THE ANTI–PROGRAMMED cell death protein 1 (anti–PD-1) checkpoint inhibitor pembrolizumab (Keytruda) was found to have antitumor activity in patients with high-risk non–muscle invasive bladder cancer who were nonresponsive to bacillus Calmette-Guérin (BCG), according to the preliminary results of the phase II KEYNOTE-057 trial, which were presented at the European Society for Medical Oncology (ESMO) 2018 Congress.1 Further follow-up from this ongoing study is needed to see whether these results hold up.
The complete response rate with pembrolizumab was 38.8%, which is the highest seen with any agent in this setting. The duration of response was at least 6 months in the majority of responders.
Ronald de Wit, MD, PhD
“This interim analysis of an ongoing study provides compelling complete response rates and duration of response in patients with BCG-unresponsive carcinoma in situ who refused or were ineligible for cystectomy and so had limited options,” said lead author Ronald de Wit, MD, PhD, of Erasmus Medical Center Daniel den Hoed Cancer Centre, Rotterdam, the Netherlands. “Of patients with recurrent non–muscle invasive bladder cancer treated with pembrolizumab, none progressed to muscle-invasive or metastatic disease. The treatment was tolerable, and a phase III study is planned.”
The phase III KEYNOTE-676 trial will study pembrolizumab in combination with BCG in patients with high-risk non–muscle invasive bladder cancer that is persistent or recurrent after BCG induction. The study will be conducted at 40 sites in 40 countries, he added.
Non–muscle invasive bladder cancer is a fairly common type of bladder cancer. For high-risk patients, standard of care is transurethral removal of the bladder tumor and intravesical BCG. The complete response rate is about 70%, but most patients with high-risk non–muscle invasive bladder cancer will recur.
“This disease is not benign and is potentially life-threatening. Radical cystectomy is associated with significant morbidity and mortality, and many patients refuse to have the surgery. There is an urgent need for local therapies to reduce the risk for recurrence and preserve the bladder,” Dr. de Wit continued.
Study Details and Results
KEYNOTE-057 IS a single-arm, open-label, phase II trial that enrolled patients with non–muscle invasive bladder cancer who refused or who are ineligible for cystectomy. The study had two cohorts: cohort A—carcinoma in situ with or without papillary disease; cohort B—papillary disease without carcinoma in situ. Dr. de Wit’s presentation focused on cohort A, representing the more difficult-to-treat type of non–muscle invasive bladder cancer.
Patients were treated with pembrolizumab at 200 mg every 3 weeks and were assessed and evaluated at intervals for up to 24 months. Treatment was discontinued for progressive disease.
The primary endpoint for cohort A was complete response. At a median follow-up of 14 months, 32 are in ongoing treatment, and 71 discontinued treatment. At month 3, the complete response rate was 38.8%. Six patients were not evaluable for response. The median duration of response was not reached. The median time to complete response was 12.4 weeks. Ten patients (25%) experienced recurrent non–muscle invasive bladder cancer after complete response. No patient in the trial developed muscle-invasive or metastatic disease.
There were 3 deaths reported, and 27 patients had grade 3 to 5 adverse events. One death was attributed to a treatment-related adverse event, but that patient did not receive steroids, Dr. de Wit noted. Treatment-related adverse events of any grade were reported in 63%. The most common treatment-related adverse events were pruritus and hypothyroidism. Grades 3 to 5 adverse events included adrenal insufficiency (1%), colitis (1%), hypophysitis (2.9%), and pruritus (1%). ■
DISCLOSURE: Dr. de Wit has received honoraria from Sanofi, Lilly, Roche/Genentech, and Merck Sharp & Dohme; has served as a consultant/advisor for Roche/Genentech, Sanofi, Merck Sharp & Dohme, and Lilly; and has received institutional research funding from Sanofi and Bayer.
1. deWit R, et al: Pembrolizumab for high-risk non–muscle invasive bladder cancer unresponsive to Bacillus Calmette-Guérin: Phase 2 KEYNOTE-057 trial. ESMO 2018 Congress. Abstract 864O. Presented October 20, 2018.
Shahrokh Shariat, MD
“BACILLUS CALMETTE-GUÉRIN (BCG) failures are quite common, with a 66% recurrence rate at 5 years, and about 25% of patients will have disease progression,” explained formal discussant Shahrokh Shariat, MD, Chair of the Department of Urology at Medical University, Vienna,...