What are the common immune‑related adverse events of pembrolizumab (Keytruda) and the recommended monitoring and management strategies?

Pembrolizumab Toxicity: Common Immune-Related Adverse Events and Management

Pembrolizumab causes immune-related adverse events (irAEs) in 63-80% of patients, with grade 3-4 toxicity occurring in 10-16%, and these events can develop anytime from weeks to over a year after treatment initiation or even discontinuation 1.

Common Immune-Related Adverse Events

Frequency and Timing

The most common organ systems affected include:

• Endocrine toxicities (12.8% overall): Hypothyroidism, hyperthyroidism, hypophysitis, type 1 diabetes - median onset at 28.6 weeks 1
• Gastrointestinal toxicities (7.1-36%): Diarrhea, colitis - median onset at 12-26 weeks 1
• Skin toxicities (7.6%): Rash, pruritus - median onset at 5.6-7.4 weeks 1
• Hepatic toxicities: Transaminitis, hepatitis - median onset at 7.4 weeks 1
• Pulmonary toxicities: Pneumonitis (1.6-2.7%) - median onset at 6.7-11.3 weeks 1
• Renal toxicities: Acute kidney injury (1-2% single agent) - median onset at 91 days 2
• Musculoskeletal toxicities: Arthralgia/myalgia (up to 40%), inflammatory arthritis, myositis 2

Critical pitfall: irAEs can occur as late as 1 year after discontinuing pembrolizumab, requiring ongoing vigilance even after treatment completion 1.

Monitoring Strategy

Baseline Assessment

Before each dose, monitor:

• Serum creatinine 2
• Liver function tests (AST, ALT, bilirubin) 3
• Thyroid function (TSH, free T4) 3
• Complete blood count 3

Symptom Surveillance

Actively assess for:

• New-onset diarrhea (≥4 stools/day above baseline)
• Skin changes or rash
• Dyspnea or cough
• Fatigue beyond expected
• Joint pain or muscle weakness
• Changes in urination or creatinine elevation

Management Algorithm by Grade

Grade 1 Toxicities

Continue pembrolizumab with close monitoring for most toxicities 4:

• Monitor creatinine changes even if <1.5× ULN (may still be clinically meaningful) 2
• Initiate symptomatic treatment (acetaminophen/NSAIDs for arthralgia) 2
• Exception: Some neurologic, hematologic, and cardiac toxicities require immediate intervention regardless of grade 4

Grade 2 Toxicities

Hold pembrolizumab temporarily 2, 4:

For renal toxicity:

• Consult nephrology immediately
• Exclude alternative causes (IV contrast, medications, volume status)
• If no alternative cause: initiate prednisone 0.5-1 mg/kg/day 2
• If worsening or no improvement: escalate to 1-2 mg/kg/day prednisone and permanently discontinue pembrolizumab
• If improved to grade 1: taper corticosteroids over 4-6 weeks, then consider resuming pembrolizumab 2

For arthritis:

• Hold pembrolizumab until symptoms controlled and prednisone ≤10 mg/day
• Escalate NSAIDs; if inadequate, start prednisone 10-20 mg/day for 4-6 weeks
• Refer to rheumatology
• May use intra-articular corticosteroid injections for large joints 2

For colitis:

• If symptoms persist >7 days or worsen without alternative cause, treat as grade 3 5

Grade 3-4 Toxicities

Permanently discontinue pembrolizumab (except for endocrinopathies controlled by hormone replacement) 4:

Immediate actions:

• Consult appropriate specialist (nephrology, rheumatology, gastroenterology)
• Initiate high-dose corticosteroids: 1-2 mg/kg/day prednisone or equivalent 2
• For severe myositis with cardiac/respiratory involvement: consider IV methylprednisolone 1-2 mg/kg or higher-dose bolus 2

If no improvement after 3-5 days (grade 3) or 2-3 days (grade 4):

• Add additional immunosuppression: mycophenolate, plasmapheresis, or IVIG 2
• For refractory arthritis: consider DMARDs (methotrexate, leflunomide) or biologics (TNF-α inhibitors, IL-6 receptor inhibitors) 2
• Caution: IL-6 inhibitors can cause intestinal perforation; avoid in patients with colitis or GI metastases 2

Corticosteroid taper:

• Once improved to grade 1, taper over minimum 4-6 weeks 2, 4
• If unable to reduce prednisone below 10 mg/day after 3 months, add steroid-sparing agent 2

Special Considerations

Acute Kidney Injury

• Incidence: 1-2% with pembrolizumab alone 2
• Pathology typically shows acute tubulointerstitial nephritis (92% of biopsied cases) 2
• Do not delay treatment for biopsy - if no alternative cause identified, proceed directly with immunosuppression 2
• Median time to diagnosis: 91 days after initiation 2

Myositis

• Diagnose with elevated CK, troponin (for cardiac involvement), EMG, or MRI 2
• Always check troponin - myocardial involvement requires immediate aggressive immunosuppression and permanent discontinuation 2
• Consider hospitalization for severe weakness 2

Colitis

• Critical: Colon mucosa may appear normal macroscopically but show microscopic autoimmune colitis 5
• Grade 2 or higher symptoms require colonoscopy 5
• Can be fatal if not recognized early 6

Endocrinopathies

• Most common irAE in real-world data (12.8%) 7, 6
• Often require lifelong hormone replacement 7, 6
• Unique exception: Pembrolizumab can be continued if endocrinopathy is controlled with hormone replacement 4

Real-World Outcomes

In contemporary practice, 34% of patients develop irAEs, with 13-14% experiencing grade ≥3 events 7, 6. Most irAEs (73%) occur during neoadjuvant treatment, but 28% occur during adjuvant therapy 7. Permanent discontinuation is required in 13-16% of patients 3, 7, 6. Importantly, 67% of irAEs remain unresolved at last follow-up, though 55% improve to grade 1 6.

No clinicopathologic factors reliably predict who will develop irAEs, emphasizing the need for universal vigilance 6.