ESMO 2018: Pembrolizumab for High-Risk Non–Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to BCG: Phase 2 Keynote-057 Trial

Munich, Germany (UroToday.com) Ronald de Wit, MD, Ph.D. presented preliminary results of the Keynote-057 trial of Pembrolizumab for high risk non-muscle invasive bladder cancer (NMIBC) patients who were unresponsive to Bacillus Calmette-Guerin (BCG) therapy. This was a single arm open-label phase 2 study. Dr. de Wit began with an introduction and review of BCG unresponsive high-risk NMIBC. Adequate BCG therapy is defined as at least 5-6 instillations of induction BCG + at least 2 of 3 doses of maintenance therapy or 2 of 6 doses of a second induction course.

BCG refractory disease is defined as stage progression at three months after adequate BCG induction, or persistent high-risk disease at six months despite adequate BCG.

Finally, BCG relapsing disease is defined as recurrence of high-risk NMIBC after the patient achieves a disease-free state within 12 months after adequate BCG therapy.

In the absence of treatment, BCG-unresponsive carcinoma in situ (CIS) will persist and progress. Radical cystectomy is the standard option for patients with BCG-unresponsive NMIBC. However, radical cystectomy entails significant morbidity and mortality, has a negative impact on the quality of life, and many patients refuse or are ineligible for this surgical treatment.  Therefore, there is an n urgent need for novel therapies to reduce the risk for recurrence and preserve the bladder.  With the lack of a suitable comparator, single arm-designs have been found suitable in the BCG unresponsive population.

Activation of the PD-1 pathway has been implicated in resistance to BCG therapy. The PD-1 inhibitor pembrolizumab has demonstrated significant antitumor activity in patients with metastatic urothelial carcinoma.  Little is known about anti-PD-1 monotherapy for NMIBC.

After concluding this introduction, Dr. de Wit moved on to discuss the design and results of the Keynote-057 trial. As mentioned previously, this was a single-arm, open-label phase 2 study (NCT02625961). The study design is shown in figure 1. High-risk NMIBC patients, who were unresponsive to BCG, and refuse, or are ineligible for radical cystectomy, were enrolled in this study. There were two cohorts in this study- cohort A – patients with CIS with or without papillary disease (high-grade Ta or T1), and cohort B – Papillary disease (high-grade Ta or any T1) with no CIS. Patients were given pembrolizumab 200 mg every three weeks and evaluated with cystoscopy, cytology, and a biopsy every 12 weeks for two years, and then every 24 weeks for two years and once yearly after that. Patients also underwent CT urogram every 24 weeks for two years. The primary endpoints were complete response rates in cohort A and disease-free survival in cohort B.

UroToday ESMO2018 Keynote057
Figure 1 - Keynote 057 trial design:

Overall, in cohort, A 103 patients were recruited and treated. A total of 71 patients had discontinued for various reasons, and 32 (31.1%) remained on treatment to date. The median follow-up was 14 months. Baseline characteristics of the patients demonstrated that the median age was 73, with 83% being males. A complete response rate was witnessed in 38.8% of patients. The median time to complete response rate was 12.4 weeks. A total of 72.5% had an ongoing response, and 25% of the patients experienced recurrent NIMBC after complete response. Only one patient in the complete response group underwent radical cystectomy, but none of the patients developed muscle-invasive bladder cancer (MIBC) or metastatic disease. 

When assessing the group of patients that achieved a complete response rate at three months after treatment, 80% of them continued to have a complete response at six months, and their median complete response rate had not been reached yet. Lastly, the adverse events that were seen were relatively low, with grade 3-5 treatment-related adverse events seen in 12.6% of patients.

Dr. de Wit concluded his talk with some important conclusions:

Pembrolizumab demonstrated encouraging anti-tumor activity, with a compelling, complete response rate and duration of response in patients with BCG-unresponsive CIS (with or without papillary disease), who refused or were ineligible for radical cystectomy. Importantly, in those patients who had a recurrence, none experienced progression to MIBC. Finally, Phase 3 randomized clinical trials to study the efficacy and safety of pembrolizumab, in combination with BCG  in patients with high-risk NMIBC, that is persistent or recurrent following BCG induction will be initiated (Keynote-676).


Presented by: Ronald de Wit, MD, Ph.D., Professor, Rotterdam, the Netherlands

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany

Further Related Content: Invited Discussant - Pembrolizumab for High-Risk Non–Muscle Invasive Bladder Cancer Unresponsive to BCG: Phase 2 Keynote-057 Trial
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