Persistent CIS Despite BCG and Valrubicin: A Case Study in Treatment Challenges - Kriti Mittal
October 13, 2023
During the State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC) multidisciplinary symposium held at the 2023 Meeting of the New England Section of the AUA Kriti Mittal presents the case of a 74-year-old male with persistent high-grade urothelial carcinoma in-situ (CIS) despite multiple treatments, including BCG, valrubicin, and pembrolizumab. She transitions into discussing the evolving role of systemic immunotherapy in BCG-refractory, non-muscle invasive bladder cancer. Dr. Mittal cites the KEYNOTE-057 study, which showed a 41% complete response rate at three months with pembrolizumab monotherapy. She also mentions data from the SWOG-1605 study, which failed to meet its primary endpoint of a 30% pathologic complete response rate at six months with atezolizumab. Highlighting ongoing trials, Dr. Mittal discusses KEYNOTE cohort C, which is evaluating the combination of pembrolizumab with TIGIT or LAG-3 inhibitors, and KEYNOTE-676, which is comparing BCG monotherapy to pembrolizumab plus BCG. She emphasizes that medical oncologists are becoming increasingly involved in the management of non-muscle invasive bladder cancer.
This video is part of the State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer multidisciplinary symposium held at the 92nd Meeting of the New England Section of the AUA, organized in partnership with the Bladder Cancer Advocacy Network and supported by Pfizer, the event featured a panel of experts from various institutions.
Biographies:
Kriti Mittal, MD, MS, Medical Oncologist, University of Massachusetts
This video is part of the State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer multidisciplinary symposium held at the 92nd Meeting of the New England Section of the AUA, organized in partnership with the Bladder Cancer Advocacy Network and supported by Pfizer, the event featured a panel of experts from various institutions.
Biographies:
Kriti Mittal, MD, MS, Medical Oncologist, University of Massachusetts
Related Content:
View the Symposium Video Channel: State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer
The Future of Radiation and Anti-PD-1 Agents in Non-Muscle Invasive Bladder Cancer: An In-Depth Look at Ongoing Trials - Kent Mouw
In the Wake of BCG Shortages: A Look at Ongoing Clinical Trials and Future Therapies for Bladder Cancer - Jennifer Yates, Lydia Saravis, & Matthew Mossanen
Advances in Treatment Options for BCG Unresponsive CIS and Papillary Non-Muscle Invasive Bladder Cancer - QUILT 3.032 - Sam Chang
View the Symposium Video Channel: State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer
The Future of Radiation and Anti-PD-1 Agents in Non-Muscle Invasive Bladder Cancer: An In-Depth Look at Ongoing Trials - Kent Mouw
In the Wake of BCG Shortages: A Look at Ongoing Clinical Trials and Future Therapies for Bladder Cancer - Jennifer Yates, Lydia Saravis, & Matthew Mossanen
Advances in Treatment Options for BCG Unresponsive CIS and Papillary Non-Muscle Invasive Bladder Cancer - QUILT 3.032 - Sam Chang
Read the Full Video Transcript
Kriti Mittal: I will proceed with presenting case three. A 74-year-old male presented with hematuria to the emergency room and imaging revealed a mass at the bladder dome. A TURBT ultimately demonstrated high grade urothelial carcinoma in-situ. The patient completed six treatments with induction BCG. A follow-up cystoscopy unfortunately revealed persistent high-grade CIS.
The patient then proceeded to receive a six-week course of intravesical valrubicin, and was found to have persistent CIS. He was then re-induced with BCG completed in October of 2019. About nine months later, recurrent CIS was noted. The patient was offered cystectomy, which he declined. And based on KEYNOTE-057 cohort A data, he was initiated on pembrolizumab every three weeks. Within a few months, the patient developed diffuse severe arthralgias, requiring high dose steroids that required a taper over six weeks. And unfortunately in the interim, a follow-up cystoscopy revealed persistent CIS.
During the last section of today's talk, we will focus on the role of systemic immunotherapy and BCG refractory, non-muscle invasive bladder cancer. Laura will then share her insights on systemic toxicities of checkpoint inhibitor therapy. And last but not least, Dr. Sonpavde will share his insight on novel intravesical and systemic agents for non-muscle invasive disease.
We all know that pembrolizumab is approved for patients with BCG-unresponsive CIS, with or without papillary tumors, based on cohort A of the KEYNOTE-057 study. This was a Phase II single arm open-label study for patients who were ineligible for or declined cystectomy. Patients received pembro every three weeks, up until either disease progression, development of toxicity, or for a total of 24 months. The primary endpoint of the study was a clinical complete response rate at three months. Of the 96 patients in this cohort, 39 met the primary endpoint. So the CR rate at three months was 41%. 42% of patients had persistent disease. None of the patients progressed to muscle invasive disease.
Pembrolizumab monotherapy was found to be tolerable. Laura will teach us a little bit about side effects observed on this study in her slide set. There was promising anti-tumor activity noted, which ultimately did lead to an FDA approval for this agent. The median duration of complete response was 16.2 months. It's important to note that the durability of response, so how many responders remained in CR for 12 months or longer, was 46% of the responders. But overall, it was 18 of the 96 patients, so the durable response rate was about 20%.
Earlier this year, at ASCO GU, we saw data from cohort B of this study, which enrolled patients with papillary tumors without CIS. Patients were treated similarly with pembrolizumab every three weeks, and the primary endpoint of this study was 12 month disease-free survival rate. The toxicity profile was manageable, and consistent with earlier studies, without any new safety signals. So the 12-month rate of DFS was 43.5%, and the median DFS was 7.7 months. The percentage of patients who remained free from progression to muscle invasion, metastases, or death, was 88.2% at 12 months.
Recently, Dr. Black's crew presented data from the SWOG-1605 study that looked at atezolizumab in patients with non-muscle invasive disease. This was also a single arm Phase II trial. Patients received intravenous atezolizumab every three weeks for one year, and the primary endpoint of the study was the pathologic CR rate at six months. Based on regulatory agency guidance, the pre-specified threshold of pathologic CR at six months was set at 30%. Unfortunately, this study did not meet its primary endpoint. The CR rate was 27%. So this was a negative trial.
I would like to highlight a couple of trials in progress. This list is by no means exhaustive. KEYNOTE cohort C is evaluating the combination of pembrolizumab with TIGIT or LAG-3 inhibitors. So immune checkpoints TIGIT and LAG-3 have been shown to contribute to treatment resistance in many cancers, and it is believed that their inhibition may enhance the activity of pembrolizumab. So patients with either CIS alone or CIS in combination with Ta or T1 will be randomized in a one-to-one fashion to either receive pembrolizumab and vibostolimab, or pembrolizumab and favezelimab. The primary endpoint of this study is also a 12-month CR rate.
The last study I would like to highlight is the KEYNOTE-676 study. This is a study enrolling patients with persistent or recurrent high-risk non-muscle invasive bladder cancer after adequate BCG induction for cohort A. Patients will be randomized to either BCG monotherapy or pembrolizumab plus BCG. Medical oncologists are increasingly more involved in the care of patients with non-muscle invasive disease.
Kriti Mittal: I will proceed with presenting case three. A 74-year-old male presented with hematuria to the emergency room and imaging revealed a mass at the bladder dome. A TURBT ultimately demonstrated high grade urothelial carcinoma in-situ. The patient completed six treatments with induction BCG. A follow-up cystoscopy unfortunately revealed persistent high-grade CIS.
The patient then proceeded to receive a six-week course of intravesical valrubicin, and was found to have persistent CIS. He was then re-induced with BCG completed in October of 2019. About nine months later, recurrent CIS was noted. The patient was offered cystectomy, which he declined. And based on KEYNOTE-057 cohort A data, he was initiated on pembrolizumab every three weeks. Within a few months, the patient developed diffuse severe arthralgias, requiring high dose steroids that required a taper over six weeks. And unfortunately in the interim, a follow-up cystoscopy revealed persistent CIS.
During the last section of today's talk, we will focus on the role of systemic immunotherapy and BCG refractory, non-muscle invasive bladder cancer. Laura will then share her insights on systemic toxicities of checkpoint inhibitor therapy. And last but not least, Dr. Sonpavde will share his insight on novel intravesical and systemic agents for non-muscle invasive disease.
We all know that pembrolizumab is approved for patients with BCG-unresponsive CIS, with or without papillary tumors, based on cohort A of the KEYNOTE-057 study. This was a Phase II single arm open-label study for patients who were ineligible for or declined cystectomy. Patients received pembro every three weeks, up until either disease progression, development of toxicity, or for a total of 24 months. The primary endpoint of the study was a clinical complete response rate at three months. Of the 96 patients in this cohort, 39 met the primary endpoint. So the CR rate at three months was 41%. 42% of patients had persistent disease. None of the patients progressed to muscle invasive disease.
Pembrolizumab monotherapy was found to be tolerable. Laura will teach us a little bit about side effects observed on this study in her slide set. There was promising anti-tumor activity noted, which ultimately did lead to an FDA approval for this agent. The median duration of complete response was 16.2 months. It's important to note that the durability of response, so how many responders remained in CR for 12 months or longer, was 46% of the responders. But overall, it was 18 of the 96 patients, so the durable response rate was about 20%.
Earlier this year, at ASCO GU, we saw data from cohort B of this study, which enrolled patients with papillary tumors without CIS. Patients were treated similarly with pembrolizumab every three weeks, and the primary endpoint of this study was 12 month disease-free survival rate. The toxicity profile was manageable, and consistent with earlier studies, without any new safety signals. So the 12-month rate of DFS was 43.5%, and the median DFS was 7.7 months. The percentage of patients who remained free from progression to muscle invasion, metastases, or death, was 88.2% at 12 months.
Recently, Dr. Black's crew presented data from the SWOG-1605 study that looked at atezolizumab in patients with non-muscle invasive disease. This was also a single arm Phase II trial. Patients received intravenous atezolizumab every three weeks for one year, and the primary endpoint of the study was the pathologic CR rate at six months. Based on regulatory agency guidance, the pre-specified threshold of pathologic CR at six months was set at 30%. Unfortunately, this study did not meet its primary endpoint. The CR rate was 27%. So this was a negative trial.
I would like to highlight a couple of trials in progress. This list is by no means exhaustive. KEYNOTE cohort C is evaluating the combination of pembrolizumab with TIGIT or LAG-3 inhibitors. So immune checkpoints TIGIT and LAG-3 have been shown to contribute to treatment resistance in many cancers, and it is believed that their inhibition may enhance the activity of pembrolizumab. So patients with either CIS alone or CIS in combination with Ta or T1 will be randomized in a one-to-one fashion to either receive pembrolizumab and vibostolimab, or pembrolizumab and favezelimab. The primary endpoint of this study is also a 12-month CR rate.
The last study I would like to highlight is the KEYNOTE-676 study. This is a study enrolling patients with persistent or recurrent high-risk non-muscle invasive bladder cancer after adequate BCG induction for cohort A. Patients will be randomized to either BCG monotherapy or pembrolizumab plus BCG. Medical oncologists are increasingly more involved in the care of patients with non-muscle invasive disease.