Keytruda® (generic: pembrolizumab) is a humanized monoclonal antibody that works as an immune checkpoint inhibitor, targeting PD-1 (programmed death-1) to restore anti-tumor immune responses. First approved by the FDA in 2014, it has since become a cornerstone in modern oncology across a wide array of solid and hematologic malignancies.
🧬 Mechanism of Action
Pembrolizumab blocks the interaction between the PD-1 receptor on T-cells and its ligands PD-L1 and PD-L2, which are often upregulated in tumors as a means of immune evasion. By inhibiting this pathway:
- T-cells are reactivated, allowing them to detect and destroy cancer cells.
- This immunologic response is non-specific, meaning it can sometimes target normal tissues—hence the risk of immune-related adverse events (irAEs).
🎯 FDA-Approved Indications (2025)
Pembrolizumab is approved either alone or in combination with other therapies for over 20 cancer types. These include:
✅ Monotherapy or Combination Therapy for:
| Cancer Type | Setting |
|---|---|
| Melanoma | Adjuvant and metastatic |
| Non–small cell lung cancer (NSCLC) | First-line (with or without chemotherapy) |
| Small cell lung cancer (SCLC) | Second-line + |
| Head and neck squamous cell carcinoma (HNSCC) | First-line or after progression |
| Classical Hodgkin lymphoma | Relapsed/refractory |
| Primary mediastinal large B-cell lymphoma (PMBCL) | Relapsed/refractory |
| Renal cell carcinoma (RCC) | With axitinib or lenvatinib |
| Urothelial carcinoma (bladder/urinary tract) | Cisplatin-ineligible or BCG-unresponsive NMIBC |
| Hepatocellular carcinoma (HCC) | After sorafenib or other systemic therapy |
| Esophageal and gastric cancers | HER2+ (with trastuzumab and chemo) or HER2- (with chemo) |
| Cervical cancer | PD-L1 positive or after prior therapy |
| Endometrial carcinoma | MSI-H/dMMR, in combination with lenvatinib |
| Triple-negative breast cancer (TNBC) | PD-L1+ in neoadjuvant or metastatic settings |
| Merkel cell carcinoma | Advanced or metastatic |
| Tumor-agnostic indications: |
- MSI-H or dMMR solid tumors
- TMB ≥10 mutations/megabase
- Unresectable or metastatic tumors with no satisfactory alternative treatments
💉 Dosing and Administration
Standard Dosing (Adults)
- 200 mg IV every 3 weeks
or - 400 mg IV every 6 weeks
Administer as a 30-minute IV infusion through a sterile, low-protein-binding, in-line filter.
🕑 Maximum duration: Up to 24 months in some settings, particularly if the patient remains in stable disease or response.
Pediatric Use
- Approved in certain indications (e.g., cHL, PMBCL, MSI-H solid tumors)
- Dosing: 2 mg/kg (max 200 mg) every 3 weeks
⚠️ Pediatric safety and efficacy in many cancers are still under study.
🔁 Combination Therapies
| Setting | Regimen |
|---|---|
| RCC | Keytruda + axitinib or lenvatinib |
| TNBC | Keytruda + chemotherapy (e.g., nab-paclitaxel) |
| Gastric/esophageal | Keytruda + trastuzumab + chemo |
| Endometrial cancer | Keytruda + lenvatinib |
| NSCLC | Keytruda + platinum doublet chemotherapy |
📌 Pembrolizumab is typically administered before chemotherapy on combination days.
⚠️ Adverse Effects
Pembrolizumab can cause immune-related adverse events (irAEs) affecting virtually any organ.
Common irAEs:
| System | Effect |
|---|---|
| Skin | Rash, pruritus, vitiligo |
| GI | Colitis, diarrhea |
| Endocrine | Hypo-/hyperthyroidism, adrenal insufficiency, diabetes, hypophysitis |
| Hepatic | Immune-mediated hepatitis |
| Pulmonary | Pneumonitis |
| Renal | Nephritis |
| Neurologic | Myasthenia gravis, Guillain–Barré, encephalitis |
| Others | Infusion reactions, myocarditis, uveitis |
Management:
- Grade 1–2: Monitor or use corticosteroids (e.g., prednisone 0.5–1 mg/kg/day)
- Grade ≥3: Hold Keytruda and initiate high-dose steroids (1–2 mg/kg/day); consider permanent discontinuation
📌 Always rule out infection before attributing symptoms to irAEs.
🔄 Drug Interactions
Pembrolizumab does not have major CYP-mediated drug interactions, but immunosuppressants (e.g., corticosteroids) can reduce efficacy:
| Drug Class | Examples |
|---|---|
| Corticosteroids | Prednisone, dexamethasone, methylprednisolone |
| Immunomodulators | Thalidomide, lenalidomide, pomalidomide |
| Biologics | Efgartigimod alfa |
📌 Use steroids only when needed for irAE management, not prophylactically.
🧪 Monitoring and Safety
| Test | Frequency |
|---|---|
| CBC, CMP, LFTs | Every 3–6 weeks |
| Thyroid panel | At baseline, then periodically |
| Blood glucose | Especially if diabetic risk or symptoms |
| Pulmonary exam | Monitor for new cough or dyspnea |
| Adrenal and cortisol testing | If fatigue, hypotension, or confusion develop |
❗ Contraindications / Cautions
| Condition | Caution |
|---|---|
| Autoimmune disease | May flare; use with extreme caution |
| Organ transplant | Risk of rejection |
| Interstitial lung disease | High pneumonitis risk |
| Pregnancy | Embryo-fetal toxicity possible |
| Lactation | Avoid; unknown excretion in milk |
🧊 Storage and Stability
- Store vials at 2°C–8°C (36°F–46°F)
- Protect from light
- Do not freeze or shake
- Use diluted solution within 6 hours at room temperature or 24 hours refrigerated
🔗 Further Information
✅ Summary (2025)
- Keytruda (pembrolizumab) is a PD-1 immune checkpoint inhibitor with broad indications across oncology
- Can be used in both biomarker-selected and tumor-agnostic contexts (e.g., MSI-H, TMB-high)
- Must be managed with awareness of immune-related toxicities
- Requires careful selection, ongoing monitoring, and multidisciplinary support