Weakness After Enfortumab and Pembrolizumab: Likely Causes
The patient's weakness after morning infusion of enfortumab vedotin and pembrolizumab is most likely due to either an infusion reaction (occurring during or shortly after infusion) or immune-related adrenal insufficiency (if weakness is more persistent and accompanied by other systemic symptoms).
Primary Differential Diagnosis
1. Infusion Reaction (Most Common if Acute)
Pembrolizumab causes infusion reactions in approximately 3% of patients, presenting with pyrexia and chills 11. These reactions typically occur during or within hours of infusion and manifest as:
- Generalized weakness/fatigue
- Fever
- Chills
- Flushing
Management approach 1:
- Grade 1-2 (mild weakness, able to perform activities): Symptomatic treatment, consider premedication with antipyretics and antihistamines for future infusions
- Grade 3-4 (severe weakness, unable to perform daily activities): Permanently discontinue pembrolizumab
2. Immune-Related Adrenal Insufficiency (If Persistent Weakness)
This is a critical diagnosis not to miss. Immune checkpoint inhibitors like pembrolizumab can cause adrenal insufficiency, presenting with:
- Profound weakness/fatigue
- Nausea
- Hypotension
- Hyponatremia
- Inability to perform daily activities
Immediate diagnostic workup required 2:
- Morning cortisol level
- ACTH level
- Electrolytes (looking for hyponatremia)
- TSH and free T4
Management based on severity 2:
Mild symptoms (G1): Consider holding immunotherapy, start prednisone 5-10 mg daily or hydrocortisone 10-20 mg morning/5-10 mg afternoon, endocrine consultation
Moderate symptoms (G2): Hold immunotherapy, start stress-dose steroids (prednisone 20 mg daily or hydrocortisone 20-30 mg morning/10-20 mg afternoon), taper over 5-10 days to maintenance
Severe symptoms (G3-4): Emergency department referral, IV normal saline (at least 2L), IV hydrocortisone 100 mg or dexamethasone 4 mg, hold immunotherapy until stabilized
3. Drug-Specific Toxicities
Common adverse effects from the combination 3:
- Fatigue (very common with enfortumab vedotin-pembrolizumab combination)
- Rash
- Nausea
- Decreased appetite
- Diarrhea
The FDA label specifically lists "feeling tired" and "weakness" as common side effects when pembrolizumab is given with enfortumab vedotin 3.
Clinical Algorithm for Evaluation
Immediate assessment:
Vital signs: Check blood pressure (hypotension suggests adrenal crisis), temperature (fever suggests infusion reaction), heart rate
Timing:
- Weakness during/within 1-2 hours of infusion → Infusion reaction
- Weakness developing hours to days later → Consider adrenal insufficiency or cumulative drug toxicity
Associated symptoms:
- Fever, chills, flushing → Infusion reaction
- Nausea, dizziness, confusion, abdominal pain → Adrenal insufficiency
- Rash, peripheral neuropathy → Drug-specific toxicity
Laboratory evaluation:
- Morning cortisol and ACTH (before 9 AM if possible)
- Complete metabolic panel (sodium, glucose)
- Complete blood count
- Thyroid function tests
Critical Pitfalls to Avoid
- Do not dismiss weakness as "expected fatigue" without ruling out adrenal insufficiency—this can be life-threatening 2
- Always start corticosteroids several days before thyroid hormone replacement if treating hypophysitis to prevent precipitating adrenal crisis 2
- For suspected adrenal crisis, use dexamethasone 4 mg IV if diagnosis uncertain and stimulation testing will be needed (doesn't interfere with cortisol assay) 2
- All patients on chronic corticosteroids need education on stress dosing and medical alert bracelet 2
Specific to This Drug Combination
Recent case reports document severe toxicities with enfortumab vedotin-pembrolizumab including rapidly progressive interstitial pneumonitis 4 and severe esophagitis 5. While these don't typically present as isolated weakness, they underscore that this combination can cause serious immune-related adverse events requiring prompt recognition and aggressive management with high-dose corticosteroids.