HER-2 Breast Cancer Chemo Drug

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What are the side effects of Kadcyla?

Hepatotoxicity

Left Ventricular Dysfunction

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 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 3 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 4. 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 3 : 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 4 :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 6. 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 5 : 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 6 : 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.

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