ASCO GU 2019: Phase II Trial of Pembrolizumab for Patients with High-Risk Non-Muscle Invasive Bladder Cancer Unresponsive to BCG

San Francisco, CA ( The primary management for non-muscle invasive bladder cancer is surgical resection via transurethral resection of bladder tumor (TURBT). Unfortunately, many patients will have disease recurrence or progression. According to the European Organization for Research and Treatment risk tables (EORTC), after a median follow up of 3.9 years, 47.8% had at least one recurrence with a median time to first recurrence of 2.7 years, and 11% of patients had progression to muscle-invasive disease.1 For low-risk patients, a single dose of intravesical chemotherapy or surveillance may be sufficient. However, for high-risk patients, first line intravesical Bacillus Calmette-Guerin (BCG) therapy is standard of care, as recommended by the American Urological Association (AUA), the European Association of Urology (EAU), and the Canadian Urological Association (CUA) bladder cancer guidelines.2-4 However, while intravesical BCG significantly reduces short term and long-term treatment failure, up to 30% of patients have recurrent disease and at 10 year follow up, only 59% had a retained bladder and disease-specific survival was 85%.5  Thus, additional therapies are necessary to rescue these patients and offer long term bladder sparing solution. In the PURE-01, pre-operative pembrolizumab was given to patients with muscle-invasive UC and found that neoadjuvant pembrolizumab could induce a pathologic complete response in 40% of the patients.6 This study provides data on the use of pembrolizumab in a BCG refractory population of non-muscle invasive patients.
1Keynote57 singlearm

This is a single arm, phase II study for patients with BCG refractory non-muscle invasive bladder cancer (NMIBC). Patients had histologically confirmed high-risk disease, defined as carcinoma in situ, T1 tumor, and/or high-grade Ta disease. The definition of BCG unresponsiveness required that patients first had adequate BCG therapy (patients with ≥5 doses of BCG of an induction course plus at least 2 doses of maintenance therapy or 2 doses of second induction course) and they were refractory/relapsing (see below).

This abstract describes the outcomes of patients in cohort A, those with carcinoma in situ (CIS) with or without papillary disease (high-grade Ta or T1). In terms of treatment, patients received pembrolizumab 200 mg every 3 weeks for 2 years or until recurrence, progression, or unacceptable toxicity.

A total of 102 patients were enrolled. The majority of patients were men (83%). These patients had a median of 12 prior BCG instillations.

After a median follow up of 15.8 months, the complete response rate was 40.2%, with a median CR duration of 12.7 months. 36.6% of patients developed recurrent NMIBC after having a complete response and no patients progressed to muscle-invasive disease/metastatic disease.

In terms of safety, 28% of patients developed grade 3/4 treatment-related events. Grade 3/4 immune-mediated adverse events occurred in 3% of patients and there was 1 treatment-related death secondary to immune-mediated colitis (which was re-classified to cohort B at the time of this presentation).

Pembrolizumab may be effective at inducing a complete response in up to 40% of patients with BCG refractory NMIBC. Very few patients had grade 3/4 immune-related adverse events. A phase 3 study evaluating pembrolizumab in high risk non-muscle invasive bladder cancer that is persistent after BCG induction (KEYNOTE 676) is underway

Clinical Trial Information: NCT02625961

Presented by: Arjun V. Balar, MD, NYU Langone Perlmutter Cancer Center, New York, New York

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

  1. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. European Urology 2006;49:466-77.
  2. Babjuk M, Böhle A, Burger M, et al. EAU guidelines on non–muscle-invasive urothelial carcinoma of the bladder: update 2016. European Urology 2017;71:447-61.
  3. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. The Journal of Urology 2016;196:1021-9.
  4. Kassouf W, Traboulsi SL, Kulkarni GS, et al. CUA guidelines on the management of non-muscle invasive bladder cancer. Canadian Urological Association Journal 2015;9:E690.
  5. Davis JW, Sheth SI, Doviak MJ, Schellhammer PF. Superficial bladder carcinoma treated with bacillus Calmette-Guerin: progression-free and disease-specific survival with minimum 10-year follow up. The Journal of Urology 2002;167:494-501.
  6. Necchi A, Briganti A, Bianchi M, et al. Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study. American Society of Clinical Oncology; 2018.