On January 8, 2020, pembrolizumab was approved for treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non–muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.^1,2

Supporting Efficacy Data

Approval was based on findings in the phase II KEYNOTE-057 trial (ClinicalTrials.gov identifier NCT02625961),^2,3 which enrolled 148 patients with high-risk non–muscle invasive bladder cancer; efficacy analysis was performed in the 96 patients with BCG-unresponsive carcinoma in situ with or without papillary tumors. Patients received pembrolizumab at 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk non–muscle invasive bladder cancer, progressive disease, or for up to 24 months in the absence of disease progression.

BCG-unresponsive high-risk non–muscle invasive bladder cancer was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as at least five of six doses of an initial induction course plus either at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. All patients had undergone transurethral resection of bladder tumor to remove resectable disease. Residual carcinoma in situ not amenable to complete resection was permitted. Patients with muscle-invasive, locally advanced, nonresectable or metastatic urothelial carcinoma, concurrent extravesical non–muscle invasive transitional cell carcinoma of the urothelium or autoimmune disease or a medical condition requiring immunosuppression were not eligible for the study.

The median follow-up was 28.0 months. The complete response rate was 41%. The median response duration was 16.2 months.

How It Works

Binding of programmed cell death ligand 1 and 2 (PD-L1/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 the inhibition of active T-cell tumor immune surveillance.

How It Is Used

The recommended dose of pembrolizumab in patients with high-risk BCG-unresponsive non–muscle invasive bladder cancer is 200 mg via intravenous infusion over 30 minutes every 3 weeks until persistent or recurrent high-risk non–muscle invasive bladder cancer, disease progression, unacceptable toxicity, or for up to 24 months in patients without disease progression.

No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling.

Product labeling provides recommended dosing modifications, including withholding, resuming, and discontinuing treatment for the following adverse reactions: immune-mediated pneumonitis, colitis, endocrinopathies, nephritis, skin adverse reactions, and hepatitis in patients with and without hepatocellular carcinoma; liver enzyme elevations in patients with renal cell carcinoma receiving combination therapy; hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; inability to taper corticosteroid treatment; persistent grade 2 or 3 adverse reactions (excluding endocrinopathy); and infusion-related reactions.

Safety Profile

The most common adverse events (reported in ≥ 20% of patients) observed in patients receiving pembrolizumab as a single agent in clinical trials have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

Among the total of 148 patients receiving pembrolizumab in KEYNOTE-057, the median duration of exposure to pembrolizumab was 4.3 months (range = 1 day–25.6 months). The most common adverse events of any grade were fatigue, diarrhea, rash, pruritus, musculoskeletal pain, hematuria, and cough. The most common grade 3 or 4 adverse events were diarrhea and urinary tract infection. The most common grade 3 or 4 laboratory abnormalities were hyperglycemia, hyponatremia, and hypophosphatemia.

Serious adverse events occurred in 28% of patients, with the most common being pneumonia, cardiac ischemia, colitis, pulmonary embolism, sepsis, and urinary tract infection. Adverse events led to interruption of pembrolizumab in 22% of patients, with the most common causes being diarrhea and urinary tract infection, and to discontinuation in 11%, with the most common cause being pneumonitis.

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis; immune-mediated colitis; immune-mediated hepatitis (and hepatotoxicity in combination with axitinib); immune-mediated endocrinopathies; immune-mediated nephritis; immune-mediated skin adverse reactions including Stevens--Johnson syndrome and toxic epidermal necrolysis; other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer. Accessed February 5, 2020.

2. Keytruda (pembrolizumab) for injection for intravenous use prescribing information. January 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s066lbl.pdf. Accessed February 5, 2020.

3. Balar AV, Kulkarni GS, Uchio EM, et al: KEYNOTE-057: Phase II trial of pembrolizumab for patients with high-risk nonmuscle invasive bladder cancer unresponsive to bacillus calmette-guérin. 2019 Genitourinary Cancers Symposium. Abstract 350. Presented February 15, 2019.