How is neuropathy from Keytruda (pembrolizumab) managed?

Management of Neuropathy from Keytruda (Pembrolizumab)

For immune checkpoint inhibitor-induced neuropathy from Keytruda (pembrolizumab), treatment should be based on severity grading, with corticosteroids as the mainstay of therapy for moderate to severe cases, while permanently discontinuing the medication for grade 3-4 toxicity.

Clinical Presentation and Evaluation

Neuropathy from pembrolizumab (Keytruda) can present in various forms:

• Peripheral sensorimotor neuropathy (most common)
• Cranial neuropathies
• Guillain-Barré syndrome (GBS)-like presentations
• Autonomic neuropathy
• Neuronopathy affecting dorsal root ganglia

Initial Assessment Should Include:

• Grading severity according to CTCAE criteria
• Neurological examination focusing on:
  • Sensory deficits (numbness, paresthesia, pain)
  • Motor weakness
  • Reflexes (often hyporeflexic)
  • Cranial nerve function
  • Autonomic symptoms

Diagnostic Workup:

• Electrodiagnostic studies (NCS and EMG)
• MRI of brain/spine if indicated
• Lumbar puncture (CSF analysis may show lymphocytic picture unlike typical GBS)
• Serum studies to exclude other causes:
  • Paraneoplastic antibodies (e.g., ANNA-1)
  • Anti-ganglioside antibodies
  • Metabolic workup (B12, folate, TSH)

Management Algorithm Based on Severity

Grade 1 (Mild symptoms, no interference with function):

• Low threshold to hold pembrolizumab
• Monitor symptoms closely for one week
• Resume if symptoms remain stable or improve
• Consider symptomatic treatment for neuropathic pain:
  • Gabapentin (300-1200 mg TID)
  • Pregabalin (100 mg TID)
  • Duloxetine (60-120 mg daily)

Grade 2 (Moderate symptoms, some interference with ADLs):

• Hold pembrolizumab
• Neurology consultation
• Initiate prednisone 0.5-1 mg/kg/day
• Resume pembrolizumab only after return to Grade 1
• Add neuropathic pain medications as above

Grade 3-4 (Severe symptoms, limiting self-care or life-threatening):

• Permanently discontinue pembrolizumab 1
• Admit patient to hospital
• Urgent neurology consultation
• Initiate high-dose IV methylprednisolone 2-4 mg/kg/day
• For GBS-like presentations:
  • Add IVIG (0.4 g/kg/day for 5 days) or plasmapheresis
  • Consider pulse steroid dosing (methylprednisolone 1g daily for 5 days)
  • Taper steroids over 4-6 weeks after acute management
• Monitor for respiratory compromise with pulmonary function tests
• Frequent neurological checks

Special Considerations

For GBS-like Presentations:

• Admission to inpatient unit with capability for ICU transfer
• Monitor for autonomic dysfunction
• Assess respiratory function (NIF or VC)
• Early initiation of IVIG or plasmapheresis is critical 1

For Cranial Neuropathies:

• These should be managed as at least moderate (Grade 2) severity
• Case reports show good response to IVIG in isolated cranial neuropathies 2

For Painful Neuropathy:

• First-line medications:
  • Gabapentin (300-1200 mg TID)
  • Pregabalin (100 mg TID)
  • Duloxetine (60-120 mg daily)
• Second-line options:
  • Tricyclic antidepressants (nortriptyline 25-75 mg at bedtime)
  • Topical agents (capsaicin cream 0.025-0.075% TID-QID) 1

Prognosis and Follow-up

• Early recognition and treatment improve outcomes
• Response to treatment is variable
• Some cases may require prolonged immunosuppression
• Interestingly, patients who develop immune-related adverse events often have favorable tumor responses 3
• Rechallenging with pembrolizumab should be approached with extreme caution in severe cases, and generally avoided in grade 3-4 toxicity 1

Important Caveats

• Unlike idiopathic GBS, corticosteroids are beneficial in immune checkpoint inhibitor-induced neuropathy 4
• Case reports suggest higher mortality in patients who did not receive steroid therapy 4
• Pembrolizumab-induced neuropathies may have different CSF and electrophysiological patterns compared to classic GBS
• Multiple domains of the peripheral nervous system may be affected simultaneously or sequentially 5
• The combination of ipilimumab and nivolumab has higher neurotoxicity rates (14%) than pembrolizumab alone 3

Remember that early recognition and prompt intervention are essential for optimal outcomes in managing neuropathy from Keytruda.