Mechanism of Action of Pembrolizumab (Keytruda)
Pembrolizumab is a humanized IgG4/kappa monoclonal antibody that binds with picomolar affinity to the programmed death-1 (PD-1) receptor on T cells, blocking its interaction with PD-L1 and PD-L2 ligands, thereby preventing immune suppression and allowing T cells to recognize and attack tumor cells. 1, 2
Molecular Mechanism
Pembrolizumab binds specifically to both the C'D and FG loops of the PD-1 receptor, preventing the receptor from engaging with its ligands PD-L1 and PD-L2 that are often expressed on tumor cells and cells in the tumor microenvironment 2
By blocking PD-1/PD-L1 and PD-1/PD-L2 interactions, pembrolizumab reverses T-cell exhaustion and restores effector T-cell function, enabling immune-mediated tumor regression 2, 3
The antibody enhances functional activity of T cells by increasing production of IL-2 and IFN-γ following antigen stimulation, as demonstrated in both healthy donor cells and cancer patient samples 2
Pembrolizumab does not mediate Fc receptor or complement-driven effector function against PD-1-expressing cells, meaning it works purely through checkpoint blockade rather than antibody-dependent cellular cytotoxicity 2
Recommended Dosing Schedule
The FDA-approved dose is 200 mg administered intravenously every 3 weeks (flat dosing), which replaced the earlier weight-based dosing of 2 mg/kg every 3 weeks 1, 4
Treatment should continue until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression 1
Pembrolizumab displays dose-dependent clearance and half-life typical for human IgG4 antibodies, with pharmacokinetics supporting the every-3-week dosing interval 2
Alternative Checkpoint Inhibitor Options
Nivolumab (another anti-PD-1 antibody) is administered at 240 mg IV every 2 weeks or 480 mg IV every 4 weeks and represents a category 1 alternative for many indications including melanoma, NSCLC, and head/neck cancer 1
Atezolizumab (anti-PD-L1 antibody) is dosed at 1200 mg IV every 3 weeks and is approved for urothelial carcinoma, NSCLC, and triple-negative breast cancer 1
Durvalumab (anti-PD-L1 antibody) is given at 10 mg/kg every 2 weeks for locally advanced or metastatic urothelial carcinoma 1
Combination therapy with ipilimumab (anti-CTLA-4) plus nivolumab is approved for metastatic melanoma, though it carries significantly higher toxicity with grade 3-4 adverse events in 55% of patients versus 10-27% with single-agent PD-1 inhibitors 1
Monitoring for Immune-Related Adverse Events (irAEs)
Common Adverse Events Requiring Surveillance
The most common adverse events are fatigue, pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough, dyspnea, and musculoskeletal pain, occurring in up to 73% of patients 1
Grade 3-4 treatment-related adverse events occur in approximately 10-16% of patients receiving pembrolizumab monotherapy, which is substantially lower than the 26-35% seen with chemotherapy or ipilimumab 1
Organ-Specific irAEs and Timing
Immune-mediated colitis typically develops within the first 2 cycles but can occur at any time, presenting with diarrhea, abdominal pain, blood or mucus in stool 5
Hepatitis manifests with elevated transaminases and typically occurs at a median of 7.4 weeks (range 2.1-48.0 weeks) after treatment initiation 1
Pneumonitis presents with dyspnea, cough, and radiographic infiltrates at a median of 6.7 weeks and requires immediate evaluation with chest imaging 1
Endocrinopathies (thyroid dysfunction, hypophysitis, adrenal insufficiency) occur at a median of 28.6 weeks (range 19.1-38.1 weeks) and may be permanent, requiring lifelong hormone replacement 1
Nephritis and renal dysfunction occur later, at a median of 50.9 weeks, and present with elevated creatinine 1
Monitoring Protocol
Assess for new-onset diarrhea, abdominal pain, blood in stool, or mucus in stool at each pembrolizumab infusion visit, as delayed recognition of colitis has resulted in fatal outcomes 5
Obtain baseline and periodic monitoring of complete blood count, comprehensive metabolic panel (including liver and renal function), and thyroid function tests (TSH, free T4) every 4-6 weeks 1
Monitor for fever >101°F on infusion day, which suggests an infusion reaction (occurring in ~3% of patients) rather than delayed irAE, and manage by slowing or stopping infusion with symptomatic treatment 6
Watch for organ-specific symptoms between visits and educate patients to report fever, persistent diarrhea, shortness of breath, severe fatigue, or jaundice immediately 5, 6
Management of irAEs
For grade 1 irAEs, continue pembrolizumab with close monitoring; for grade 2 irAEs, hold pembrolizumab and initiate corticosteroids (prednisone 0.5-1 mg/kg/day) 1
For grade 3-4 irAEs, permanently discontinue pembrolizumab and administer high-dose corticosteroids (methylprednisolone 1-2 mg/kg/day IV or equivalent), with consideration for additional immunosuppression if no improvement in 48-72 hours 1
Do not rechallenge pembrolizumab after a prior grade 3-4 immune-related adverse event, as recurrence occurs in up to 74% of patients (approximately 20% grade 3-4) 7
Predictive Biomarkers
PD-L1 expression (≥1% by immunohistochemistry using the 22C3 antibody) predicts higher response rates, with pembrolizumab achieving ORR of 29% in PD-L1 positive versus 6% in PD-L1 negative tumors across multiple cancer types 1
Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors show exceptional responses to pembrolizumab, with ORR of 40% in colorectal cancer and 71% in non-colorectal MSI-H tumors 1
Tumor mutational burden ≥10 mutations/megabase (TMB-H) predicts response, with ORR of 29% in TMB-H versus 6% in non-TMB-H solid tumors 1
High gene mutation burdens result in formation of more tumor-related neo-antigens and correlate with better pembrolizumab responses 3
Critical Contraindications and Precautions
Pembrolizumab is contraindicated in patients with active autoimmune disease requiring systemic immunosuppression, as checkpoint blockade may exacerbate underlying autoimmune conditions 1
Hold pembrolizumab in patients with severe hepatic dysfunction (bilirubin >3× upper limit of normal) until liver function improves, as hepatotoxicity risk increases 7
Avoid combination with certain chemotherapy agents during active biliary obstruction or severe hepatic impairment, as this markedly increases toxicity risk 7
Infusion reactions occur in approximately 3% of patients; consider premedication with antipyretics and antihistamines for subsequent doses if reaction occurred 6