What are the side effects of Keytruda (pembrolizumab)?

Side Effects of Keytruda (Pembrolizumab)

Pembrolizumab causes frequent immune-related adverse events (irAEs) affecting multiple organ systems, with the most common being diarrhea, nausea, pruritus, rash, arthralgia, and fatigue occurring in over 10% of patients, while rare but life-threatening toxicities include pneumonitis, colitis, endocrinopathies, and neurological complications that require immediate recognition and treatment. 1

Common Side Effects (>10% Incidence)

The most frequently reported adverse events with pembrolizumab monotherapy include: 1

• Gastrointestinal: Diarrhea, nausea, decreased appetite, vomiting, constipation 1, 2
• Dermatologic: Pruritus (13-20%), rash (15%), fatigue 1
• Musculoskeletal: Arthralgia and fatigue 1
• Constitutional: Fatigue (most common), pyrexia 2

When pembrolizumab is combined with platinum chemotherapy and pemetrexed, the incidence increases significantly, with fatigue/asthenia (56%), nausea (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%) being most common. 2

Dermatologic Toxicities

Skin reactions are among the most frequent irAEs, occurring in 34% of patients on anti-PD-1 therapy, though severe (grade 3-4) reactions are rare at <3%. 1

• Rash typically develops within the first few weeks of treatment and covers varying body surface areas 1
• Pruritus affects 13-20% of patients and can be managed with topical or oral antihistamines 1
• Vitiligo occurs in up to 25% of melanoma patients and paradoxically correlates with better clinical responses 1
• Rare severe reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and DRESS syndrome, which require permanent discontinuation and hospitalization 1

Endocrine Toxicities

Thyroid dysfunction is the most common endocrine irAE, occurring in approximately 5-10% of patients receiving pembrolizumab. 3

• Both hypothyroidism and hyperthyroidism can occur, with thyroid dysfunction typically manageable without treatment discontinuation 3
• Monitor TSH and free T4 every 4-6 weeks during therapy 3
• Anti-thyroid antibodies are detected in approximately 80% of patients who develop thyroid dysfunction requiring hormone replacement 3
• Rare but serious: Type 1 diabetes with diabetic ketoacidosis can occur, requiring immediate insulin therapy and permanent discontinuation 1, 4, 5
• Isolated ACTH deficiency and adrenal insufficiency have been reported, presenting with severe fatigue and requiring cortisol replacement 1, 4

Gastrointestinal Toxicities

• Diarrhea is the most common GI side effect 1
• Colitis with risk of gastrointestinal perforation is a rare but life-threatening complication requiring high-dose corticosteroids 1
• Immune-mediated glossitis (tongue ulcerations) has been reported, responding to oral prednisone 40 mg with tapering 6

Pulmonary Toxicities

Pneumonitis, including acute interstitial pneumonia and acute respiratory distress syndrome, is a rare (<10%) but potentially fatal complication. 1, 7

• Presents with shortness of breath and coughing 1
• Requires immediate treatment discontinuation and high-dose corticosteroids 1
• Can occur at any time during or after treatment 1

Neurological Toxicities

Neurological irAEs occur in 6.1% of patients on anti-PD-1 monotherapy, with onset typically between 6-13 weeks. 1

• Reported manifestations include polyneuropathy, Guillain-Barré syndrome, myasthenia gravis, encephalitis, transverse myelitis, and aseptic meningitis 1
• For all but mild (grade 1) symptoms, pembrolizumab should be withheld until the nature of the adverse event is defined 1
• Severe cases require high-dose steroids (1-2 mg/kg prednisolone) and may need plasmapheresis or IV immunoglobulin 1

Cardiac Toxicities

Cardiac adverse events occur in <1% of patients but include serious complications such as myocarditis, pericarditis, and arrhythmias. 1

• High-dose corticosteroids should be instituted rapidly if cardiac irAEs are suspected 1
• May require escalation to infliximab, mycophenolate mofetil, or anti-thymocyte globulin if unresponsive to steroids 1

Ocular Toxicities

Vision loss and ocular inflammation are rare (<1%) but can be devastating complications. 1, 8

• Manifestations include uveitis, choroidal effusion, retinal detachment, and optic disc edema 1, 8
• Can occur at any point during treatment and may require permanent discontinuation 8
• Treatment includes topical and systemic corticosteroids, with vision often recovering within weeks to months 8

Hematologic Toxicities

Rare but serious hematologic irAEs include: 1

• Aplastic anemia, autoimmune hemolytic anemia, and immune thrombocytopenic purpura 1
• Require high-dose corticosteroids and management in collaboration with hematology 1

Infusion Reactions

Infusion reactions and anaphylactic shock are rare but can occur, particularly on the first day of treatment. 1, 9

• Fever >101°F on day one suggests infusion reaction rather than delayed irAE 9
• Management includes stopping or slowing infusion, administering acetaminophen and diphenhydramine 9
• Consider premedication with antipyretics and antihistamines for subsequent infusions 9

Critical Timing and Monitoring Considerations

Immune-related adverse events can occur at any time: at the beginning, during, or after treatment discontinuation. 1

• Early identification and treatment are essential to limit duration and severity 1
• Most irAEs are mild and reversible if detected early 1
• Patients should be educated to report new symptoms immediately, including diarrhea, blood in stool, severe abdominal pain, fatigue, weight loss, extensive rash, shortness of breath, headache, muscle weakness, joint swelling, or unexplained fever 1

Management Principles

The use of immunosuppressive agents (primarily corticosteroids) for managing irAEs does not appear to affect the clinical outcome of cancer treatment. 1

• For most irAEs, pembrolizumab can be continued during management of mild toxicities 3
• Moderate to severe toxicities require treatment interruption and corticosteroid therapy 1
• Life-threatening or recurrent serious adverse events necessitate permanent discontinuation 1
• When corticosteroids are stopped, gradual dose tapering must be initiated 1