0 |
| Nervous System | ||||
| Peripheral neuropathies1 | 47 | 9 | 44 | 5 |
| Headache | 23 | <1 | 22 | <1 |
| Dysgeusia | 14 | 0 | 14 | 0 |
| Dizziness | 14 | 0 | 11 | 0 |
| General | ||||
| Fatigue | 47 | 4 | 45 | 3.4 |
| Pyrexia | 19 | <1 | 11 | 0 |
| Peripheral Edema | 15 | <1 | 16 | 1.4 |
| Asthenia | 12 | <1 | 11 | <1 |
| Gastrointestinal | ||||
| Nausea | 46 | 1.1 | 38 | 1.8 |
| Diarrhea | 33 | 1.3 | 34 | 2.1 |
| Constipation | 25 | <1 | 25 | <1 |
| Vomiting | 20 | <1 | 17 | 1.1 |
| Abdominal pain | 10 | <1 | 12 | <1 |
| Respiratory, Thoracic, and Mediastinal | ||||
| Cough | 25 | 0 | 19 | 0 |
| Dyspnea | 16 | <1 | 15 | <1 |
| Metabolism and Nutrition | ||||
| Decreased Appetite | 20 | <1 | 18 | <1 |
| Musculoskeletal and Connective Tissue | ||||
| Arthralgia | 18 | <1 | 16 | <1 |
| Back pain | 15 | 1.3 | 13 | <1 |
| Myalgia | 14 | <1 | 15 | <1 |
| Pain in extremity | 11 | <1 | 10 | <1 |
| Endocrine | ||||
| Hypothyroidism | 14 | 0 | 3.4 | 0 |
| Infections | ||||
| Urinary tract infection | 12 | <1 | 11 | <1 |
| Upper respiratory tract infection | 11 | 1.1 | 9 | 0 |
| Nasopharyngitis | 11 | 0 | 8 | 0 |
| Graded per NCI CTCAE v4.0 1 Includes peripheral neuropathy, peripheral sensory neuropathy, paresthesia, and polyneuropathy |
||||
Table 12: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with TNBC in IMpassion130
| Laboratory Abnormality | TECENTRIQ with Paclitaxel Protein-Bound | Placebo in combination with Paclitaxel Protein-Bound | ||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Hematology | ||||
| Decreased Hemoglobin | 79 | 3.8 | 73 | 3 |
| Decreased Leukocytes | 76 | 14 | 71 | 9 |
| Decreased Neutrophils | 58 | 13 | 54 | 13 |
| Decreased Lymphocytes | 54 | 13 | 47 | 8 |
| Increased Prothrombin INR | 25 | <1 | 25 | <1 |
| Chemistry | ||||
| Increased ALT | 43 | 6 | 34 | 2.7 |
| Increased AST | 42 | 4.9 | 34 | 3.4 |
| Decreased Calcium | 28 | 1.1 | 26 | <1 |
| Decreased Sodium | 27 | 4.2 | 25 | 2.7 |
| Decreased Albumin | 27 | <1 | 25 | <1 |
| Increased Alkaline Phosphatase | 25 | 3.3 | 22 | 2.7 |
| Decreased Phosphate | 22 | 3.6 | 19 | 3.7 |
| Increased Creatinine | 21 | <1 | 16 | <1 |
| Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: TECENTRIQ with paclitaxel protein-bound (range: 316-452); placebo with paclitaxel protein-bound (range: 299-438). Graded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for Grade 1 events (NCI CTCAE v5.0). | ||||
Small Cell Lung Cancer (SCLC)
The safety of TECENTRIQ with carboplatin and etoposide was evaluated in IMpower133, a randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ESSCLC received TECENTRIQ 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m2 intravenously on Days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by TECENTRIQ 1200 mg every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies]. Among 198 patients receiving TECENTRIQ, 32% were exposed for 6 months or longer and 12% were exposed for 12 months or longer.
Fatal adverse reactions occurred in 2% of patients receiving TECENTRIQ. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each).
Serious adverse reactions occurred in 37% of patients receiving TECENTRIQ. Serious adverse reactions in >2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%).
TECENTRIQ was discontinued due to adverse reactions in 11% of patients. The most frequent adverse reaction requiring permanent discontinuation in >2% of patients was infusion-related reactions (2.5%).
Adverse reactions leading to interruption of TECENTRIQ occurred in 59% of patients; the most common (>1%) were neutropenia (22%), anemia (9%), leukopenia (7%), thrombocytopenia (5%), fatigue (4.0%), infusion-related reaction (3.5%), pneumonia (2.0%), febrile neutropenia (1.5%), increased ALT (1.5%), and nausea (1.5%).
Tables 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with carboplatin and etoposide in IMpower133.
Table 13 : Adverse Reactions Occurring in ≥20% of Patients with SCLC Receiving TECENTRIQ in IMpower133
| Adverse Reaction | TECENTRIQ with Carboplatin and Etoposide N = 198 |
Placebo with Carboplatin and Etoposide N = 196 |
||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| General | ||||
| Fatigue/asthenia | 39 | 5 | 33 | 3 |
| Gastrointestinal | ||||
| Nausea | 38 | 1 | 33 | 1 |
| Constipation | 26 | 1 | 30 | 1 |
| Vomiting | 20 | 2 | 17 | 3 |
| Skin and Subcutaneous Tissue | ||||
| Alopecia | 37 | 0 | 35 | 0 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 27 | 1 | 18 | 0 |
| Graded per NCI CTCAE v4.0 | ||||
Table 14: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with SCLC Receiving TECENTRIQ in IMpower133
| Laboratory Abnormality | TECENTRIQ with Carboplatin and Etoposide | Placebo with Carboplatin and Etoposide | ||
| All Grades (%) |
Grades 3–4 (%) |
All Grades (%) |
Grades 3–4 (%) |
|
| Hematology | ||||
| Anemia | 94 | 17 | 93 | 19 |
| Neutropenia | 73 | 45 | 76 | 48 |
| Thrombocytopenia | 58 | 20 | 53 | 17 |
| Lymphopenia | 46 | 14 | 38 | 11 |
| Chemistry | ||||
| Hyperglycemia | 67 | 10 | 65 | 8 |
| Increased Alkaline Phosphatase | 38 | 1 | 35 | 2 |
| Hyponatremia | 34 | 15 | 33 | 11 |
| Hypoalbuminemia | 32 | 1 | 30 | 0 |
| Decreased TSH2 | 28 | NA1 | 15 | NA1 |
| Hypomagnesemia | 31 | 5 | 35 | 6 |
| Hypocalcemia | 26 | 3 | 28 | 5 |
| Increased ALT | 26 | 3 | 31 | 1 |
| Increased AST | 22 | 1 | 21 | 2 |
| Increased Blood Creatinine | 22 | 4 | 15 | 1 |
| Hyperphosphatemia | 21 | NA1 | 23 | NA1 |
| Increased TSH2 | 21 | NA1 | 7 | NA1 |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 181-193); Placebo (range: 181-196). Graded per NCI CTCAE v4.0 1 NA = Not applicable. 2 TSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories. |
||||
Hepatocellular Carcinoma (HCC)
The safety of TECENTRIQ in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment. Patients received 1,200 mg of TECENTRIQ intravenously followed by 15 mg/kg bevacizumab (n=329) every 3 weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 7.4 months (range: 0-16 months) and to bevacizumab was 6.9 months (range: 0-16 months).
Fatal adverse reactions occurred in 4.6% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%).
Serious adverse reactions occurred in 38% of patients in the TECENTRIQ and bevacizumab arm. The most frequent serious adverse reactions (≥ 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%).
Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to TECENTRIQ discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%).
Adverse reactions leading to interruption of TECENTRIQ occurred in 41% of patients in the TECENTRIQ and bevacizumab arm; the most common (≥ 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatase (8%); infections (6%); gastrointestinal hemorrhages (3.6%); thrombocytopenia/decreased platelet count (3.6%); hyperthyroidism (2.7%); and pyrexia (2.1%).
Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 12% of patients in the TECENTRIQ and bevacizumab arm.
Tables 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ and bevacizumab in IMbrave150.
Table 15: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving TECENTRIQ in IMbrave150
| Adverse Reaction | TECENTRIQ in combination with Bevacizumab (n = 329) |
Sorafenib (n=156) |
||
| All Grades2 (%) |
Grades 3–42 (%) |
All Grades2 (%) |
Grades 3–42 (%) |
|
| Vascular Disorders | ||||
| Hypertension | 30 | 15 | 24 | 12 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue/asthenia1 | 26 | 2 | 32 | 6 |
| Pyrexia | 18 | 0 | 10 | 0 |
| Renal and Urinary Disorders | ||||
| Proteinuria | 20 | 3 | 7 | 0.6 |
| Investigations | ||||
| Weight Decreased | 11 | 0 | 10 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Pruritus | 19 | 0 | 10 | 0 |
| Rash | 12 | 0 | 17 | 2.6 |
| Gastrointestinal Disorders | ||||
| Diarrhea | 19 | 1.8 | 49 | 5 |
| Constipation | 13 | 0 | 14 | 0 |
| Abdominal Pain | 12 | 0 | 17 | 0 |
| Nausea | 12 | 0 | 16 | 0 |
| Vomiting | 10 | 0 | 8 | 0 |
| Metabolism and Nutrition Disorders | ||||
| Decreased Appetite | 18 | 1.2 | 24 | 3.8 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 12 | 0 | 10 | 0 |
| Epistaxis | 10 | 0 | 4.5 | 0 |
| Injury, Poisoning and Procedural Complications | ||||
| Infusion-Related Reaction | 11 | 2.4 | 0 | 0 |
| 1 Includes fatigue and asthenia 2 Graded per NCI CTCAE v4.0 |
||||
Table 16: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with HCC Receiving TECENTRIQ in IMbrave150
| Laboratory Abnormality | TECENTRIQ in combination with Bevacizumab (n = 329) |
Sorafenib (n=156) |
||
| All Grades1 (%) |
Grades 3–41 (%) |
All Grades1 (%) |
Grades 3–41 (%) |
|
| Chemistry | ||||
| Increased AST | 86 | 16 | 90 | 16 |
| Increased Alkaline Phosphatase | 70 | 4 | 76 | 4.6 |
| Increased ALT | 62 | 8 | 70 | 4.6 |
| Decreased Albumin | 60 | 1.5 | 54 | 0.7 |
| Decreased Sodium | 54 | 13 | 49 | 9 |
| Increased Glucose | 48 | 9 | 43 | 4.6 |
| Decreased Calcium | 30 | 0.3 | 35 | 1.3 |
| Decreased Phosphorus | 26 | 4.7 | 58 | 16 |
| Increased Potassium | 23 | 1.9 | 16 | 2 |
| Hypomagnesemia | 22 | 0 | 22 | 0 |
| Hematology | ||||
| Decreased Platelet | 68 | 7 | 63 | 4.6 |
| Decreased Lymphocytes | 62 | 13 | 58 | 11 |
| Decreased Hemoglobin | 58 | 3.1 | 62 | 3.9 |
| Increased Bilirubin | 57 | 8 | 59 | 14 |
| Decreased Leukocyte | 32 | 3.4 | 29 | 1.3 |
| Decreased Neutrophil | 23 | 2.3 | 16 | 1.1 |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ plus bevacizumab (222-323) and sorafenib (90-153) 1 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. 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 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 17 and 18 summarize the incidence of adverse reactions and laboratory abnormalities in Study IMspire150.
Table 17: 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)
| Adverse Reaction | TECENTRIQ in combination with Cobimetinib and Vemurafenib (n=230) |
Placebo with Cobimetinib and Vemurafenib (n=281) |
||
| All Grades (%) |
Grade 3–4 (%) |
All Grades (%) |
Grade 3–4 (%) |
|
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash 1 | 75 | 27 | 72 | 23 |
| Pruritus | 26 | <1 | 17 | <1 |
| Photosensitivity reaction | 21 | <1 | 25 | 3.2 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue 2 | 51 | 3 | 45 | 1.8 |
| Pyrexia 3 | 49 | 1.7 | 35 | 2.1 |
| Edema 4 | 26 | <1 | 21 | 0 |
| Gastrointestinal Disorders | ||||
| Hepatotoxicity 5 | 50 | 21 | 36 | 13 |
| Nausea | 30 | <1 | 32 | 2.5 |
| Stomatitis 6 | 23 | 1.3 | 15 | <1 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Musculoskeletal pain 7 | 62 | 4.3 | 48 | 3.2 |
| Endocrine Disorders | ||||
| Hypothyroidism 8 | 22 | 0 | 10 | 0 |
| Hyperthyroidism | 18 | <1 | 8 | 0 |
| Injury, Poisoning and Procedural Complications | ||||
| Infusion-related reaction 9 | 10 | 2.6 | 8 | <1 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Pneumonitis 10 | 12 | 1.3 | 6 | <1 |
| Vascular Disorders | ||||
| Hypertension 11 | 17 | 10 | 18 | 7 |
| 1 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 generalised and rash morbilliform 2 Includes fatigue, asthenia and malaise 3 Includes pyrexia and hyperpyrexia 4 Includes edema peripheral, lymphoedema, oedema, face oedema, eyelid oedema, periorbital oedema, lip oedema and generalised oedema 5 Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasaemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinaemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal 6 Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 7 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 8 Includes hypothyroidism and blood thyroid stimulating hormone increased 9 Includes infusion related reaction and hypersensitivity 10 Includes pneumonitis and interstitial lung disease 11 Includes 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 18: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients 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
| Laboratory Abnormality | TECENTRIQ in combination with Cobimetinib and Vemurafenib (n=230) |
Placebo with Cobimetinib and Vemurafenib (n=281) |
||
| All Grades (%) |
Grade 3–4 (%) |
All Grades (%) |
Grade 3–4 (%) |
|
| Hematology | ||||
| Decreased Lymphocytes | 80 | 24 | 72 | 17 |
| Decreased Hemoglobin | 77 | 2.6 | 72 | 2.2 |
| Decreased Platelet | 34 | 1.3 | 24 | 0.4 |
| Decreased Neutrophils | 26 | 2.2 | 19 | 1.5 |
| Chemistry | ||||
| Increased Creatine Kinase | 88 | 22 | 81 | 18 |
| Increased AST | 80 | 13 | 68 | 6 |
| Increased ALT | 79 | 18 | 62 | 12 |
| Increased Triacylglycerol Lipase | 75 | 46 | 62 | 35 |
| Increased Alkaline Phosphatase | 73 | 6 | 63 | 2.9 |
| Decreased Phosphorus | 67 | 22 | 64 | 14 |
| Increased Amylase | 51 | 13 | 45 | 13 |
| Increased Blood Urea Nitrogen | 47 | NA1 | 37 | NA1 |
| Decreased Albumin | 43 | 0.9 | 34 | 1.5 |
| Increased Bilirubin | 42 | 3.1 | 33 | 0.7 |
| Decreased Calcium | 41 | 1.3 | 28 | 0 |
| Decreased Sodium | 40 | 5 | 34 | 7 |
| Decreased Thyroid-Stimulating Hormone | 38 | NA1 | 23 | NA1 |
| Increased Thyroid-Stimulating Hormone 2 | 37 | NA1 | 33 | NA1 |
| Decreased Potassium | 36 | 5 | 22 | 4.3 |
| Increased Triiodothyronine | 33 | NA1 | 18 | NA1 |
| Increased Free Thyroxine | 32 | NA1 | 21 | NA1 |
| Decreased Total Triiodothyronine | 32 | NA1 | 8 | NA1 |
| Increased Potassium | 29 | 1.3 | 19 | 1.4 |
| Decreased Triiodothyronine | 27 | NA1 | 21 | NA1 |
| Increased Sodium | 20 | 0 | 13 | 0.4 |
| Graded per NCI CTCAE v4.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230). 1 NA= Not applicable. NCI CTCAE v4.0 does not include these laboratories. 2 Increased Thyroid Stimulating Hormone has a difference <5% (All Grades) between arms and is included for clinical completeness. |
||||
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to atezolizumab in the studies described above with the incidence of antibodies in other studies or to other products may be misleading.
Among 565 patients with NSCLC in OAK, 30% tested positive for treatment-emergent anti-drug antibodies (ADA) at one or more post-dose time points. The median onset time to ADA formation was 3 weeks. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposure. Exploratory analyses showed that the subset of patients who were ADA positive by week 4 (21%; 118/560) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
Among 111 patients in IMvigor210 (Cohort 1), 48% tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposures. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
Among 364 ADA-evaluable patients with NSCLC who received TECENTRIQ with bevacizumab, paclitaxel and carboplatin in IMpower150, 36% (n=132) tested positive for treatment-emergent ADA at one or more post-dose time points and 83% of these 132 patients tested ADA positive prior to receiving the second dose of atezolizumab. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA negative. The presence of ADA did not increase the incidence or severity of adverse reactions.
Among 434 patients with TNBC in IMpassion130, 13% tested positive for treatment-emergent ADA at one or more post-dose time points. Among 178 patients in PD-L1 positive subgroup with TNBC in IMpassion130, 12% tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had decreased systemic atezolizumab exposure. There are insufficient numbers of patients in the PD-L1 positive subgroup with ADA to determine whether ADA alters the efficacy of atezolizumab. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
Among 315 ADA-evaluable patients with HCC who received TECENTRIQ and bevacizumab in IMbrave150, 28% (n=88) tested positive for treatment-emergent ADA at one or more post-dose time points and 66% (58/88) of these 88 patients tested ADA-positive prior to receiving the third dose of TECENTRIQ. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA-negative. Exploratory analyses showed that the subset of patients who were ADA-positive by week 6 (20%; 58/288) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 6; .The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
Among 218 ADA-evaluable patients with melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib in IMspire150, 13% (n=29) tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had decreased systemic atezolizumab exposure.There are insufficient numbers of patients with positive ADA to determine whether ADA alters the efficacy or incidence or severity of adverse reactions.
SRC: NLM .