TYKERB SIDE EFFECTS

  • Generic Name: lapatinib
  • Brand Name: Tykerb
  • Drug Class: Antineoplastics EGFR Inhibitors, Antineoplastic Tyrosine Kinase Inhibitors, Antineoplastics, Anti-HER2
Last updated on MDtodate: 10/12/2022

SIDE EFFECTS

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.

HER2-Positive Metastatic Breast Cancer

The safety of TYKERB has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. Adverse reactions, which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm, are shown in Table 1.

The most common adverse reactions (greater than 20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.

The most common Grades 3 and 4 adverse reactions (NCI CTCAE v3.0) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.

Table 1: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients

 

Reactions TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m2/day
(N = 198)
Capecitabine
2,500 mg/m2/day
(N = 191)
All Grades a% Grade 3% Grade 4% All Gradesa % Grade 3% Grade 4%
Gastrointestinal disorders
Diarrhea 65 13 1 40 10 0
Nausea 44 2 0 43 2 0
Vomiting 26 2 0 21 2 0
Stomatitis 14 0 0 11 < 1 0
Dyspepsia 11 < 1 0 3 0 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia 53 12 0 51 14 0
Rashb 28 2 0 14 1 0
Dry skin 10 0 0 6 0 0
General disorders and administration site conditions
Mucosal inflammation 15 0 0 12 2 0
Musculoskeletal and connective tissue disorders
Pain in extremity 12 1 0 7 < 1 0
Back pain 11 1 0 6 < 1 0
Respiratory, thoracic, and mediastinal disorders
Dyspnea 12 3 0 8 2 0
Psychiatric disorders
Insomnia 10 < 1 0 6 0 0
a NCI CTCAE v3.0.
b Grade 3 dermatitis acneiform was reported in less than 1% of patients in the group receiving TYKERB plus capecitabine.

 

Table 2: Selected Laboratory Abnormalities

 

Parameters TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m²/day Capecitabine 2,500 mg/m²/day
All Gradesa% Grade 3% Grade 4% All Gradesa% Grade 3% Grade 4%
Hematologic
Hemoglobin 56 < 1 0 53 1 0
Platelets 18 < 1 0 17 < 1 < 1
Neutrophils 22 3 < 1 31 2 1
Hepatic
Total Bilirubin 45 4 0 30 3 0
AST 49 2 < 1 43 2 0
ALT 37 2 0 33 1 0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
a NCI CTCAE v3.0.

 

Hormone Receptor-Positive, Metastatic Breast Cancer

In a randomized, Phase 3 clinical trial of patients (N = 1286) with hormone receptor-positive, metastatic breast cancer, who had not received chemotherapy for their metastatic disease, patients received letrozole with or without TYKERB. In this trial, the safety profile of TYKERB was consistent with previously reported results from trials of TYKERB in the advanced or metastatic breast cancer population. Adverse reactions, which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 3. Selected laboratory abnormalities are shown in Table 4.

Table 3: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients

 

Reactions TYKERB 1,500 mg/day + Letrozole 2.5 mg/day
(N = 654)
Letrozole 2.5 mg/day
(N = 624)
All Gradesa% Grade 3% Grade 4% All Gradesa% Grade 3% Grade 4%
Gastrointestinal disorders
Diarrhea 64 9 < 1 20 < 1 0
Nausea 31 < 1 0 21 < 1 0
Vomiting 17 1 < 1 11 < 1 < 1
Anorexia 11 < 1 0 9 < 1 0
Skin and subcutaneous tissue disorders
Rashb 44 1 0 13 0 0
Dry skin 13 < 1 0 4 0 0
Alopecia 13 < 1 0 7 0 0
Pruritus 12 < 1 0 9 < 1 0
Nail disorder 11 < 1 0 < 1 0 0
General disorders and administration site conditions
Fatigue 20 2 0 17 < 1 0
Asthenia 12 < 1 0 11 < 1 0
Nervous system disorders
Headache 14 < 1 0 13 < 1 0
Respiratory, thoracic, and mediastinal disorders
Epistaxis 11 < 1 0 2 < 1 0
a NCI CTCAE v3.0.
b In addition to the rash reported under “Skin and subcutaneous tissue disorders”, 3 additional subjects in each treatment arm had rash under “Infections and infestations”; none were Grade 3 or 4.

 

Table 4: Selected Laboratory Abnormalities

 

Hepatic Parameters TYKERB 1,500 mg/day + Letrozole 2.5 mg/day Letrozole 2.5 mg/day
All Gradesa% Grade 3 % Grade 4 % All Gradesa% Grade 3 % Grade 4 %
AST 53 6 0 36 2 < 1
ALT 46 5 < 1 35 1 0
Total Bilirubin 22 < 1 < 1 11 1 < 1
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
NCI CTCAE v3.0.

 

Hormone Receptor-Positive, HER2+ Metastatic Breast Cancer

In another randomized, Phase 3 clinical trial of postmenopausal patients (N = 355) with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) which had progressed after prior trastuzumab-containing chemotherapy and endocrine therapies, patients received TYKERB with trastuzumab and an aromatase inhibitor (AI) (letrozole, exemestane, or anastrozole), TYKERB with an AI, or trastuzumab with an AI. In this trial, the safety profile of the treatment groups was consistent with the known safety of these agents. The most frequent study treatment-related AEs (> 10%) in each of the TYKERB-containing treatment arms were diarrhea, rash, paronychia, nausea, stomatitis, dermatitis acneiform, and decreased appetite, which were infrequent to absent in the trastuzumab treatment arm. The frequency of cardiac AEs (mostly decrease in ejection fraction) was 7% in the TYKERB+trastuzumab+AI group, 2% in the TYKERB+AI group and 3% in the trastuzumab+AI group. Adverse reactions which occurred in at least 10% of patients in the treatment arms are shown in Table 5.

Table 5: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients

 

Reactions TYKERB (1,000 mg) + Trastuzumab + AI
(N = 118)
TYKERB (1,500 mg) + AI
(N = 119)
Trastuzumab + AI
(N = 116)
All Gradesa(%) Grade 3 (%) Grade 4 (%) All Gradesa(%) Grade 3(%) Grade 4 (%) All Gradesa(%) Grade 3 (%) Grade 4 (%)
Gastrointestinal disorders
Diarrhea 69 13 0 51 6 0 9 0 0
Nausea 22 0 0 22 2 0 9 0 0
Stomatitis 17 0 0 13 < 1 0 3 0 0
Vomiting 10 0 0 14 0 0 < 1 < 1 0
Skin and subcutaneous tissue disorders
Rashb 54 0 0 44 3 0 5 0 0
Palmar-plantar erythrodysesthesia 10 0 0 8 < 1 0 < 1 0 0
Alopecia 10 0 0 7 0 0 2 0 0
General disorders and administration site conditions
Fatigue 12 < 1 0 14 2 0 10 0 0
Musculoskeletal and connective tissue disorders
Arthralgia 13 < 1 0 14 0 0 12 0 0
Pain in extremity 7 < 1 0 10 0 0 3 0 0
Respiratory, thoracic, and mediastinal disorders
Cough 8 0 0 8 0 0 15 0 0
Metabolism and nutrition disorders
Decreased appetite 18 0 0 13 0 0 3 0 0
Infections and infestations
Paronychia 30 0 0 15 2 0 0 0 0
Investigations
Alanine aminotransferase increased 7 0 0 15 3 < 1 6 4 0
Aspartate aminotransferase increased 6 0 0 17 5 0 9 4 0
Nervous system disorders
Headache 5 0 0 16 2 0 10 < 1 0
a NCI CTCAE v3.0.
b Includes multiple adverse reaction terms for rash.

 

Decreases In Left Ventricular Ejection Fraction

Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are greater than or equal to Grade 3 (NCI CTCAE v3.0), or a greater than or equal to 20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution’s lower limit of normal. Among 198 patients who received combination treatment with TYKERB/capecitabine, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3.0). Among 654 patients who received combination treatment with TYKERB/letrozole, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions.

Hepatotoxicity

TYKERB has been associated with hepatotoxicity.

Interstitial Lung Disease/Pneumonitis

TYKERB has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TYKERB. 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.

Immune System Disorders

Hypersensitivity reactions, including anaphylaxis.

Skin And Subcutaneous Tissue Disorders

Nail disorders, including paronychia. Severe cutaneous adverse reactions, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), skin fissures.

Cardiac Disorders

Ventricular arrhythmias/Torsades de Pointes (TdP). Electrocardiogram (ECG) QT prolongation.

 

SRC: NLM .