Pembrolizumab (Keytruda)

Pembrolizumab is an immune checkpoint inhibitor (ICI) and a type of immunotherapy used to treat multiple cancers, including bladder cancer. It works by blocking the PD-1/PD-L1 pathway, enabling the immune system to recognize and attack cancer cells more effectively.

Key Features

• Drug Class: Anti-PD-1 monoclonal antibody.
• Administration: Intravenous (IV) infusion (every 3 or 6 weeks).
• FDA Approvals in Bladder Cancer:
  • 1st-line for cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (UC) (PD-L1+).
  • 2nd-line for PD-L1+ UC progressing after platinum chemo.
  • BCG-unresponsive NMIBC (non-muscle-invasive, high-risk).

How Pembrolizumab Works

1. Blocks PD-1 (on immune T-cells) from binding PD-L1 (on cancer cells).
2. Releases the “brakes” on the immune system, allowing T-cells to attack tumors.
3. Induces long-term responses in some patients (durable remissions).

Clinical Use in Blancer Cancer

1. Metastatic/Locally Advanced UC

• 1st-line (Cisplatin-Ineligible):
  • Used if tumor is PD-L1+ (CPS ≥10) or patient cannot tolerate platinum chemo.
  • Response rate: ~30% (higher in PD-L1+ tumors).
• 2nd-line (After Platinum Failure):
  • Improves survival vs. chemotherapy in PD-L1+ patients.

2. BCG-Unresponsive NMIBC

• Alternative to radical cystectomy (bladder removal).
• Approval based on KEYNOTE-057 trial:
  • Complete response (CR) rate: ~41% (durable in ~20% at 2 years).

Side Effects

Common (≥20%):

• Fatigue, rash, diarrhea, nausea.
• Immune-related adverse events (irAEs):
  • Pneumonitis (lung inflammation).
  • Colitis (diarrhea, abdominal pain).
  • Hepatitis, Thyroid dysfunction.
  • Skin reactions (vitiligo, pruritus).

Management:

• Steroids (e.g., prednisone) for moderate-severe irAEs.
• Permanent discontinuation in life-threatening cases.

Effectiveness

Who Should NOT Receive Pembrolizumab?

• Active autoimmune disease (e.g., lupus, severe Crohn’s).
• Organ transplant recipients (high rejection risk).
• Pregnancy (potential fetal harm).

Future Directions

• Combination therapies (e.g., pembrolizumab + chemo/BCG).
• Biomarker research to improve patient selection.

Takeaway

Pembrolizumab is a breakthrough immunotherapy for advanced bladder cancer and BCG-unresponsive NMIBC, offering durable responses in some patients. However, immune-related side effects require careful monitoring.