On May 18, 2017, pembrolizumab (Keytruda) was granted regular approval for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.^1,2 Pembrolizumab was also granted accelerated approval for treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. 

Supporting Efficacy Data 

THE REGULAR APPROVAL for second-line treatment was based on findings in a phase III trial (KEYNOTE-045)^2,3 in which 542 patients were randomized to receive pembrolizumab at 200 mg every 3 weeks (n = 270) or investigator’s choice of a chemotherapy regimen (n = 272; paclitaxel = 84, docetaxel = 84, or vinflunine = 87) every 3 weeks. Median overall survival was 10.3 months in the pembrolizumab group vs 7.4 months in the control group (hazard ratio [HR] = 0.73, P = .004). Objective response rates were 21% vs 11% (P = .002). There was no difference in progression-free survival (median = 2.1 vs 3.3 months, HR = 0.98, P = .833). 

The accelerated approval for the first-line indication was based on data from a single-arm trial (KEYNOTE-052) in which 370 patients received pembrolizumab at 200 mg every 3 weeks.² With a median follow-up of 7.8 months, the objective response rate was 28.6%; the median duration of response was not reached, with a range of 1.4+ to 17.8+ months. 

How It Works 

BINDING OF PROGRAMMED cell death ligand 1 (PD-L1) and PD-L2 to the programmed cell death protein 1 (PD-1) receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth. 

How It Is Used 

THE RECOMMENDED DOSE of pembrolizumab in urothelial carcinoma is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. 

Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of the product labeling. Pembrolizumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathy, grade 4 hematologic toxicity in patients with classical Hodgkin lymphoma, grade 2 nephritis, aspartate transaminase (AST) or alanine transaminase (ALT) level > 3 to 5 times or total bilirubin level > 1.5 to 3 times the upper limit of normal (ULN), and any other severe or grade 3 treatment-related adverse reaction. Treatment can be resumed when adverse reactions recover to grade 0 or 1. 

Pembrolizumab should be permanently discontinued for grade 3 or 4 infusion-related reactions, any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy or hematologic toxicity in patients with classical Hodgkin lymphoma), grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis, grade 3 or 4 nephritis, AST or ALT level > 5 times or total bilirubin level > 3 times ULN, AST or ALT level increases of ≥ 50% persisting for ≥ 1 week in patients with liver metastasis who began treatment with grade 2 increased AST or ALT level, inability to reduce corticosteroid dose to ≤ 10 mg/d of prednisone or equivalent within 12 weeks, persistent grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) that do not recover to grade 0 or 1 within 12 weeks of the last dose, and any recurrent severe or grade 3 treatment-related adverse reaction. 

Safety Profile 

IMMUNE-MEDIATED adverse events, including pneumonitis, colitis, hepatitis, and endocrinopathies, were reported in both trials in urothelial carcinoma and were managed according to label guidelines. 

In the KEYNOTE-045 study, the most common adverse events of any grade in the pembrolizumab group were fatigue (38% vs 56% in control group), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), and nausea (21% vs 29%); the most common grade 3 or 4 adverse events were urinary tract infection (4.9% vs 4.3%), fatigue (4.5% vs 11%), and decreased appetite (3.8% vs 1.2%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (15% vs 25%), decreased hemoglobin (13% vs 18%), decreased sodium (9% vs 13%), and increased glucose (8% vs 7%). 

Serious adverse events occurred in 39% of pembrolizumab patients, with the most common (≥ 2%) being urinary tract infection, pneumonia, anemia, and pneumonitis. Adverse events led to treatment interruption in 20% of pembrolizumab patients, with the most common causes being urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Adverse events led to treatment discontinuation in 8%, with the most common cause being pneumonitis (1.9%). 

In the single-arm KEYNOTE-052 study, the most common adverse events of any grade were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). The most common grade 3 or 4 adverse events were anemia (7%), fatigue (6%), musculoskeletal pain (4.9%), and hyponatremia (4.1%). 

Serious adverse events occurred in 42% of patients, with the most frequent (≥ 2%) being urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. Adverse events led to treatment interruption in 22% (including liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia) and to treatment discontinuation in 11%. Immune-related adverse events requiring systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to immune-related adverse events occurred in 8%, and 5% required ≥ 1 steroid dose ≥ 40 mg oral prednisone equivalent. Eighteen patients (5%) died of causes other than disease progression; 5 (1.4%) died of sepsis and 3 (0.8%) died of pneumonia. 

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), immune-mediated nephritis, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Breastfeeding women should discontinue treatment or breastfeeding. ■

REFERENCES 

1. U.S. Food and Drug Administration: Pembrolizumab (Keytruda): Advanced or metastatic urothelial carcinoma. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm559300.htm. Accessed January 8, 2018. 

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co., Inc., May 2017. Available at https://www.accessdata. fda.gov/drugsatfda_docs/label/2017/125514s017s018lbl.pdf. Accessed January 8, 2018. 

3. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017.