What are the cardiovascular considerations for Tagrisso (osimertinib) therapy?

Cardiovascular Considerations for Tagrisso (Osimertinib) Therapy

Tagrisso requires mandatory baseline and ongoing cardiac monitoring due to significant risks of cardiomyopathy, QTc prolongation, and heart failure, with specific monitoring protocols differing based on whether the drug is used as monotherapy or in combination with chemotherapy. 1

Critical Cardiovascular Risks

Cardiomyopathy and Heart Failure

• Cardiomyopathy occurs in 3.8% of patients on osimertinib monotherapy, with 0.1% fatal cases 1
• When combined with pemetrexed and platinum-based chemotherapy, cardiomyopathy incidence increases to 9%, with 1.1% fatal cases 1
• Left ventricular ejection fraction (LVEF) decline ≥10 percentage points to <50% occurs in 4.2% of patients 1
• Real-world data shows osimertinib-related cardiac dysfunction requiring cardiologic intervention occurs in 3.4% of patients, with overall cardiotoxicity incidence of 4.7% 2
• Recovery of cardiac dysfunction is possible in 82.4% of cases, regardless of whether osimertinib is discontinued 2

QTc Interval Prolongation

• QTc >500 msec occurs in 1.1% of monotherapy patients and 1.8% of combination therapy patients 1
• QTc increase from baseline >60 msec occurs in 4.3% of monotherapy patients and 10.5% of combination therapy patients 1
• Median QTc prolongation of 14 ms (from 437 to 451 ms) has been documented in real-world practice 3

Arrhythmias

• Newly developed arrhythmias, including atrial fibrillation, have been reported in clinical practice 4
• Pre-existing arrhythmia increases risk of grade ≥2 cardiac events 3.9-fold 3

Mandatory Baseline Assessment

For Monotherapy Patients

• Assess LVEF at baseline in patients with cardiac risk factors 1
• Obtain baseline ECG in patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities 1
• Screen for cardiovascular risk factors including hypertension, diabetes, hyperlipidemia, and obesity 3, 4

For Combination Therapy Patients (with Pemetrexed and Platinum-based Chemotherapy)

• Conduct cardiac monitoring including LVEF assessment at baseline in ALL patients, regardless of cardiac risk factors 1
• Obtain baseline ECG and electrolyte panel 1

High-Risk Patient Identification

The following factors independently predict osimertinib-related cardiotoxicity and require heightened surveillance:

• Advanced age (hazard ratio 1.07 per year increase) 2
• History of heart failure (hazard ratio 3.35) 2
• Pre-existing atrial fibrillation (hazard ratio 3.42) 2
• Baseline low left ventricular strain (hazard ratio 0.87) 2
• Higher body mass index (hazard ratio 1.07 per unit increase) 3
• Pre-existing arrhythmia (hazard ratio 3.90) 3

Ongoing Monitoring Protocol

During Treatment

• Conduct periodic ECG and electrolyte monitoring in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those taking QTc-prolonging medications 1
• Perform serial LVEF assessments during treatment for all patients on combination therapy and for monotherapy patients with cardiac risk factors 1
• Assess LVEF immediately in patients who develop cardiac signs or symptoms (dyspnea, chest discomfort, edema, fatigue) 1, 5
• Monitor for signs of fluid retention and heart failure throughout treatment 5

Frequency Considerations

• The 2-year cumulative incidence of grade ≥2 cardiac events is 19.2%, with grade ≥3 events at 8.5% 3
• Median time to cardiotoxicity development is approximately 4 months after osimertinib initiation 6

Management of Cardiovascular Complications

QTc Prolongation

• Permanently discontinue osimertinib if QTc interval prolongation occurs with signs/symptoms of life-threatening arrhythmia 1
• For asymptomatic QTc prolongation, optimize electrolytes and reassess risk-benefit 1

Cardiomyopathy and Heart Failure

• For symptomatic congestive heart failure, permanently discontinue osimertinib 1
• For asymptomatic LVEF decline, initiate guideline-directed medical therapy (GDMT) with beta-blockers, ACE inhibitors/ARBs, and diuretics as appropriate 5
• Consider osimertinib rechallenge after LVEF recovery while continuing GDMT, as successful rechallenge without recurrence has been documented 5
• Treatment with furosemide, carvedilol, and enalapril can lead to cardiac function improvement within 3 weeks of osimertinib withdrawal 6

Prophylactic Strategies

Prophylactic use of guideline-directed medical therapy before initiating osimertinib may reduce the risk of future cardiotoxic events in high-risk patients 5

• This approach is particularly relevant for patients with multiple cardiovascular risk factors 5
• GDMT enables safe continuation of osimertinib even after cardiotoxicity development 5

Critical Contraindications and Precautions

• Clinical trials excluded patients with baseline QTc >470 msec 1
• Patients with pre-existing severe cardiac dysfunction should have careful risk-benefit assessment before osimertinib initiation 4
• Vigilant monitoring is crucial given the long-term nature of osimertinib therapy and increased mortality associated with cardiotoxicity 2