Pembrolizumab: Indications, Dosing, and Clinical Considerations
Pembrolizumab is a PD-1 inhibitor approved for multiple cancer types with specific biomarker requirements, dosed at 200 mg IV every 3 weeks or 400 mg every 6 weeks, demonstrating superior survival outcomes compared to chemotherapy in appropriately selected patients. 1
Mechanism of Action
Pembrolizumab is a humanized monoclonal IgG4 antibody that binds to the PD-1 receptor on T cells, blocking its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response and restoring anti-tumor immunity 1. This mechanism fundamentally differs from cytotoxic chemotherapy by activating rather than suppressing the immune system 2.
FDA-Approved Indications
Non-Small Cell Lung Cancer (NSCLC)
First-line monotherapy: Pembrolizumab 200 mg every 3 weeks is the standard first-line option for metastatic NSCLC with PD-L1 expression ≥50% (tumor proportion score) in patients without EGFR mutations, ALK rearrangements, or ROS1 rearrangements 3. The KEYNOTE-024 trial demonstrated doubled median overall survival (30 vs 14 months; HR 0.6,95% CI 0.41-0.89, P=0.005) compared to platinum-doublet chemotherapy, with superior safety profile (73.4% any adverse events vs higher rates with chemotherapy) 3.
Second-line therapy: For previously treated metastatic NSCLC with PD-L1 ≥1%, pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks demonstrated superior overall survival compared to docetaxel in KEYNOTE-010 3. At 2 mg/kg, median OS was 10.4 months (HR 0.71, P=0.0008); at 10 mg/kg, median OS was 12.7 months (HR 0.61, P<0.0001) versus 8.5 months with docetaxel 3. For patients with PD-L1 ≥50%, OS benefit was even more pronounced (14.9-17.3 months vs 8.2 months with docetaxel) 3.
Melanoma
Pembrolizumab is recommended as first-line therapy for unresectable or metastatic melanoma based on KEYNOTE-006 results 3. At 10 mg/kg every 2 or 3 weeks, pembrolizumab achieved 36-37% response rates, 28-31% 2-year PFS rates, and 55% 2-year OS rates compared to 13%, 14%, and 43% respectively with ipilimumab 3. Long-term follow-up (median 33.9 months) confirmed sustained improvement in PFS and OS compared to ipilimumab monotherapy 3.
For ipilimumab-refractory melanoma, KEYNOTE-002 demonstrated 22-28% response rates with pembrolizumab versus 4% with chemotherapy (P<0.0001) 3.
Urothelial Carcinoma
Pembrolizumab is preferred second-line therapy for locally advanced or metastatic urothelial carcinoma following platinum-based chemotherapy 4. The KEYNOTE-045 trial showed superior median OS of 10.3 months versus 7.4 months with chemotherapy, with significantly fewer grade 3-5 adverse events (15.0% vs 49.4%) and median duration of response of 20.9 months 4.
For first-line treatment in cisplatin-ineligible patients with PD-L1 combined positive score ≥10, KEYNOTE-052 achieved 29% overall response rate with 7% complete responses 4.
Biomarker-Directed Indications (Tumor-Agnostic)
MSI-H/dMMR solid tumors: Pembrolizumab received FDA approval for unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment, regardless of tumor type 3, 4. Overall response rate was 39.6% with 78% of responders maintaining response for ≥6 months 4. In KEYNOTE-158 for noncolorectal MSI-H/dMMR tumors, ORR was 34.3%, median PFS 4.1 months, and median OS 23.5 months 4.
Other FDA-Approved Indications
- Classic Hodgkin lymphoma: For refractory or relapsed disease after ≥3 prior lines of therapy 3
- Cervical cancer: Combined with chemotherapy ± bevacizumab for persistent, recurrent, or metastatic disease, improving median PFS from 8.2 to 10.4 months (HR 0.62, P<0.001) 4
- Head and neck squamous cell carcinoma: For recurrent or metastatic disease with progression on or after platinum-based therapy 3
Dosing and Administration
Standard dosing: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks 1. Both regimens achieve comparable steady-state concentrations and demonstrate no clinically significant differences in efficacy or safety 1.
Pharmacokinetics: Steady-state is reached by 16 weeks with 2.1-fold systemic accumulation, terminal half-life of 22 days, and volume of distribution of 6.0 L 1. No dose adjustments are required for age (15-94 years), sex, race, renal impairment (eGFR ≥15 mL/min/1.73 m²), or mild-to-moderate hepatic impairment 1.
Pediatric dosing: 2 mg/kg every 3 weeks achieves comparable concentrations to adults at the same dose 1.
Biomarker Testing Requirements
PD-L1 testing is mandatory for NSCLC indications using FDA-approved companion diagnostic assays 5. For first-line NSCLC, eligibility requires tumor proportion score ≥50% with confirmed absence of EGFR mutations, ALK rearrangements, and ROS1 rearrangements 5. Complete all molecular testing before treatment initiation to avoid delays and ensure appropriate patient selection 5.
Critical pitfall: Different PD-L1 assays are not interchangeable—pembrolizumab requires the 22C3 companion assay with specific scoring thresholds that differ from other checkpoint inhibitors 5. For metastatic disease, rebiopsy of a metastatic site is recommended as biomarker status may differ from the primary tumor 5.
MSI-H/dMMR testing is required for tumor-agnostic indications and should be performed in metastatic castration-resistant prostate cancer to identify pembrolizumab candidates 5.
Safety Profile and Immune-Related Adverse Events
Pembrolizumab demonstrates a favorable safety profile compared to chemotherapy, with grade 3-4 treatment-related adverse events occurring in 9-18% of patients across studies versus 26-49% with chemotherapy 4, 3. The most common treatment-related adverse events are fatigue (58%), diarrhea (52%), hypertension (47%), and hypothyroidism (42%) 6.
Immune-related adverse events (irAEs) include pneumonitis, colitis, hepatitis, endocrinopathies, and skin reactions 3, 4. Grade 3-4 irAEs occur in 10-17% of pembrolizumab-treated patients 3. Thyroid function testing at baseline is recommended as hypothyroidism is the most common immune-mediated adverse event 5.
Timing of irAEs: Most immune-related toxicities develop early, but new adverse events can continue to develop throughout the treatment period as patients receive ongoing therapy, unlike ipilimumab where toxicity rates taper after completion of the 4-cycle regimen 3.
Absolute Contraindications
Solid organ transplantation is an absolute contraindication to pembrolizumab 2. The drug induces systemic, nonspecific immunostimulatory responses with proinflammatory cytokine secretion that directly antagonizes immunosuppression required to prevent transplant rejection 2. This contraindication supersedes any potential oncologic benefit, even in tumors with favorable biomarkers 2.
Severe autoimmune disease requiring systemic immunosuppression is also a contraindication 3.
Special Populations
Elderly patients: No overall differences in safety or effectiveness were observed between patients ≥65 years and younger patients across multiple indications 1. However, patients ≥75 years treated with pembrolizumab plus enfortumab vedotin experienced higher incidence of fatal adverse reactions (7% vs 4% in younger patients) 1.
Severe hepatic impairment: The impact of severe hepatic impairment (total bilirubin >3× ULN and any AST) on pembrolizumab pharmacokinetics is unknown 1.
Combination Therapy Considerations
Pembrolizumab plus lenvatinib demonstrated promising activity in phase Ib/II trials, with the recommended phase II dose established at lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks 6. Week 24 objective response rates were: RCC 63%, endometrial cancer 52%, melanoma 48%, SCCHN 36%, NSCLC 33%, and urothelial cancer 25% 6.
Combination with ipilimumab for metastatic melanoma results in 95% treatment-related adverse events with 55% grade 3 or higher, significantly higher than monotherapy 3. Grade 3-4 toxicities develop earlier and over a more prolonged period with combination therapy compared to monotherapy 3.
Duration of Therapy
Treatment duration in KEYNOTE-024 was up to 2 years 3. Median duration of response varies by indication: 20.9 months in urothelial carcinoma (KEYNOTE-045) 4, 12.5 months in NSCLC (KEYNOTE-001) 3.