Results from Cohort B of the Phase 2 KEYNOTE-057 Trial, Pembrolizumab Monotherapy for Patients with High-Risk Non–muscle-Invasive Bladder Cancer Unresponsive to BCG - Andrea Necchi
March 16, 2023
Andrea Necchi joins Alicia Morgans in a discussion on longer-term outcome data for non-muscle invasive bladder cancer patients without a carcinoma in-situ, cohort B in the KEYNOTE-057 study. The cohort B of the study focused on the patients without a CIS component and with only pTa or T1 papillary disease, high-risk disease, BCG-unresponsive disease. This is a difficult-to-treat patient population, and there is no strong data from the literature regarding standard therapies. The standard of care is radical cystectomy. Pembrolizumab monotherapy was provided to patients every three weeks until disease progression or recurrence or up to two years in patients without recurrence. The disease-free survival at one year was the primary endpoint, and the proportion of patients achieving this goal was 43%. The safety data aligned with available data from pembro monotherapy in various disease settings, and no death event occurred. Dr. Necchi emphasizes that there may be an additional therapeutic opportunity for these patients, and there may be room for re-discussing the opportunities for conducting trials as single-arm trials instead of randomized studies.
Biographies:
Andrea Necchi, MD, Medical Oncologist, Associate Professor of Oncology, Vita-Salute San Raffaele University, Chief of Genitourinary, Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Andrea Necchi, MD, Medical Oncologist, Associate Professor of Oncology, Vita-Salute San Raffaele University, Chief of Genitourinary, Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here with Andrea Necchi, speaking about Keynote 057 and a really exciting oral presentation that you gave at ASCO GU 2023, updating the data for non-muscle invasive bladder cancer. Thank you so much for being here.
Andrea Necchi: Thank you, Alicia. Thank you today for inviting me.
Alicia Morgans: Always happy to talk with you. So tell us a little bit about the study, sort of the setup, what you intended to do and then, of course, share these longer term outcome data with us.
Andrea Necchi: Yeah, well they were presented in the ASCO GU meeting that would be the results from the cohort B of the Keynote 057 study. The study was a multi cohort study, the results from cohort A, which was including patients with the carcinoma in situ component with or without papillary tumor had been already disclosed and published and resulted in FDA, U.S. FDA approval of pembrolizumab monotherapy in patients with high risk CIS BCG-unresponsive tumor. The cohort B of the study focused on the patient's without a CIS component and with only PTA or T1 papillary disease, high risk disease, BCG-unresponsive disease. So this similar patient population, but without the CIS component in the histological examination. It's a very, very difficult patient population, difficult to treat. There is medical need for these patients because we don't have any strong data, robust data from the literature regarding standard therapies. The standard of care is radical cystectomy.
Here we are dealing with patients who are refusing or who are ineligible for radical cystectomy basically. And the study was providing pembrolizumab monotherapy according to standard schedule every three weeks until disease progression or recurrence or up to two years in patients without any recurrence. The disease-free survival at one year for high risk disease was the primary endpoint and revealed a proportion of 43% of patients achieving this goal, which is quite competitive I think. And this data achieved on the population of 132 patients are among the most robust data already available in this special patient population with longer term follow up With the median followup was about 45 months, so a robust followup.
And also we did not record any particular safety signal. Safety data were completely in line with available data from pembro monotherapy in various disease setting, in various disease stages, including the Cohort A of the same study. No death event occurred. So I think that it may be an option for extending the indication of pembrolizumab towards this population without a CIS component to receive a standard of care therapy, a potential standard of care therapy or newer treatment options in case they are ineligible for or elect not to undergo radical cystectomy.
Alicia Morgans: Just to clarify for listeners, why were these two populations separated out into separate cohorts to begin with? Is there a biologic difference between patients with CIS and those without in terms of disease aggressiveness or options for therapy that we think might be effective?
Andrea Necchi: Yeah, it's a good point. The patients with CIS component are a bit different from patients without CIS because of the fact that here in patients with CIS, there is less impact of the TURBT resection in conditioning or in being associated with the survival and disease-free survival outcome in these patients. So we clearly need newer therapies, intravesically or intravenously in this patient population in case they are failing the BCG treatment according to conventional definitions. Both CIS and papillary tumors define the population of higher risk and non-muscle invasive tumor. For patients without a CIS component, there is a strong role for TURBT. So here for these patients in particular, there may be a huge bias represented by the heterogeneity and completeness of a TURBT. And this of course may be a bias and this is one of the reasons why the regulators are asking for randomized clinical trials in non-CIS patient population in order to set potential new standard of care in this setting, in the post BCG setting.
The problem is how to best identify the standard of care therapy to provide intravesically for these patients. We have very limited and sparse data from the literature. We don't have any strong data. So we are still searching for something that may be used to compare in randomized studies, this population. So this, it is an open question. I think that the results from cohort B of Keynote 057 will raise substantial discussion around this. And I think there may be room for re-discussing the opportunities of setting new standard therapies in this very special disease population.
Alicia Morgans: I could not agree more. And thank you so much for walking us through that. So bottom line, final word, what are your thoughts here? What should we take home from this presentation?
Andrea Necchi: I think that the take home message here is that we may have an additional therapeutic opportunity for these patients. Most importantly, I think that we could re-discuss at the multi-stakeholder table the way to move forward in clinical trials in this special population of papillary PTA or PT-1 tumors without the CIS in case they are failing or unresponsive or relapse after BCG. I think that we may re-discuss the opportunities for conducting trials as single arm trials instead of randomized studies. And I think that with further discussion should be needed with the urologists, regulators, patient advocates. The patient voice will be critical in this space. I think that the data will be great because they will likely generate a newer discussion around this.
Alicia Morgans: Wonderful. Well thank you so much for your time, for your efforts, and for talking us through this very important data.
Andrea Necchi: Thank you.
Alicia Morgans: Hi, I'm so excited to be here with Andrea Necchi, speaking about Keynote 057 and a really exciting oral presentation that you gave at ASCO GU 2023, updating the data for non-muscle invasive bladder cancer. Thank you so much for being here.
Andrea Necchi: Thank you, Alicia. Thank you today for inviting me.
Alicia Morgans: Always happy to talk with you. So tell us a little bit about the study, sort of the setup, what you intended to do and then, of course, share these longer term outcome data with us.
Andrea Necchi: Yeah, well they were presented in the ASCO GU meeting that would be the results from the cohort B of the Keynote 057 study. The study was a multi cohort study, the results from cohort A, which was including patients with the carcinoma in situ component with or without papillary tumor had been already disclosed and published and resulted in FDA, U.S. FDA approval of pembrolizumab monotherapy in patients with high risk CIS BCG-unresponsive tumor. The cohort B of the study focused on the patient's without a CIS component and with only PTA or T1 papillary disease, high risk disease, BCG-unresponsive disease. So this similar patient population, but without the CIS component in the histological examination. It's a very, very difficult patient population, difficult to treat. There is medical need for these patients because we don't have any strong data, robust data from the literature regarding standard therapies. The standard of care is radical cystectomy.
Here we are dealing with patients who are refusing or who are ineligible for radical cystectomy basically. And the study was providing pembrolizumab monotherapy according to standard schedule every three weeks until disease progression or recurrence or up to two years in patients without any recurrence. The disease-free survival at one year for high risk disease was the primary endpoint and revealed a proportion of 43% of patients achieving this goal, which is quite competitive I think. And this data achieved on the population of 132 patients are among the most robust data already available in this special patient population with longer term follow up With the median followup was about 45 months, so a robust followup.
And also we did not record any particular safety signal. Safety data were completely in line with available data from pembro monotherapy in various disease setting, in various disease stages, including the Cohort A of the same study. No death event occurred. So I think that it may be an option for extending the indication of pembrolizumab towards this population without a CIS component to receive a standard of care therapy, a potential standard of care therapy or newer treatment options in case they are ineligible for or elect not to undergo radical cystectomy.
Alicia Morgans: Just to clarify for listeners, why were these two populations separated out into separate cohorts to begin with? Is there a biologic difference between patients with CIS and those without in terms of disease aggressiveness or options for therapy that we think might be effective?
Andrea Necchi: Yeah, it's a good point. The patients with CIS component are a bit different from patients without CIS because of the fact that here in patients with CIS, there is less impact of the TURBT resection in conditioning or in being associated with the survival and disease-free survival outcome in these patients. So we clearly need newer therapies, intravesically or intravenously in this patient population in case they are failing the BCG treatment according to conventional definitions. Both CIS and papillary tumors define the population of higher risk and non-muscle invasive tumor. For patients without a CIS component, there is a strong role for TURBT. So here for these patients in particular, there may be a huge bias represented by the heterogeneity and completeness of a TURBT. And this of course may be a bias and this is one of the reasons why the regulators are asking for randomized clinical trials in non-CIS patient population in order to set potential new standard of care in this setting, in the post BCG setting.
The problem is how to best identify the standard of care therapy to provide intravesically for these patients. We have very limited and sparse data from the literature. We don't have any strong data. So we are still searching for something that may be used to compare in randomized studies, this population. So this, it is an open question. I think that the results from cohort B of Keynote 057 will raise substantial discussion around this. And I think there may be room for re-discussing the opportunities of setting new standard therapies in this very special disease population.
Alicia Morgans: I could not agree more. And thank you so much for walking us through that. So bottom line, final word, what are your thoughts here? What should we take home from this presentation?
Andrea Necchi: I think that the take home message here is that we may have an additional therapeutic opportunity for these patients. Most importantly, I think that we could re-discuss at the multi-stakeholder table the way to move forward in clinical trials in this special population of papillary PTA or PT-1 tumors without the CIS in case they are failing or unresponsive or relapse after BCG. I think that we may re-discuss the opportunities for conducting trials as single arm trials instead of randomized studies. And I think that with further discussion should be needed with the urologists, regulators, patient advocates. The patient voice will be critical in this space. I think that the data will be great because they will likely generate a newer discussion around this.
Alicia Morgans: Wonderful. Well thank you so much for your time, for your efforts, and for talking us through this very important data.
Andrea Necchi: Thank you.