Tucatinib (Tukysa) Side Effects
The most common side effects of tucatinib when used with trastuzumab and capecitabine are diarrhea (81%), palmar-plantar erythrodysesthesia syndrome (63%), nausea (58%), and hepatotoxicity (42%), with diarrhea and elevated liver enzymes being the most clinically significant grade 3+ toxicities requiring monitoring and dose modifications. 1
Most Common Side Effects (≥20% incidence)
When tucatinib is combined with trastuzumab and capecitabine in HER2-positive breast cancer patients:
- Diarrhea occurs in 81% of patients (12% grade 3), making it the most frequent adverse event 1, 2
- Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) affects 63% of patients (13% grade 3) 1
- Nausea occurs in 58% of patients (3.7% grade 3) 1
- Hepatotoxicity develops in 42% of patients (9% grade 3) 1
- Vomiting affects 36% of patients (3% grade 3) 1
- Stomatitis (mouth sores) occurs in 32% of patients (2.5% grade 3) 1
- Decreased appetite affects 25% of patients 1
- Anemia occurs in 21% of patients (3.7% grade 3) 1
- Rash develops in 20% of patients 1
Serious Adverse Events Requiring Immediate Attention
Severe Diarrhea
- Can lead to dehydration, acute kidney injury, and death if not managed promptly 1
- Requires antidiarrheal treatment as clinically indicated 1
- May necessitate dose interruption, reduction, or permanent discontinuation based on severity 1
Hepatotoxicity
- Severe liver problems can occur, requiring blood test monitoring 1
- ALT, AST, and bilirubin must be checked before starting tucatinib, every 3 weeks during treatment, and as clinically indicated 1
- Dose modifications or discontinuation may be required based on severity 1
Laboratory Abnormalities (≥20% incidence)
- Decreased hemoglobin: 59% (3.3% grade ≥3) 1
- Decreased phosphate: 57% (8% grade ≥3) 1
- Increased bilirubin: 47% (1.5% grade ≥3) 1
- Increased ALT: 46% (8% grade ≥3) 1
- Increased AST: 43% (6% grade ≥3) 1
- Decreased magnesium: 40% 1
- Decreased potassium: 36% (6% grade ≥3) 1
- Increased creatinine: 33% (reversible, due to inhibition of renal tubular transport without affecting glomerular function) 1
Treatment Discontinuation and Dose Modifications
- 6% of patients discontinued tucatinib due to adverse reactions, with hepatotoxicity (1.5%) and diarrhea (1%) being the most common reasons 1
- 21% of patients required dose reductions, most commonly for hepatotoxicity (8%) and diarrhea (6%) 1
- 26% of patients experienced serious adverse reactions, including diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%) 1
Tolerability Profile from Clinical Trials
The ESO-ESMO guidelines note that tucatinib's increased toxicity—mostly grade 3 diarrhea and elevated aminotransferase levels—did not lead to frequent treatment discontinuation, indicating manageable toxicity with appropriate supportive care 3. The median duration of treatment in the HER2CLIMB trial was 5.8 months, demonstrating that most patients can continue therapy despite these side effects 1.
Fatal Adverse Reactions
Fatal adverse reactions occurred in 2% of patients receiving tucatinib, including sudden death, sepsis, dehydration, and cardiogenic shock 1. This underscores the critical importance of monitoring for severe diarrhea and dehydration.
Special Monitoring Considerations
Creatinine Elevation
- Mean increase in serum creatinine is 32% within the first 21 days of treatment 1
- Elevations persist throughout treatment but are reversible upon completion 1
- Consider alternative markers of renal function if persistent elevations occur, as this represents inhibition of renal tubular transport rather than true kidney injury 1
Fertility Concerns
Tucatinib may cause fertility problems in both males and females, potentially affecting the ability to have children 1. Patients should discuss fertility concerns with their healthcare provider before starting treatment 1.