The FDA recently approved pembrolizumab (Keytruda®, Merck) for the treatment of patients with high-risk non-muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG) therapy. The approval was based on Keynote 057 (NCT02625961), a phase 2 trial in which pembrolizumab produced a complete response rate of 41% in patients with this disease. In this interview with i3 Health, Ashish Kamat, MD, MBBS, Professor of Urologic Oncology (Surgery) and Cancer Research at MD Anderson Cancer Center and one of Keynote 057's investigators, discusses the benefits of pembrolizumab and the future of treatment for patients with high-risk BCG-unresponsive NMIBC.
What are some of the most challenging aspects of treating patients with high-risk BCG-unresponsive NMIBC?
Ashish Kamat, MD, MBBS: The greatest challenge for this particular patient population is the fact that no treatment is as oncologically efficacious as radical cystectomy. At the same time, it is not a surgery to be taken lightly, because it is life-altering for patients. The challenge lies in understanding the window of opportunity for trying agents to allow the patients to save their bladder, while also minimizing the risk for disease progression. This window is important because if bladder cancer becomes metastatic, it can quickly become incurable. Then it's not a matter of trying to save the patient's bladder, but of struggling to save the patient's life.
Can you comment on the significance of the approval of pembrolizumab for patients with high-risk BCG-unresponsive NMIBC?
Dr. Kamat: The approval is obviously a win for our patients, because now they have more options before a radical cystectomy. That being said, it's not a home run as far as the efficacy of the drug is considered. When patients are being counseled, they should obviously be informed that a radical cystectomy is still the safest and most effective therapy, but that we do have another option that is now approved.
Another significant factor is that over the years, the FDA has reached out to us as experts in the field, and we and the FDA together have come forward to improve our understanding of the nuances of NMIBC and how people respond or do not respond to BCG therapy. The FDA has subsequently come up with a guidance to allow investigators and drug developers to assess drugs in a controlled fashion. This particular trial was the first one to be evaluated under the new paradigm that the FDA has put forth. I think that going through this whole process does allow pharmaceutical companies, investigators, and patients to recognize that there is a new protocol for approval to be followed and that this paradigm has been carefully vetted by the FDA.
How do you foresee the treatment of high-risk BCG-unresponsive NMIBC evolving?
Dr. Kamat: There's a great deal of interest in this field, which is good. There are a number of drugs, both local and systemic, that are being looked at and developed in this space. Over the last five to six years, we've seen one drug already approved, two that are in fast track for potential approval, and at least four more that are currently being studied. This field is going to continue to evolve fairly rapidly, which will be great for patients. However, it's also going to be a little hard to continue to conduct clinical trials in this space, mainly because there won't be enough patients to enroll in the trials. That's why a group of experts had an intense discussion with the FDA regarding patients who are BCG-unresponsive and may not have a good result with one drug in a particular trial, in the hopes that these patients be allowed to enroll in other trials with the same designation. The FDA has been open to that. This is something that we'll have to consider carefully when counseling patients on options once drugs are approved and available.
Do you have any words of advice for community oncologists, urologists, and other members of the cancer care team treating patients with high-risk BCG-unresponsive NMIBC?
Dr. Kamat: The management of bladder cancer has always been very complex. It has been siloed in the past, in that early-stage disease has been managed by urologists or urologic oncologists, more advanced or metastatic disease has been managed by medical oncologists, and the stages in between have been managed jointly in a multidisciplinary fashion. We at MD Anderson and other cancer centers have recognized for a long time that all of these patients really need multidisciplinary care. Now, with the approval of a systemic agent, it's even more important that the whole community of treating physicians—which includes both medical oncologists and urologic oncologists—works together for the optimal benefit of our patients.
About Dr. Kamat
Ashish Kamat, MD, MBBS, is a Professor of Urologic Oncology (Surgery) and Wayne B. Duddlesten Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas. He is also President of the International Bladder Cancer Group and Co-President of the International Bladder Cancer Network. Dr. Kamat specializes in the treatment of urologic cancers, with an emphasis on immunotherapy, organ sparing therapies, minimally invasive techniques, and orthotopic bladder substitution. He has authored over 275 peer-reviewed publications, editorials, and book chapters, and his research focuses on the development of novel therapies to personalize treatment and improve outcomes in patients with bladder cancer.
For More Information
Balar AV, Kulkarni GS, Uchio EM, et al (2019). Keynote 057: phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG). J Clin Oncol (2019 Genitourinary Cancers Symposium Abstracts), 37(suppl_7). Abstract 350. DOI:10.1200/JC0.2019.37.7_suppl.350
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.