Drug Monograph
Pembrolizumab (Keytruda)
pembrolizumab — humanized IgG4 anti-PD-1 monoclonal antibody
Pharmacokinetic Profile
Half-Life
26 days (terminal)
Metabolism
Non-specific catabolism
Protein Binding
Not plasma-protein bound
Bioavailability
100% (IV); SC non-inferior
Volume of Distribution
7.4 L (Vdss)
Clinical Information
Drug Class
PD-1 inhibitor (IgG4 mAb)
Available Doses
100 mg/4 mL vial (IV); 395 mg & 790 mg vials (SC)
Route
IV infusion (30 min); SC injection
Renal Adjustment
None required (mild–moderate)
Hepatic Adjustment
None for mild; not studied moderate–severe
Pregnancy
Contraindicated — fetal harm
Lactation
Discontinue nursing
Schedule / Legal
Rx only (no DEA schedule)
Generic Available
No
Therapeutic Index
Immune-mediated toxicity risk
Indications
Pembrolizumab holds the largest number of FDA-approved oncology indications of any single agent, spanning solid tumors and select hematologic malignancies across more than 20 tumor types. Many indications require biomarker testing (PD-L1 expression by TPS or CPS, MSI-H/dMMR status, or TMB-H) prior to initiating therapy. The table below summarizes the major approved categories; refer to the full prescribing information for complete details on each indication.
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Unresectable or metastatic melanoma | Adults & pediatric ≥12 yr | Monotherapy | FDA Approved |
| Adjuvant melanoma (Stage IIB, IIC, III) | Adults & pediatric ≥12 yr | Monotherapy (post-resection) | FDA Approved |
| Metastatic NSCLC — first-line, nonsquamous | Adults (no EGFR/ALK) | + pemetrexed/platinum | FDA Approved |
| Metastatic NSCLC — first-line, squamous | Adults | + carboplatin/(nab-)paclitaxel | FDA Approved |
| NSCLC, PD-L1 TPS ≥1% — first-line or post-platinum | Adults (no EGFR/ALK) | Monotherapy | FDA Approved |
| Resectable NSCLC (neoadjuvant/adjuvant) | Adults (≥4 cm or node-positive) | + platinum chemo then mono | FDA Approved |
| Adjuvant NSCLC (Stage IB ≥4 cm, II, IIIA) | Adults (post-resection, post-platinum) | Monotherapy | FDA Approved |
| HNSCC — first-line metastatic/recurrent | Adults | + platinum/5-FU or mono (CPS ≥1) | FDA Approved |
| HNSCC — resectable locally advanced (perioperative) | Adults (PD-L1 CPS ≥1) | Neo + adj with RT ± cisplatin | FDA Approved |
| Classical Hodgkin lymphoma | Adults & pediatric | Monotherapy (relapsed/refractory) | FDA Approved |
| Urothelial carcinoma — locally advanced/metastatic | Adults | + enfortumab vedotin or mono | FDA Approved |
| MSI-H/dMMR solid tumors (tissue-agnostic) | Adults & pediatric | Monotherapy (post-prior treatment) | FDA Approved |
| MSI-H/dMMR colorectal cancer | Adults | Monotherapy (first-line unresectable/metastatic) | FDA Approved |
| Gastric/GEJ adenocarcinoma (HER2-negative) | Adults (CPS ≥1) | + fluoropyrimidine/platinum chemo | FDA Approved |
| Esophageal/GEJ carcinoma | Adults | + platinum/fluoropyrimidine chemo or mono | FDA Approved |
| Cervical cancer (FIGO III–IVA with CRT; recurrent/metastatic) | Adults | + CRT; or + chemo ± bevacizumab | FDA Approved |
| Hepatocellular carcinoma | Adults | Monotherapy (post-sorafenib/oxaliplatin) | FDA Approved |
| Biliary tract cancer | Adults | + gemcitabine/cisplatin | FDA Approved |
| Renal cell carcinoma — advanced first-line | Adults | + axitinib or + lenvatinib | FDA Approved |
| RCC — adjuvant (intermediate-high/high risk) | Adults | Monotherapy (post-nephrectomy) | FDA Approved |
| Endometrial carcinoma — advanced/recurrent | Adults | + carboplatin/paclitaxel; or + lenvatinib (pMMR/not MSI-H); or mono (MSI-H/dMMR) | FDA Approved |
| Triple-negative breast cancer (high-risk early or metastatic) | Adults (CPS ≥10 for metastatic) | + chemotherapy | FDA Approved |
| TMB-H solid tumors (≥10 mut/Mb) | Adults & pediatric | Monotherapy (post-prior treatment) | FDA Approved |
| Malignant pleural mesothelioma | Adults | + pemetrexed/platinum | FDA Approved |
| Platinum-resistant ovarian/fallopian tube/peritoneal cancer | Adults (CPS ≥1) | + paclitaxel ± bevacizumab | FDA Approved |
| Merkel cell carcinoma | Adults & pediatric | Monotherapy (recurrent/metastatic) | FDA Approved |
| Cutaneous squamous cell carcinoma | Adults | Monotherapy (recurrent/metastatic or locally advanced not curable) | FDA Approved |
| BCG-unresponsive high-risk NMIBC with CIS | Adults (ineligible for/declined cystectomy) | Monotherapy | FDA Approved |
| Primary mediastinal large B-cell lymphoma | Adults & pediatric | Monotherapy (relapsed/refractory after ≥2 prior lines) | FDA Approved |
Pembrolizumab’s tissue-agnostic approvals (MSI-H/dMMR solid tumors, TMB-H solid tumors) were among the first biomarker-driven, site-agnostic oncology approvals in FDA history. For many indications, companion diagnostic testing with PD-L1 IHC 22C3 pharmDx is required before initiating treatment. The scoring system varies by tumor type: Tumor Proportion Score (TPS) for NSCLC and Combined Positive Score (CPS) for most other solid tumors.
Select Off-Label Uses
Thymic carcinoma (refractory) — Evidence quality: Moderate (Phase II data, KEYNOTE-158)
Small cell lung cancer (third-line+) — Evidence quality: Low (limited single-arm cohort data)
Prostate cancer (MSI-H/dMMR subset) — Evidence quality: Moderate (tissue-agnostic approval may cover; some patients treated under this approval)
Dosing
Pembrolizumab uses a flat-dose regimen (not weight-based) for all adult indications. No dose reductions are permitted; the drug is either withheld or permanently discontinued based on adverse reaction severity. Duration varies by clinical context: up to 24 months for metastatic disease (unless progression occurs sooner) and up to 12 months for most adjuvant settings.
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Metastatic solid tumors — standard monotherapy or combination (melanoma, NSCLC, HNSCC, urothelial, gastric, esophageal, cervical, HCC, BTC, MCC, cSCC, MSI-H, TMB-H, MPM, ovarian) | 200 mg IV q3wk | 200 mg IV q3wk or 400 mg IV q6wk | 400 mg q6wk | Infuse over 30 min; treat until progression, unacceptable toxicity, or up to 24 months Administer pembrolizumab before chemotherapy when given on the same day |
| Adjuvant therapy — melanoma, NSCLC (post-resection), RCC (post-nephrectomy) | 200 mg IV q3wk | 200 mg IV q3wk or 400 mg IV q6wk | 400 mg q6wk | Treat until disease recurrence, unacceptable toxicity, or up to 12 months Patients with disease progression during neoadjuvant phase should not receive adjuvant pembrolizumab |
| Neoadjuvant/adjuvant NSCLC — resectable, with platinum chemotherapy | 200 mg IV q3wk | 200 mg IV q3wk or 400 mg IV q6wk | 400 mg q6wk | Neoadjuvant: 4 cycles with platinum chemo pre-surgery; Adjuvant: continue mono up to 13 cycles post-surgery |
| Perioperative HNSCC — resectable, PD-L1 CPS ≥1 | 200 mg IV q3wk | 200 mg IV q3wk or 400 mg IV q6wk | 400 mg q6wk | Neoadjuvant: 2 cycles mono; Adjuvant: 3 cycles with RT ± cisplatin, then mono Administer prior to chemotherapy when given on the same day |
| Advanced RCC — first-line with axitinib | 200 mg IV q3wk | 200 mg IV q3wk or 400 mg IV q6wk | 400 mg q6wk | Axitinib 5 mg PO BID; dose escalation of axitinib at ≥6 wk intervals if tolerated Monitor LFTs closely — Grade 3–4 ALT elevation in ~20% of patients |
| Advanced RCC or endometrial carcinoma — with lenvatinib | 200 mg IV q3wk | 200 mg IV q3wk or 400 mg IV q6wk | 400 mg q6wk | Lenvatinib 20 mg PO daily (RCC) or 20 mg PO daily (endometrial) Refer to lenvatinib PI for dose modifications |
| Subcutaneous formulation (Keytruda Qlex) — all approved adult solid tumor indications | 395 mg SC q3wk | 395 mg SC q3wk or 790 mg SC q6wk | 790 mg SC q6wk | Do not administer intravenously; injection administered by healthcare professional Approved Sept 2025; non-inferior PK to IV formulation (KEYNOTE-D77) |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| cHL, PMBCL, MSI-H/dMMR tumors, TMB-H tumors, MCC (pediatric) | 2 mg/kg IV q3wk | 2 mg/kg IV q3wk | 200 mg q3wk | Weight-based dosing for pediatric patients; infuse over 30 min Maximum single dose must not exceed 200 mg |
| Adjuvant melanoma (pediatric ≥12 yr) | 2 mg/kg IV q3wk | 2 mg/kg IV q3wk | 200 mg q3wk | Up to 12 months or disease recurrence |
Clinical Pearl: Dose Modification Strategy
Pembrolizumab has no dose reductions. Management of immune-mediated adverse reactions uses a binary approach: withhold for Grade 2–3 events (resume when toxicity resolves to Grade 0–1 and corticosteroids tapered to ≤10 mg/day prednisone equivalent) or permanently discontinue for Grade 4 events, recurrent Grade 3 events requiring systemic immunosuppression, or inability to taper corticosteroids within 12 weeks. This applies across all indications.
Pharmacology
Mechanism of Action
Pembrolizumab is a humanized IgG4-kappa monoclonal antibody that targets the programmed cell death-1 (PD-1) receptor on T lymphocytes. Under normal physiological conditions, PD-1 acts as an immune checkpoint, dampening T-cell activity when engaged by its ligands PD-L1 and PD-L2. Many tumors exploit this pathway by upregulating PD-L1, thereby evading immune surveillance. By binding to PD-1 with high affinity, pembrolizumab blocks the interaction between PD-1 and both ligands, restoring the anti-tumor immune response. This reactivation of cytotoxic T-cell function leads to tumor cell recognition and destruction. The IgG4 isotype was specifically selected to minimize antibody-dependent cellular cytotoxicity and complement-mediated lysis, ensuring that the therapeutic effect is driven by T-cell restoration rather than direct cytotoxicity against cells expressing the target receptor.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV: 100% bioavailability; SC (Keytruda Qlex): non-inferior AUC to IV (GMR 1.14, 96% CI 1.06–1.22) | SC formulation offers comparable exposure with faster administration time (~1 min vs 30 min infusion) |
| Distribution | Vdss 7.4 L (CV 19%); confined to extracellular fluid; does not bind to plasma proteins | Small volume of distribution indicates limited extravascular penetration, consistent with a large monoclonal antibody remaining primarily in the vascular compartment |
| Metabolism | Non-specific catabolism to small peptides and amino acids; no CYP involvement | No pharmacokinetic drug interactions expected via metabolic pathways; eliminates the hepatic enzyme interaction risk seen with small-molecule oncology agents |
| Elimination | CL 0.2 L/day (CV 37%); t½ 26 days (CV 24%); steady state by ~18 weeks (q3wk dosing); accumulation ratio 2.1–2.2-fold | Long half-life supports both q3wk and q6wk dosing schedules; CL increases with body weight but flat dosing adequately covers the population; dose-proportional exposure across 2–10 mg/kg range |
Side Effects
Pembrolizumab’s adverse effect profile is dominated by immune-mediated reactions resulting from T-cell activation against normal tissues. The rates below are derived from monotherapy data across pivotal trials involving 2,799 patients (pooled safety population) unless otherwise specified. Combination therapy with chemotherapy or targeted agents increases the frequency and spectrum of adverse effects.
≥10%
Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Fatigue / asthenia | 28–40% | Most common complaint across all trials; dose-independent; may indicate occult endocrinopathy (hypothyroidism, adrenal insufficiency) |
| Musculoskeletal pain | 24–41% | Includes arthralgia, myalgia, back pain; distinguish from immune-mediated arthritis which may require corticosteroids |
| Rash | 19.8–30% | Usually maculopapular; may indicate early dermatologic immune-related adverse event (irAE); Grade 1–2 manageable with topical steroids |
| Diarrhea | 14.8–27% | Must distinguish non-specific diarrhea from immune-mediated colitis; colitis requires prompt work-up including CMV exclusion in steroid-refractory cases |
| Pruritus | 22.8–23% | Often precedes rash; manage with emollients and antihistamines; persistent pruritus may warrant systemic evaluation |
| Decreased appetite | 20–22% | Screen for adrenal insufficiency and hypothyroidism if accompanied by weight loss |
| Nausea | 10–21% | Usually mild; higher incidence with combination chemotherapy regimens |
| Hypothyroidism | 12–21% | Most common endocrine irAE; may follow a transient hyperthyroid phase; most patients require lifelong levothyroxine replacement |
| Constipation | 21% | Non-immune-mediated; more frequent in adjuvant settings |
| Cough | 11–21% | Assess for pneumonitis in any patient with new or worsening cough; obtain chest imaging |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Pyrexia | 8–10% | Fever may be first sign of infection or immune-related event; evaluate promptly |
| Dyspnea | 8–10% | Always evaluate for pneumonitis; CT chest recommended for new onset |
| Headache | 5–8% | Persistent headache with visual symptoms warrants evaluation for hypophysitis |
| Abdominal pain | 5–9% | Differentiate from immune-mediated colitis or hepatitis |
| Hyperthyroidism | 3–8% | Often transient destructive thyroiditis preceding hypothyroidism; typically self-limiting; beta-blockers for symptomatic relief |
| Vitiligo | 6–13% | Most frequent in melanoma trials; associated with improved treatment response; permanent in most cases |
| ALT/AST elevation | 1–4% (Grade 3+) | More frequent with axitinib combination (~20% Grade 3–4 ALT); autoimmune hepatitis pattern; exclude viral reactivation |
| Infusion-related reactions | 1–6% | Rigors, flushing, pruritus, hypotension, wheezing; severe reactions in ~0.2% of patients |
Serious
Serious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Immune-mediated pneumonitis | 2.9–7% | Median 5 months (range 0.3 wk–26 mo) | Grade 2: withhold, start prednisone 1–2 mg/kg/day; Grade 3–4 or recurrent: permanently discontinue; fatal cases reported (0.1–0.2%) |
| Immune-mediated colitis | 1–2% | Median 3–4 months | Grade 2–3: withhold, high-dose corticosteroids; steroid-refractory: infliximab; exclude CMV reactivation; Grade 4: permanently discontinue |
| Immune-mediated hepatitis | 0.7% (up to 20% with axitinib) | Variable, often weeks 3–12 | Withhold for Grade 2 (AST/ALT 3–5x ULN); permanently discontinue for Grade 3–4; start corticosteroids; consider mycophenolate if steroid-refractory |
| Immune-mediated nephritis | 0.3–0.5% | Months 2–12 | Withhold for Grade 2; permanently discontinue for Grade 3–4; corticosteroids; rule out other nephrotoxins |
| Adrenal insufficiency | 0.8–1% | Any time during treatment | Hormone replacement (hydrocortisone); may be lifelong; withhold pembrolizumab for Grade 3–4 until stable on replacement |
| Hypophysitis | 0.5–0.6% | Months 1–17 | MRI pituitary; hormone axis evaluation; high-dose corticosteroids then replacement; often requires lifelong hormone therapy |
| Type 1 diabetes mellitus (new-onset) | 0.2% | Weeks to months | Monitor glucose; DKA may be presenting feature; initiate insulin therapy; withhold pembrolizumab if hyperglycemia severe |
| Myocarditis | Rare (<1%) | Median 30 days (range days–months) | Permanently discontinue; high-dose corticosteroids immediately; cardiology consultation; mortality rate 25–50% if not promptly treated |
| Myasthenia gravis / Guillain-Barré syndrome | Rare (<0.1%) | Weeks 2–12 | Permanently discontinue; neurology consultation; plasmapheresis or IVIG for severe cases; may overlap with myocarditis |
| Stevens-Johnson syndrome / Toxic epidermal necrolysis | Very rare | Any time | Permanently discontinue immediately; dermatology and burn unit consultation; supportive care |
Discontinuation
Discontinuation Rates
Monotherapy (Melanoma, KEYNOTE-006)
9% vs 13% ipilimumab
Top reasons: Colitis (1.4%), autoimmune hepatitis (0.7%), pneumonitis
Adjuvant Monotherapy (RCC, KEYNOTE-564)
21% vs 2% placebo
Top reasons: Elevated ALT (1.6%), colitis (1%), adrenal insufficiency (1%)
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Pneumonitis | 1.3–5.4% | Higher in adjuvant NSCLC (4.5%) than metastatic melanoma (1.3%); thoracic radiation may increase risk |
| Colitis | 1–1.4% | Consistent across tumor types |
| Hepatitis / elevated transaminases | 0.7–1.6% | Substantially higher with TKI combinations (axitinib, lenvatinib) |
| Adrenal insufficiency | 1% | Primarily in adjuvant settings where duration is up to 12 months |
Immune-Mediated Adverse Reaction Management
Between 15% and 25% of pembrolizumab-treated patients develop clinically significant immune-related adverse events. Early recognition is critical: any new symptom during treatment should prompt evaluation for an immune-mediated etiology. Most grade 2+ irAEs respond to corticosteroids (prednisone 1–2 mg/kg/day with gradual taper over ≥4 weeks), but steroid-refractory cases may require infliximab, mycophenolate, or other immunosuppressive agents. Endocrine irAEs (hypothyroidism, adrenal insufficiency) frequently require permanent hormone replacement even after pembrolizumab discontinuation.
Drug Interactions
As a monoclonal antibody catabolized via non-specific proteolysis, pembrolizumab has no identified CYP450-mediated pharmacokinetic drug interactions. No formal drug interaction studies have been conducted. However, important pharmacodynamic interactions exist, particularly with immunosuppressive agents and other immunotherapy drugs.
Major
Systemic Corticosteroids (high-dose)
MechanismBroad immunosuppression attenuates the T-cell activation that pembrolizumab depends on for efficacy
EffectPotential reduction in anti-tumor efficacy; baseline corticosteroid use (>10 mg/day prednisone equivalent) associated with worse outcomes in retrospective analyses
ManagementAvoid systemic corticosteroids before starting pembrolizumab; physiologic replacement doses and short courses for irAE management are acceptable
FDA PI & ASCO Guidelines
Major
Other Immunosuppressants (azathioprine, cyclosporine, MMF)
MechanismDirect suppression of T-cell proliferation and function
EffectMay reduce anti-tumor immune response; also increases infection risk in already immunomodulated patients
ManagementAvoid concurrent use unless managing an irAE; document risk-benefit assessment; autoimmune disease is a relative contraindication to immunotherapy
NCCN Guideline
Major
Anti-CTLA-4 Agents (ipilimumab)
MechanismDual checkpoint blockade amplifies T-cell activation synergistically
EffectMarkedly increased irAE incidence and severity compared to either agent alone; Grade 3–4 irAEs rise from ~15% to 55%
ManagementPembrolizumab + ipilimumab is not an FDA-approved combination; nivolumab + ipilimumab is the standard dual checkpoint approach; heightened monitoring if dual blockade is used in any trial setting
Clinical Studies
Major
Axitinib (when combined)
MechanismAdditive hepatotoxicity; VEGFR inhibition may alter immune microenvironment
EffectGrade 3–4 ALT elevation in ~20% and AST elevation in ~13% of patients — substantially higher than either drug alone
ManagementMonitor LFTs every 2 weeks initially, then monthly; consider sequential rechallenge after resolution; dose modify axitinib first for hepatotoxicity
FDA PI (KEYNOTE-426)
Moderate
Lenvatinib (when combined)
MechanismOverlapping toxicity profiles; VEGF/FGFR inhibition adds hypertension, proteinuria, and hepatotoxicity
EffectIncreased rates of hypothyroidism, hypertension, fatigue, and diarrhea compared to pembrolizumab alone
ManagementMonitor BP, thyroid, and hepatic function more frequently; lenvatinib dose modifications separate from pembrolizumab decisions
FDA PI (KEYNOTE-581/CLEAR)
Moderate
Live Vaccines
MechanismTheoretical risk of uncontrolled infection from live organisms due to immune modulation; heightened risk if patient is also receiving corticosteroids for irAE management
EffectPossible disseminated vaccine-strain infection; efficacy of vaccine may also be reduced
ManagementAvoid live vaccines during treatment and for at least 4 months after last dose; inactivated vaccines are acceptable
Lexicomp
Moderate
Thalidomide / Lenalidomide
MechanismImmunomodulatory overlap; both modify T-cell and cytokine function
EffectIncreased risk of immune-mediated toxicity including fatal myocarditis observed in clinical trials of pembrolizumab with lenalidomide in multiple myeloma (increased mortality noted)
ManagementThis combination should only be used in clinical trial settings; not recommended outside of a structured protocol
FDA Safety Communication
Minor
Allogeneic Hematopoietic Stem Cell Transplant (pre/post)
MechanismPD-1 blockade may intensify graft-versus-host disease (GVHD) by amplifying alloreactive T cells
EffectSevere and fatal GVHD, hepatic veno-occlusive disease, and steroid-requiring febrile syndrome reported after allogeneic HSCT following prior pembrolizumab
ManagementWeigh benefits and risks carefully; monitor closely for hyper-acute GVHD; the benefit-risk of HSCT before or after pembrolizumab must be carefully assessed
FDA PIMonitoring
-
Thyroid Function
Baseline, then q6wk during treatment
Routine TSH and free T4; hypothyroidism develops in 12–21% of patients. If TSH is elevated, initiate levothyroxine replacement. Transient hyperthyroidism may precede hypothyroidism — recheck in 4–6 weeks before starting antithyroid treatment. -
Hepatic Function
Baseline, then before each cycle
Routine AST, ALT, bilirubin, alkaline phosphatase. Particularly important with axitinib (q2wk for first 12 weeks) or lenvatinib combinations. Withhold pembrolizumab if AST/ALT >3–5x ULN; permanently discontinue if >5x ULN. -
Renal Function
Baseline, then before each cycle
Routine Creatinine and eGFR. Immune-mediated nephritis occurs in ~0.3–0.5% of patients. Rising creatinine warrants urinalysis, proteinuria quantification, and renal biopsy consideration. -
Blood Glucose
Baseline, then each cycle; urgently if symptoms
Routine New-onset type 1 diabetes or DKA can develop suddenly. Patients presenting with polyuria, polydipsia, or unexplained weight loss need immediate glucose and ketone assessment. C-peptide and anti-GAD antibodies confirm immune etiology. -
Cortisol / ACTH
If fatigue, hypotension, or electrolyte abnormalities
Trigger-based Morning cortisol <5 mcg/dL or abnormal cosyntropin stimulation confirms adrenal insufficiency. Also evaluate for hypophysitis with pituitary MRI and full anterior pituitary hormone panel if clinical suspicion. -
Chest Imaging
Baseline; repeat if new cough, dyspnea, or hypoxia
Trigger-based CT chest for suspected pneumonitis. Ground-glass opacities or organizing pneumonia patterns are typical. Pneumonitis occurs in 2.9–7% of patients across indications. -
Cardiac Biomarkers
If chest pain, new dyspnea, or arrhythmia
Trigger-based Troponin, BNP, ECG, echocardiogram. Myocarditis is rare but carries 25–50% mortality if not recognized early. High index of suspicion required for any new cardiac symptom. -
PD-L1 / MSI / TMB Testing
Before initiating treatment (select indications)
Routine Required for many indications: PD-L1 IHC 22C3 pharmDx for TPS (NSCLC) or CPS (HNSCC, gastric, cervical, esophageal, urothelial). MSI-H/dMMR testing for tissue-agnostic and CRC indications. TMB by validated NGS assay.
Contraindications & Cautions
Absolute Contraindications
- History of severe hypersensitivity to pembrolizumab or any excipient — life-threatening anaphylaxis or severe infusion reactions warrant permanent avoidance
- Pregnancy — pembrolizumab can cause fetal harm by disrupting PD-1-mediated maternal immune tolerance to the fetus; animal models show increased fetal loss
Relative Contraindications (Specialist Input Recommended)
- Active autoimmune disease requiring systemic immunosuppression — conditions such as active lupus, rheumatoid arthritis on DMARDs, or inflammatory bowel disease; PD-1 blockade may trigger severe flares. Patients with controlled hypothyroidism or vitiligo may be considered.
- Prior organ transplant — checkpoint inhibitor therapy carries high risk of graft rejection (~40% in case series); use only if no alternative and with transplant team involvement
- Prior allogeneic HSCT (within 5 years or with active GVHD) — increased risk of fatal GVHD with PD-1 blockade; GVHD must be fully resolved and off immunosuppression
- Moderate to severe hepatic impairment — pembrolizumab has not been studied in this population; use with close monitoring and specialist input
Use with Caution
- Performance status ECOG ≥3 — most pivotal trials enrolled ECOG 0–1; limited efficacy and safety data for debilitated patients
- History of pneumonitis from prior immunotherapy — recurrence risk is higher; close surveillance with serial chest imaging
- Pre-existing endocrine disorders — baseline dysfunction may be exacerbated; establish accurate baseline hormone levels before initiation
- Elderly patients (≥75 years) — no dose adjustment required; however, immune-related adverse events may be more severe; no overall differences in efficacy reported between patients aged ≥65 and younger patients
FDA Warnings & Precautions
Immune-Mediated Adverse Reactions
Pembrolizumab can cause severe and fatal immune-mediated adverse reactions in any organ system or tissue, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, myocarditis, and neurological toxicities. These reactions may occur at any time during or after treatment. Early identification and management are essential. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue pembrolizumab and administer corticosteroids based on severity of the adverse reaction.
Embryo-Fetal Toxicity: Based on its mechanism of action, pembrolizumab can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for at least 4 months after the last dose.
Patient Counselling
Purpose of Therapy
Pembrolizumab works by activating the body’s own immune system to recognize and attack cancer cells. Unlike traditional chemotherapy that directly kills dividing cells, this treatment removes a “brake” on the immune system. This means the side effects are fundamentally different from chemotherapy: instead of hair loss and low blood counts, the primary concern is the immune system attacking normal tissues by mistake.
How to Take
Pembrolizumab is given as an intravenous infusion over 30 minutes every 3 weeks, or as a longer-interval infusion every 6 weeks, at a clinic or infusion center. A subcutaneous injection formulation (Keytruda Qlex) is also available, which takes approximately 1 minute to administer. Treatment duration depends on the specific cancer being treated and the clinical response.
Immune-Related Side Effects (General)
Tell patient
This treatment can cause the immune system to attack healthy organs. Side effects can appear at any time during or even after treatment ends. Any new or worsening symptom should be reported, even if it seems unrelated to cancer treatment. Early detection leads to better outcomes.
Call prescriber
New or worsening cough, shortness of breath, chest pain, persistent diarrhea (more than 3 loose stools/day), blood in stool, yellowing of skin or eyes, dark urine, severe abdominal pain, unusual fatigue, dizziness, fainting, rapid heartbeat, or any new symptom that concerns you.
Endocrine Changes (Thyroid, Diabetes, Adrenal)
Tell patient
Your hormone glands may be affected. Thyroid problems are common (up to 1 in 5 patients) and can cause fatigue, weight changes, or feeling hot/cold. In rare cases, new diabetes may develop suddenly. You may need to take hormone replacement medications long-term, even after pembrolizumab stops.
Call prescriber
Extreme thirst, frequent urination, unexplained weight loss (possible diabetes), severe fatigue with dizziness or salt craving (possible adrenal insufficiency), persistent headache with vision changes (possible pituitary inflammation), or rapid heart rate with tremor and weight loss (possible hyperthyroidism).
Lung Inflammation (Pneumonitis)
Tell patient
Inflammation of the lungs can occur in approximately 3–7% of patients. It is usually treatable with steroids if caught early, but can be serious or even fatal if delayed. Do not ignore respiratory symptoms.
Call prescriber
New or worsening cough, shortness of breath at rest or with minimal exertion, chest pain with breathing, or any difficulty breathing — even if mild. Seek immediate attention if severe.
Skin Reactions
Tell patient
Rash and itching are common (affecting up to 30% of patients) and are usually mild. Most rashes can be managed with moisturizers and topical treatments. Vitiligo (loss of skin color) is possible, especially with melanoma, and may be a sign the treatment is working.
Call prescriber
Blistering, peeling skin, mouth sores, painful rash, or any rash covering a large area of the body. These may indicate a severe skin reaction requiring immediate medical attention.
Fertility & Contraception
Tell patient
Pembrolizumab may harm an unborn baby by disrupting the immune system’s normal tolerance of pregnancy. Women of childbearing potential must use effective contraception during treatment and for at least 4 months after the last dose. Breastfeeding should be avoided during treatment and for 4 months afterward.
Call prescriber
If you become pregnant or suspect pregnancy during treatment, contact your oncology team immediately.
Infusion-Day Information
Tell patient
The infusion typically takes 30 minutes. You will be monitored during and briefly after the infusion. Reactions during infusion are uncommon (affecting about 1–6% of patients) and usually mild. Routine pre-medication is not required.
Call prescriber
Fever, chills, shaking, itching, flushing, difficulty breathing, dizziness, or feeling faint during or soon after infusion. Alert the infusion nurse immediately if any of these occur.
Sources
Regulatory (PI / SmPC)
- Keytruda (pembrolizumab) injection, for intravenous use. Prescribing Information. Merck Sharp & Dohme LLC; revised 2025. merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf Primary source for all FDA-approved indications, dosing, adverse reactions, pharmacokinetics, and monitoring requirements.
- Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) injection, for subcutaneous use. Prescribing Information. Merck Sharp & Dohme LLC; 2025. accessdata.fda.gov/drugsatfda_docs/label/2025/761467s000lblOrig2.pdf Prescribing information for the subcutaneous formulation approved September 2025 for adult solid tumor indications.
- FDA approves pembrolizumab with paclitaxel for platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. FDA. February 10, 2026. fda.gov/drugs (ovarian approval) Most recent indication approval documenting pembrolizumab use in platinum-resistant ovarian cancer (KEYNOTE-B96).
Key Clinical Trials
- Robert C, Schachter J, Long GV, et al; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–2532. doi:10.1056/NEJMoa1503093 Phase III trial establishing pembrolizumab superiority over ipilimumab in advanced melanoma; source for melanoma safety data.
- Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833. doi:10.1056/NEJMoa1606774 KEYNOTE-024 trial demonstrating superior PFS and OS with first-line pembrolizumab in PD-L1 TPS ≥50% NSCLC.
- Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078–2092. doi:10.1056/NEJMoa1801005 KEYNOTE-189 trial establishing pembrolizumab + pemetrexed/platinum as first-line standard for nonsquamous metastatic NSCLC.
- Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829–841; Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma (KEYNOTE-426). N Engl J Med. 2019;380(12):1116–1127. doi:10.1056/NEJMoa1816714 KEYNOTE-426 establishing pembrolizumab/axitinib as first-line RCC; key source for hepatotoxicity data with this combination.
Guidelines
- NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities, Version 1.2025. National Comprehensive Cancer Network. nccn.org (immunotherapy guidelines) Comprehensive guidelines for monitoring and managing immune-related adverse events from checkpoint inhibitors including pembrolizumab.
- Brahmer JR, Abu-Sbeih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor–related adverse events. J Immunother Cancer. 2021;9(6):e002435. doi:10.1136/jitc-2021-002435 SITC consensus guideline on irAE management algorithms, used to inform the monitoring and management sections.
Mechanistic / Basic Science
- Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18(3):153–167. doi:10.1038/nri.2017.108 Authoritative review of PD-1/PD-L1 biology, explaining the mechanistic basis for pembrolizumab’s immunotherapeutic action and immune-related toxicities.
Pharmacokinetics / Special Populations
- Ahamadi M, Freshwater T, Prohn M, et al. Model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti–PD-1 monoclonal antibody in advanced solid tumors. CPT Pharmacometrics Syst Pharmacol. 2017;6(1):49–57. doi:10.1002/psp4.12139 Population PK analysis supporting flat dosing; demonstrates that covariates such as age, gender, renal function, and mild hepatic impairment have no clinically significant effect on pembrolizumab clearance.
- Li H, Yu J, Liu C, et al. Time-dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. J Pharmacokinet Pharmacodyn. 2017;44(5):403–414. doi:10.1007/s10928-017-9528-y Characterized time-varying clearance of pembrolizumab and exposure-response relationships across solid tumors.
- Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020;131:68–75. doi:10.1016/j.ejca.2020.02.016 PK modeling study supporting the 400 mg every 6 weeks regimen, demonstrating comparable predicted trough concentrations to 200 mg every 3 weeks.