What cardiac side effects can occur with Padcev (enfortumab vedotin‑ejfv) and Keytruda (pembrolizumab), especially when used together?

Cardiac Side Effects of Padcev and Keytruda

Both Padcev (enfortumab vedotin) and Keytruda (pembrolizumab) carry significant cardiac risks, with Keytruda's immune-mediated cardiotoxicity being particularly severe and potentially fatal, while Padcev's cardiac effects are less well-defined but appear less prominent in the safety profile.

Keytruda (Pembrolizumab) Cardiac Toxicity

Primary Cardiac Risks

Keytruda as an immune checkpoint inhibitor causes immune-mediated cardiovascular toxicities that are rare but devastating 1. The FDA label for Keytruda does not prominently feature cardiac toxicity in its primary adverse event listings, but guideline evidence reveals critical concerns 2:

• Incidence: Cardiovascular immune-related adverse events occur in approximately 0.1% of patients on single-agent PD-1 inhibitors, but this increases to 0.28% with combination therapy 1
• Mortality: When cardiac toxicity occurs, mortality is extremely high, frequently due to refractory arrhythmia or cardiogenic shock 1
• Timing: Median onset is 6 weeks, with a range of 2-54 weeks 1

Specific Cardiac Manifestations

The cardiovascular complications include 1:

• Myocarditis (most critical - can be fulminant and life-threatening)
• Pericarditis and pericardial effusions
• Arrhythmias and conduction abnormalities (including heart block and cardiac arrest)
• Impaired ventricular function with heart failure
• Cardiomyopathy and myocardial fibrosis
• Vasculitis
• Venous thromboembolism

Recent pharmacovigilance data confirms pembrolizumab is significantly associated with myocarditis, pericardial disease, heart failure, and atrial fibrillation, with 34.3% of cardiac adverse events ending fatally 3. Meta-analysis demonstrates that immune checkpoint inhibitors increase cardiotoxicity risk by 62% compared to controls (RR=1.62,95% CI 1.18-2.24) 4.

Clinical Presentation Warning Signs

Look specifically for 1:

• Progressive fatigue, myalgia, or weakness
• Palpitations or chest pain
• Presyncope, syncope, or sudden death
• Shortness of breath or peripheral edema
• Critical pitfall: Symptoms often overlap with other immune-related adverse events (myositis, pneumonitis, hypothyroidism) or can be masked by underlying malignancy

Padcev (Enfortumab Vedotin) Cardiac Toxicity

Primary Safety Profile

Padcev's FDA label does not list cardiac toxicity as a prominent adverse event 5. In the pivotal EV-302 trial combining Padcev with pembrolizumab (n=440), the most common adverse reactions were:

• Rash (68%), peripheral neuropathy (67%), fatigue (51%)
• No specific cardiac adverse events listed in the ≥15% frequency table 5

Cardiac Events in Combination Therapy

When reviewing serious adverse reactions in EV-302 5:

• Fatal adverse reactions occurred in 1.9% of patients
• Specific fatal cardiac events included: cardiac arrest (0.7%) and cardiac failure (mentioned but frequency not specified)
• These represent a small fraction of the overall toxicity profile

In the EV-103 trial (Padcev + pembrolizumab in cisplatin-ineligible patients, n=121) 5:

• Fatal adverse reactions in 5% of patients
• No cardiac-specific fatal events prominently listed
• Hypotension occurred as a serious adverse reaction (2.5%)

Real-World Evidence

Recent real-world studies of Padcev plus pembrolizumab show 6, 7, 8, 9:

• No life-threatening toxicity clearly attributable to enfortumab vedotin in platinum-ineligible patients 7
• Cardiac toxicity is not highlighted as a major concern in large registry analyses 9
• The combination is generally well-tolerated even in elderly and comorbid populations

Combined Therapy Considerations

When Padcev and Keytruda are used together, the cardiac risk is primarily driven by pembrolizumab's immune-mediated cardiotoxicity 1, 5. The combination does not appear to synergistically increase cardiac risk beyond what is expected from pembrolizumab alone, based on available safety data 5, 6.

Risk Stratification

Higher risk patients include 1:

• Those receiving combination immune checkpoint inhibitor therapy (0.28% vs 0.06% for monotherapy)
• Patients with pre-existing cardiac disease
• Those developing concurrent immune-related adverse events (myositis, pneumonitis)

Monitoring Algorithm

For patients on Padcev plus Keytruda, implement 1:

1. Baseline assessment: History focusing on cardiac symptoms, physical examination, consider baseline ECG and troponin in high-risk patients
2. During treatment: Serial monitoring for:
   • New fatigue, weakness, or myalgia (may indicate myocarditis/myositis overlap)
   • Chest pain, palpitations, dyspnea
   • Peripheral edema or exercise intolerance
3. If symptoms develop:
   • Immediate ECG, troponin, BNP
   • Echocardiogram to assess ventricular function
   • Consider cardiology consultation urgently
   • Hold both agents immediately if myocarditis suspected

Management of Cardiac Toxicity

If immune-mediated cardiotoxicity occurs 1:

• Permanent discontinuation of pembrolizumab for Grade 2 or higher cardiac toxicity
• High-dose corticosteroids (methylprednisolone 1-2 mg/kg/day or equivalent)
• Intensive care monitoring for severe cases
• Consider additional immunosuppression (mycophenolate, infliximab, IVIG) for refractory cases
• Supportive cardiac care per standard guidelines

Critical Pitfalls to Avoid

1. Do not dismiss vague fatigue or weakness - these may be early myocarditis symptoms that rapidly progress to cardiogenic shock 1, 10
2. Do not attribute all symptoms to cancer progression - maintain high suspicion for immune-mediated cardiac toxicity throughout treatment 1
3. Do not delay workup - cardiac immune-related adverse events can be fulminant and fatal within days 10
4. Do not restart pembrolizumab after cardiac toxicity - rechallenge is contraindicated due to high mortality risk 1