KADCYLA SIDE EFFECTS
- Generic Name: ado-trastuzumab emtansine injection for iv use
- Brand Name: Kadcyla
- Drug Class: Antineoplastics, Anti-HER2
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the label:
- Hepatotoxicity.
- Left Ventricular Dysfunction.
- Embryo-Fetal Toxicity.
- Pulmonary Toxicity.
- Infusion-Related Reactions, Hypersensitivity Reactions.
- Hemorrhage.
- Thrombocytopenia.
- Neurotoxicity.
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 in the WARNINGS AND PRECAUTIONS reflect exposure to KADCYLA as a single agent at 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) in 1624 patients including 884 patients with HER2-positive metastatic breast cancer and 740 patients with HER2-positive early breast cancer (KATHERINE trial).
Metastatic Breast Cancer
In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common ( ≥ 25%) adverse reactions were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis.
The adverse reactions described in Table 3 were identified in patients with HER2-positive metastatic breast cancer treated in the EMILIA trial [see Clinical Studies]. Patients were randomized to receive KADCYLA or lapatinib plus capecitabine. The median duration of study treatment was 7.6 months for patients in the KADCYLA-treated group and 5.5 months and 5.3 months for patients treated with lapatinib and capecitabine, respectively.
In the EMILIA trial, 43% of patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 59% of patients in the lapatinib plus capecitabine-treated group.
Dose adjustments for KADCYLA were permitted. Thirty-two patients (7%) discontinued KADCYLA due to an adverse reaction, compared with 41 patients (8%) who discontinued lapatinib, and 51 patients (10%) who discontinued capecitabine due to an adverse reaction. The most common adverse reactions leading to KADCYLA discontinuation were thrombocytopenia and increased transaminases. Eighty patients (16%) treated with KADCYLA had adverse reactions leading to dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, and peripheral neuropathy. Adverse reactions that led to dose delays occurred in 116 (24%) of KADCYLA treated patients. The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases and pyrexia.
Table 1 reports the adverse reactions that occurred in patients in the KADCYLA-treated group (n=490) of the EMILIA trial. Selected laboratory abnormalities are shown in Table 2. The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (frequency > 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.
Table 1 Adverse Reactions Occurring in ≥ 10% of Patients on the KADCYLA Treatment Arm in the EMILIA Trial1
| Adverse Reactions | KADCYLA (3.6 mg/kg) n=490 |
Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 |
||
| All Grades (%) |
Grade 3 – 4 (%) |
All Grades (%) |
Grade 3 – 4 (%) |
|
| Blood and Lymphatic System Disorders | ||||
| Thrombocytopenia | 31 | 15 | 3.3 | 0.4 |
| Anemia | 14 | 4.1 | 11 | 2.5 |
| Gastrointestinal Disorders | ||||
| Nausea | 40 | 0.8 | 45 | 2.5 |
| Constipation | 27 | 0.4 | 11 | 0 |
| Diarrhea | 24 | 1.6 | 80 | 21 |
| Vomiting | 19 | 0.8 | 30 | 4.5 |
| Abdominal pain | 19 | 0.8 | 18 | 1.6 |
| Dry Mouth | 17 | 0 | 4.9 | 0.2 |
| Stomatitis | 14 | 0.2 | 33 | 2.5 |
| General Disorders and Administration | ||||
| Fatigue | 36 | 2.5 | 28 | 3.5 |
| Pyrexia | 19 | 0.2 | 8 | 0.4 |
| Asthenia | 18 | 0.4 | 18 | 1.6 |
| Investigations | ||||
| Transaminases increased | 29 | 8.0 | 14 | 2.5 |
| Metabolism and Nutrition Disorders | ||||
| Hypokalemia | 10 | 2.7 | 9 | 4.7 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Musculoskeletal pain | 36 | 1.8 | 31 | 1.4 |
| Arthralgia | 19 | 0.6 | 8 | 0 |
| Myalgia | 14 | 0.6 | 3.7 | 0 |
| Nervous System Disorders | ||||
| Headache | 28 | 0.8 | 15 | 0.8 |
| Peripheral neuropathy | 21 | 2.2 | 14 | 0.2 |
| Dizziness | 10 | 0.4 | 11 | 0.2 |
| Psychiatric Disorders | ||||
| Insomnia | 12 | 0.4 | 9 | 0.2 |
| Respiratory, Thoracic, and Mediastinal Disorders | ||||
| Epistaxis | 23 | 0.2 | 8 | 0 |
| Cough | 18 | 0.2 | 13 | 0.2 |
| Dyspnea | 12 | 0.8 | 8 | 0.4 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash | 12 | 0 | 28 | 1.8 |
| Vascular Disorders | ||||
| Hemorrhage | 32 | 1.8 | 16 | 0.8 |
| 1 Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Abdominal pain: abdominal pain, abdominal pain upper Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Hypokalemia: hypokalemia, blood potassium decreased Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow). SMQ=standardized MedDRA queries | ||||
The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in EMILIA: dyspepsia (9%), urinary tract infection (9%), chills (8%), dysgeusia (8%), neutropenia (7%), peripheral edema (7%), pruritus (6%), hypertension (5%), blood alkaline phosphatase increased (4.7%), vision blurred (4.5%), conjunctivitis (3.9%), dry eye (3.9%), lacrimation increased (3.3%), drug hypersensitivity (2.2%), left ventricular dysfunction (1.8%), infusion-related reaction (1.4%), pneumonitis (1.2%), nodular regenerative hyperplasia (0.4%), portal hypertension (0.4%).
Table 2: Selected Laboratory Abnormalities (EMILIA)
| Parameter | KADCYLA (3.6 mg/kg) | Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) | ||||
| All Grades (%) |
Grade 3 (%) |
Grade 4 (%) |
All Grades (%) |
Grade 3 (%) |
Grade 4 (%) |
|
| Chemistry | ||||||
| Increased AST | 98 | 7 | 0.5 | 65 | 3 | 0 |
| Increased ALT | 82 | 5 | 0.2 | 54 | 3 | 0 |
| Decreased potassium | 33 | 3 | 0 | 31 | 6 | 0.8 |
| Increased bilirubin | 17 | 0.6 | 0 | 57 | 2 | 0 |
| Hematology | ||||||
| Decreased platelet count | 83 | 14 | 3 | 21 | 0.4 | 0.6 |
| Decreased hemoglobin | 60 | 4 | 1 | 64 | 3 | 0.2 |
| Decreased neutrophils | 39 | 3 | 0.6 | 38 | 6 | 2 |
Early Breast Cancer
KADCYLA has been evaluated as a single-agent in 740 patients with HER2-positive early breast cancer.
The adverse reactions described in Table 5 were identified in patients with HER2-positive early breast cancer treated in the KATHERINE trial. Patients were randomized to receive KADCYLA or trastuzumab. The median duration of study treatment was 10 months for patients in the KADCYLA-treated group and 10 months for patients treated with trastuzumab.
One hundred and ninety (26%) patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 111 (15%) patients in the trastuzumab group. One hundred and thirty-three patients (18%) discontinued KADCYLA due to an adverse reaction, compared with 15 patients (2.1%) who discontinued trastuzumab due to an adverse reaction.
The most common adverse reactions leading to KADCYLA discontinuation (in ≥ 1% of patients) were platelet count decreased, blood bilirubin increased, ejection fraction decreased, AST increased, ALT increased, and peripheral neuropathy.
Dose adjustments for KADCYLA were permitted. One hundred and six patients (14%) treated with KADCYLA had dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, blood bilirubin and fatigue. Adverse reactions that led to dose delays occurred in 106 (14%) of KADCYLA treated patients. The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia and AST increased.
Selected laboratory abnormalities are shown in Table 3. The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia.
The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (> 2%) were thrombocytopenia and hypertension.
Table 3: Adverse Reactions Occurring in ≥ 10% of Patients in the KATHERINE Trial1
| Adverse Reactions | KADCYLA n=740 |
Trastuzumab n=720 |
||
| All grades (%) |
Grade 3 – 4 (%) |
All grades (%) |
Grade 3 – 4 (%) |
|
| Blood and Lymphatic System Disorders | ||||
| Thrombocytopenia | 29 | 6 | 2.4 | 0.3 |
| Anemia | 10 | 1.1 | 9 | 0.1 |
| Gastrointestinal Disorders | ||||
| Nausea | 42 | 0.5 | 13 | 0.3 |
| Constipation | 17 | 0.1 | 8 | 0 |
| Stomatitis | 15 | 0.1 | 8 | 0.1 |
| Vomiting | 15 | 0.5 | 5 | 0.3 |
| Dry Mouth | 14 | 0.1 | 1.3 | 0 |
| Diarrhea | 12 | 0.8 | 13 | 0.3 |
| Abdominal pain | 11 | 0.4 | 7 | 0.3 |
| General Disorders and Administration | ||||
| Fatigue | 50 | 1.1 | 34 | 0.1 |
| Pyrexia | 10 | 0 | 4 | 0 |
| Infections and Infestations | ||||
| Urinary tract infection | 10 | 0.3 | 6 | 0.1 |
| Investigations | ||||
| Transaminases increased | 32 | 1.5 | 8 | 0.4 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Musculoskeletal pain | 30 | 0.7 | 29 | 0.7 |
| Arthralgia | 26 | 0.1 | 21 | 0 |
| Myalgia | 15 | 0.4 | 11 | 0 |
| Nervous System Disorders | ||||
| Headache | 28 | 0 | 17 | 0.1 |
| Peripheral neuropathy | 28 | 1.6 | 14 | 0.1 |
| Dizziness | 10 | 0.1 | 8 | 0.3 |
| Psychiatric Disorders | ||||
| Insomnia | 14 | 0 | 12 | 0.1 |
| Respiratory, Thoracic, and Mediastinal Disorders | ||||
| Epistaxis | 22 | 0 | 3.5 | 0 |
| Cough | 14 | 0.1 | 12 | 0 |
| Vascular Disorders | ||||
| Hemorrhage | 29 | 0.4* | 10 | 0.3 |
| 1 Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Abdominal pain: abdominal pain, abdominal pain upper Urinary Tract Infection: urinary tract infection, cystitis Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow) *Included one fatal hemorrhage. SMQ=standardized MedDRA queries |
||||
The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in KATHERINE: blood alkaline phosphatase increased (8%), dysgeusia (8%), dyspnea (8%), neutropenia (8%), blood bilirubin increased (7%), hypokalemia (7%), pruritus (7%), hypertension (6%), lacrimation increased (6%), chills (5%), dry eye (4.5%), dyspepsia (4.3%), peripheral edema (3.9%),vision blurred (3.9%), conjunctivitis (3.5%), left ventricular dysfunction (3.0%), drug hypersensitivity (2.7%), infusion-related reaction (1.6%), radiation pneumonitis (1.5%), pneumonitis (1.1%), rash (1.1%), asthenia (0.4%), nodular regenerative hyperplasia (0.3%).
Table 4 Selected Laboratory Abnormalities (KATHERINE)
| Parameter | KADCYLA n=740 |
Trastuzumab n=720 |
||||
| All Grade (%) |
Grade 3 (%) |
Grade 4 (%) |
All Grade (%) |
Grade 3 (%) |
Grade 4 (%) |
|
| Chemistry | ||||||
| Increased AST | 79 | 0.8 | 0 | 21 | 0.1 | 0 |
| Increased ALT | 55 | 0.7 | 0 | 21 | 0.1 | 0 |
| Decreased potassium | 26 | 2 | 0.5 | 9 | 0.7 | 0.1 |
| Increased bilirubin | 12 | 0 | 0 | 4 | 0.7 | 0 |
| Hematology | ||||||
| Decreased platelet count | 51 | 4 | 2 | 13 | 0.1 | 0.1 |
| Decreased hemoglobin | 31 | 1 | 0 | 29 | 0.3 | 0 |
| Decreased neutrophils | 24 | 1 | 0 | 19 | 0.6 | 0.6 |
Immunogenicity
As with all therapeutic proteins, there is the potential for an immune response to KADCYLA. A total of 1243 patients from seven clinical studies were tested at multiple time points for anti-drug antibody (ADA) responses to KADCYLA. Following KADCYLA dosing, 5.1% (63/1243) of patients tested positive for anti-KADCYLA antibodies at one or more post-dose time points. In clinical studies, 6.4% (24/376) of patients tested positive for anti-KADCYLA antibodies. In EMILIA, 5.2% (24/466) of patients tested positive for anti-KADCYLA antibodies, of which 13 were also positive for neutralizing antibodies. In KATHERINE, 3.7% (15/401) of patients tested positive for anti-KADCYLA antibodies, of which 5 were also positive for neutralizing antibodies. Due to the low incidence of ADA, conclusions cannot be made on the impact of anti-KADCYLA antibodies on the pharmacokinetics, safety, and efficacy of KADCYLA. The presence of KADCYLA in patient serum at the time of ADA sampling may interfere with the ability of this assay to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to KADCYLA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-KADCYLA antibodies is not yet known.
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of KADCYLA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse Reactions from Observational Studies
- CHF and > 10% reduction in LVEF in patients with HER2-positive metastatic breast cancer with a baseline LVEF of 40-49% treated with KADCYLA.
Adverse Reactions From Postmarketing Spontaneous Reports
- Tumor lysis syndrome (TLS)
- Skin/tissue necrosis after extravasation
SRC: NLM .