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Keytruda for patients with 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, approved by FDA


The FDA ( U.S. Food and Drug Administration ) has approved Keytruda ( Pembrolizumab ), an anti-PD-1 therapy, as monotherapy for the treatment of patients with Bacillus Calmette-Guerin ( BCG )-unresponsive, high-risk, non-muscle invasive bladder cancer ( NMIBC ) with carcinoma in situ ( CIS ) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with Pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation ( HSCT ).
Based on the severity of the adverse reaction, Pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate.
Pembrolizumab can also cause severe or life-threatening infusion-related reactions.
Based on its mechanism of action, Pembrolizumab can cause fetal harm when administered to a pregnant woman.

High-risk, non-muscle invasive bladder cancer is a serious disease, characterized by frequent recurrences and progression.
Historically, patients with high-risk, non-muscle invasive bladder cancer with carcinoma in situ ( CIS ) whose cancer is unresponsive to BCG treatment had limited non-surgical treatment options.

The approval was based on data from KEYNOTE-057, a multicenter, open-label, single-arm trial in 96 patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer ( NMIBC ) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
In this study, BCG-unresponsive high-risk NMIBC 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 administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course.
Prior to treatment, all patients had undergone transurethral resection of bladder tumor ( TURBT ) to remove all resectable disease ( Ta and T1 components ).
Residual CIS ( Tis components ) not amenable to complete resection was allowed.
The trial excluded patients with muscle invasive ( i.e., T2, T3, T4 ) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical ( i.e., urethra, ureter or renal pelvis ) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression.

Patients received Pembrolizumab 200 mg every three weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease.
Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months.
The major efficacy outcome measures were complete response ( as defined by negative results for cystoscopy [ with TURBT / biopsies as applicable ], urine cytology, and computed tomography urography [ CTU ] imaging ) and duration of response.

The study population characteristics were: median age 73 years ( range: 44 to 92 ); 44% age greater than or equal to 75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively.
Tumor pattern at study entry was CIS with T1 ( 13% ), CIS with high grade TA ( 25% ), and CIS ( 63% ).
Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent.
The median number of prior instillations of BCG was 12.

The median follow-up time was 28.0 months ( range: 4.6 to 40.5 months ).
Pembrolizumab has demonstrated a complete response rate of 41% ( range: 31 to 51 ). Among the 39 patients who achieved a complete response, the median duration of response was 16.2 months ( range: 0.0+ to 30.4+ ), and 46% ( n=18 ) had a response of 12 months or longer.

The safety of Pembrolizumab was investigated in KEYNOTE-057, which enrolled 148 patients with high-risk NMIBC, 96 of whom had BCG-unresponsive CIS with or without papillary tumors.
The median duration of exposure to Pembrolizumab was 4.3 months ( range: 1 day to 25.6 months ).

Pembrolizumab was discontinued due to adverse reactions in 11% of patients. The most common adverse reaction ( more than 1% ) resulting in permanent discontinuation of Pembrolizumab was pneumonitis ( 1.4% ).
Adverse reactions leading to interruption of Pembrolizumab occurred in 22% of patients; the most common ( greater than or equal to 2% ) were diarrhea ( 4% ) and urinary tract infection ( 2% ).
Serious adverse reactions occurred in 28% of Pembrolizumab-treated patients. The most frequent serious adverse reactions ( greater than or equal to 2% ) in Pembrolizumab-treated patients were pneumonia ( 3% ), cardiac ischemia ( 2% ), colitis ( 2% ), pulmonary embolism ( 2% ), sepsis ( 2% ), and urinary tract infection ( 2% ).
The most common adverse reactions ( greater than or equal to 20% ) with Pembrolizumab were fatigue ( 29% ), diarrhea ( 24% ) and rash ( 24% ). ( Xagena )

Source: Merck, 2020

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