Can Keytruda (pembrolizumab) cause peripheral neuropathy?

Can Keytruda Cause Peripheral Neuropathy?

Yes, Keytruda (pembrolizumab) can cause peripheral neuropathy, though it occurs less frequently than with traditional chemotherapy agents. According to the FDA label, peripheral neuropathy occurred in 7-22% of patients receiving Keytruda in combination with enfortumab vedotin, with 3.3-5% experiencing grade 3-4 severity requiring dose interruption or permanent discontinuation 1.

Incidence and Clinical Presentation

Monotherapy vs Combination Therapy

• Keytruda monotherapy: Peripheral neuropathy occurs in approximately 10-11% of patients with classical Hodgkin lymphoma, with grade 3-4 severity in less than 1% 1
• Keytruda plus enfortumab vedotin: The incidence increases substantially to 65-67% (all grades), with 3.3% grade 3-4 severity 1
• In cisplatin-ineligible urothelial cancer patients receiving the combination, peripheral neuropathy was the most common reason (22%) for dose interruption 1

Symptom Characteristics

The neuropathy associated with Keytruda typically presents as:

• Predominantly sensory symptoms including paresthesia, numbness, and dysesthesia 1
• Distal, symmetric distribution affecting lower extremities first (length-dependent pattern) 2
• Motor involvement is rare with immunotherapy alone but can occur with combination regimens 1

Risk Factors and Mechanisms

Pre-existing Conditions That Increase Risk

Patients with the following conditions have heightened susceptibility to developing peripheral neuropathy on Keytruda:

• Pre-existing neuropathy from any cause (diabetes, alcohol, hereditary conditions) 3, 2
• Diabetes mellitus (most common cause of baseline neuropathy, affecting 206 million people worldwide) 2
• Nutritional deficiencies, particularly vitamin B12 deficiency 2
• Renal failure or hepatic disease 3, 4

Combination Therapy Considerations

Critical caveat: When Keytruda is combined with enfortumab vedotin (an antibody-drug conjugate), the risk of peripheral neuropathy increases dramatically from 10-11% to 65-67% because enfortumab vedotin itself is neurotoxic 1. This represents an additive neurotoxic effect requiring heightened monitoring.

Management Algorithm

Monitoring Strategy

Before each treatment cycle, assess for:

• New onset numbness, tingling, or burning sensations in distal extremities 5
• Changes in gait or balance suggesting proprioceptive loss 5
• Orthostatic hypotension (occurs in ~10% with certain agents, suggesting autonomic involvement) 3

Dose Modification Guidelines

For Grade 2 peripheral neuropathy (moderate symptoms interfering with instrumental activities of daily living):

• Interrupt Keytruda until symptoms improve to grade ≤1 1
• Resume at same dose once resolved 1

For Grade 3-4 peripheral neuropathy (severe symptoms limiting self-care or life-threatening):

• Permanently discontinue Keytruda 1
• This occurred in 5% of patients receiving Keytruda plus enfortumab vedotin 1

Symptomatic Treatment

First-line pharmacologic options for neuropathic pain:

• Pregabalin 300-600 mg/day 5
• Duloxetine 60 mg once daily 5
• Gabapentin 300-2,400 mg/day (38% achieve ≥50% pain reduction at 1200 mg daily) 5, 2

Important limitation: No pharmacological agents effectively prevent immunotherapy-induced peripheral neuropathy; only symptomatic management is available 5, 4

Diagnostic Considerations

When Standard Testing May Be Normal

Critical pitfall: Conventional nerve conduction studies and electromyography may be completely normal in small fiber neuropathy, which is common with certain immunotherapy combinations 5, 6.

If clinical suspicion remains high despite normal electrodiagnostic studies:

• Obtain skin biopsy with intraepidermal nerve fiber (IENF) density measurement (45-90% sensitivity, 95-97% specificity for small fiber neuropathy) 5
• This is particularly important when symptoms began before cancer treatment, raising concern for alternative etiologies like hereditary transthyretin amyloidosis 6

Distinguishing Keytruda-Related from Other Causes

In patients receiving Keytruda who develop neuropathy, consider:

• Timing: Symptoms appearing 6-12 months before cancer diagnosis suggest alternative etiology (paraneoplastic, hereditary amyloidosis) rather than drug effect 6
• Pattern: Asymmetric or rapidly progressive symptoms are atypical for Keytruda and warrant investigation for other causes 2
• Baseline testing: Check fasting glucose, hemoglobin A1c, vitamin B12 with methylmalonic acid, and serum protein electrophoresis with immunofixation before attributing neuropathy solely to Keytruda 2

Prognosis and Recovery

Unlike chemotherapy-induced neuropathy (where 53-74% of patients experience improvement after drug discontinuation within 2-3 months), 3 the reversibility of Keytruda-associated peripheral neuropathy is less well-characterized in the literature. However, the FDA label indicates that dose interruption for peripheral neuropathy was common (7-22% of patients), suggesting symptoms were manageable with temporary cessation 1.

Complete reversal of nerve damage is uncommon even when the causative agent is removed, emphasizing the importance of early detection and prompt intervention 2.