Lead Investigator Highlights Pembrolizumab Potential in BCG-Resistant Bladder Cancer

Ronald de Wit MD, PhD

Pembrolizumab (Keytruda) demonstrated durable activity in patients with high-risk nonmuscle—invasive bladder cancer (NMIBC) who were resistant to Bacillus Calmette-Guérin (BCG), according to an interim analysis from the single-arm, open-label, phase II KEYNOTE-057 trial.

Findings presented at the 2018 ESMO Congress showed a 38.8% complete response (CR) rate for cohort A, which comprised patients with NMIBC who have carcinoma in situ (CIS) or CIS plus papillary disease (n = 130). At a median follow-up of 3 months, approximately 80% of these responses were maintained after 6 months, explained lead author Ronald de Wit, MD, PhD.

"Treatment options for high-risk NMIBC have historically been limited, with many patients relying on radical cystectomy as their only option following disease recurrence. Additionally, about 40% of patients with high-risk nonmuscle—invasive bladder cancer progress to muscle-invasive disease," said de Wit, group leader of the experimental systematic therapy of urogenital cancers program at Erasmus MC Cancer Institute, Rotterdam, Netherlands.

OncLive: Please provide an overview of the KEYNOTE-057 trial.

In an interview with OncLive at the 2018 ESMO Congress, de Wit discussed the clinical implications of pembrolizumab in this NMIBC patient population.DeWit: I presented the interim results of an ongoing study testing the efficacy and duration of response of pembrolizumab in patients with NMIBC at high risk for disease progression and who were unresponsive to BCG therapy. The data I presented were from cohort A, which was a high-risk population. We had a data cut-off of April 1, 2018, to ensure a sufficient follow-up time for this interim analysis. At that time, we had enrolled 103 patients, and I presented on these patients.

What we found was a 39% CR rate at a median of 12 weeks. We also found that 75% of these responses were maintained for a median duration of response of more than 6 months. Many patients are still in response. In terms of safety profile, there was nothing unexpected. No patients progressed to muscle-invasive disease. There was 1 patient who died from a treatment-related adverse event. This patient had grade 3 colitis that was not properly managed.

What is the difficulty in treating this patient population?

Will immunotherapy eventually have a bigger role in bladder cancer?

These results are encouraging, and we have to realize the only other option for these patients is radical cystectomy. This procedure has morbidity and mortality, and it is associated with adverse quality of life. Some patients even refuse that procedure or are ineligible for that procedure. This is an important new avenue for treatment, especially if we can preserve the bladder for these patients.Historically, we know that in high-risk NMIBC, about one-third of patients have disease recurrence within 1 year. If not properly treated, 40% will ultimately have MIBC and then the risk of dying from metastatic disease. This is not a benign disease. If patients recur after being treated with BCG, the next step is radical cystectomy. This is the patient population we are talking about. They need a treatment that will allow them to keep their bladder and eliminate that risk of dying from the disease.The use of checkpoint inhibition is obvious in bladder cancer, similar to other diseases, such as melanoma and lung cancer. It has to do with the mutational profile of these diseases. We know of the survival benefit for second-line immunotherapy following platinum-based therapy [in bladder cancer]. Pembrolizumab has evidence of providing survival benefit, particularly for frontline treatment of cisplatin-ineligible patients.

What is the take-home message of KEYNOTE-057?

In PD—L1-positive patients, the median OS for patients was 18 months. Just for comparison, we know the median OS for patients treated with gemcitabine was 9 months. We are seeing robustly better results with immunotherapy.First of all, we have to realize, as medical oncologists, that NMIBC is not a benign disease. It really needs adequate treatment. Based on these encouraging results we presented, I would suggest patients be referred to the sites that will be accruing in the upcoming study of BCG with or without pembrolizumab.

De Wit R, Kulkarni G, Uchio E, et al. Pembrolizumab for high-risk (HR) non—muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): phase 2 KEYNOTE-057 trial. Presented at ESMO 2018; October 19-23, Munich, Germany. 864O.