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Section 6: Adverse Reactions

This article reviews adverse reaction data from two KADCYLA pivotal clinical trials, the EMILIA trial for patients with MBC and the KATHERINE trial for patients with EBC. This includes the potential for hepatotoxicity, left ventricular dysfunction, embryo-fetal toxicity, pulmonary toxicity, infusion-related reactions/hypersensitivity reactions, hemorrhage, thrombocytopenia, and neurotoxicity that are described in greater detail in the Warnings and Precautions section of the Prescribing Information, which was covered in the previous Article.

6.1 Clinical Trial Experience

In clinical trials, KADCYLA has been evaluated as a single agent in 884 patients with HER2+ MBC, which includes patients from the EMILIA trial (n = 490) as well as other trials. The most common (frequency ≥25%) adverse reactions seen in patients treated with KADCYLA were

  • Fatigue
  • Nausea
  • Musculoskeletal pain
  • Hemorrhage
  • Thrombocytopenia
  • Headache
  • Increased transaminases
  • Constipation
  • Epistaxis

The remainder of the adverse reaction information in the KADCLYA Prescribing Information is organized by indication and includes information about the therapeutic regimen, the most common ARs occurring in each trial, and treatment discontinuations in each study. Details on the rates of ARs occurring in ≥10% of KADCYLA-treated patients and selected laboratory abnormalities are also provided. Keep in mind that 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 clinical practice.

Metastatic Breast Cancer (MBC): The EMILIA Trial

In the EMILIA trial, 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.

The most common adverse reactions (≥ 25%) in the EMILIA trial were.

  • Nausea
  • Fatigue
  • Musculoskeletal pain
  • Hemorrhage
  • Thrombocytopenia
  • Increased transaminases
  • Headache
  • Constipation

The most common Grade ≥3 adverse reactions (frequency >2%) were.

  • Thrombocytopenia
  • Increased transaminases
  • Anemia
  • Hypokalemia
  • Peripheral neuropathy
  • Fatigue
  • 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 were allowed for KADCYLA.
  • A total of 32 patients (7%) discontinued KADCYLA due to an adverse reaction, compared to 41 patients (8%) who discontinued lapatinib and 51 patients (10%) who discontinued capecitabine due to an adverse reaction.
    • The most common ARs that led to discontinuation for KADCYLA were thrombocytopenia and increased transaminases.
  • Eighty patients (16%) treated with KADCYLA had ARs leading to dose reduction.
    • The most frequent ARs leading to dose reduction of KADCYLA included thrombocytopenia, increased transaminases, and peripheral neuropathy.
  • Adverse reactions that led to dose delays occurred in 116 (24%) of KADCYLA patients.

Table 3 in the KADCYLA Prescribing Information summarizes adverse reactions that occurred in ≥10% of patients in the KADCYLA arm (n = 490) of the EMILIA trial. Take a moment to review the interactive table below for details on the specific ARs that occurred and the rate of each one, as outlined in the Prescribing Information.

Select each row to learn more.

Adverse Reactions Occurring in ≥10% of Patients on the KADCYLA Treatment Arm in the EMILIA Trial

Adverse Reaction KADCYLA (3.6 mg/kg) n = 490 Lapatinib (1250 mg) + Capecitabine (2000 mg/m2 ) n = 488
All Grades % Grades 3 – 4 % All Grades % Grades 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

Table 4 in the KADCYLA Prescribing Information summarizes data regarding selected laboratory abnormalities occurring in the EMILIA trial. A number of the Grade ≥3 adverse reactions in the EMILIA trial (eg, thrombocytopenia, increased transaminases) manifest as abnormal laboratory test results.

Selected Laboratory Abnormalities in the EMILIA Trial

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: The KATHERINE Trial

Now let's turn our attention to AR data from the KATHERINE trial. Select each of the tabs for more information.

In the KATHERINE trial, patients received either KADCYLA or trastuzumab. KADCYLA was evaluated as a single agent in 740 patients with HER2+ EBC. The median duration of study treatment was 10 months for patients in both study arms.

The most common adverse reactions (≥ 25%) include.

  • Fatigue
  • Nausea
  • Increased transaminases
  • Musculoskeletal pain
  • Hemorrhage
  • Thrombocytopenia
  • Headache
  • Peripheral neuropathy
  • Arthralgia

The most common Grade ≥3 adverse reactions (frequency >2%) were:

  • Thrombocytopenia
  • Hypertension
  • One hundred and ninety (26%) patients experienced Grade >3 adverse reaction in the KADCYLA-treated group compared to 111 (15%) patients in the trastuzumab group.
  • Discontinuations due to an adverse reaction were reported by 133 patients (18%) in KADCYLA group compared to 15 (2.1%) of the trastuzumab group.
  • The most common ARs leading to KADCYLA discontinuation were platelet count decreased, blood bilirubin increased, ejection fraction decreased, AST increased, ALT increased, and peripheral neuropathy.
  • Dose adjustments for KADCYLA were permitted.
  • Dose reductions were reported for 106 (14%) of KADCYLA patients.
    • The most frequent ARs that led to dose reduction included thrombocytopenia, increased transaminases, blood bilirubin, and fatigue.
  • Adverse reactions led to a dose delay in 106 (14%) of KADCYLA patients.
    • The most frequent ARs leading to a dose delay included neutropenia, thrombocytopenia, and AST increased.

The ARs described in Table 5 in the KADCYLA Prescribing Information were identified in patients with HER2-positive early breast cancer treated in the KATHERINE trial. Note that Table 5 summarizes adverse reactions occurring in ≥10% of all patients in the KATHERINE trial, whereas ARs reported for the EMILIA trial occurred in ≥10% of KADCYLA-treated patients.

Select each row in the table below to learn more.

Adverse Reactions Occurring in ≥10% of Patients in the KATHERINE Trial

Adverse Reaction 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

*Included one fatal hemorrhage.

Now take a moment to review selected laboratory abnormality data from the KATHERINE trial, which is presented in Table 6 in the Prescribing Information. Recall that thrombocytopenia, which is indicated by a decreased platelet count, was one of the most common Grade ≥ 3 ARs (> 2%) occurring in KADCYLA-treated patients in the KATHERINE trial.

Selected Laboratory Abnormalities in the KATHERINE Trial

Parameter KADCYLA n = 740 Trastuzumab n = 720
All Grades % Grade 3 (%) Grade 4 (%) All Grades % 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
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

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for an immune response to KADCYLA. A total of 1243 patients from seven clinical trials were tested at multiple time points for anti-drug antibody (ADA) responses to KADCYLA.

  • 5.1% (63/1243) patients tested positive for anti-KADCYLA at one or more post-dose time points
  • 6.4% (24/376) patients tested positive for anti-KADCYLA in clinical studies
  • In EMILIA, 5.2% (24/466) tested positive for anti-KADCYLA, of which 13 were also positive for neutralizing antibodies
  • In KATHERINE, 3.7% (15/401) tested positive for anti-KADCYLA, of which 5 were also positive for neutralizing antibodies
  • No conclusions can be drawn based on the low incidence of ADA across all patient populations

6.3 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.

  • Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with KADCYLA. Patients with significant tumor burden (eg, bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.
Are there any known drug-drug interactions with KADCYLA?

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