Neoadjuvant Atezolizumab with Gemcitabine and Cisplatin in Patients with Muscle-Invasive Bladder Cancer - Samuel A. Funt
July 29, 2021
In this UroToday discussion between Alicia Morgans and Samuel Funt, they discuss Samuel Funt’s recent phase 2 trial evaluating the use of atezolizumab, with gemcitabine and cisplatin, as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC). The conversation begins with background on the study, beginning with Dr. Funt’s description of neoadjuvant cisplatin-based chemotherapy as the standard of care for patients with MIBC, who are cisplatin-eligible. Dr. Funt then describes his rationale for including atezolizumab, with gemcitabine and cisplatin, which is that chemotherapy may modulate the immune microenvironment and make a more permissive environment for anti-tumor immunity. As the conversation progresses, Dr. Morgans makes an important point about how this treatment could avoid over-treatment in MIBC, a problem in this cancer type. This conversation concludes with a call to further investigation into this combination of therapies.
Biographies:
Samuel A. Funt, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Biographies:
Samuel A. Funt, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Read the Full Video Transcript
Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the US. I'm so excited to have here with me today, Dr. Sam Funt, who is a GU Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York. Thank you so much for being here with me today.
Samuel Funt: Thank you for having me.
Alicia Morgans: Wonderful. I wanted to talk with you a little bit about your recent presentation at ASCO 2021, where you talked about the use of atezolizumab, in addition to gemcitabine and cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. This was a phase two study. Can you tell us a little bit about it?
Samuel Funt: Yes, absolutely. As you may be aware, neoadjuvant cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive bladder cancer, who are cisplatin eligible. And we are looking to improve upon the efficacy of gemcitabine and cisplatin, which is the standard of care and used widely as a neoadjuvant regimen. And we elected to combine gemcitabine and cisplatin with the immune checkpoint inhibitor, atezolizumab. And the rationale for that is threefold. We know that immunotherapy is active in patients with platinum-refractory disease in the metastatic setting and in fact atezolizumab is approved for patients with metastatic bladder cancer. And there is also a thought that chemotherapy might modulate the immune microenvironment, make it more permissive to anti-tumor immunity. And also we know now that immunotherapy, PD-1 blockade specifically, has efficacy as monotherapy in patients with muscle-invasive bladder cancer. So for those reasons we launched our phase two study evaluating atezolizumab, gemcitabine, and cisplatin as neoadjuvant therapy.
Alicia Morgans: Great. And that definitely makes sense. As I understand, this was although a single-arm trial, this was a multicenter study. How many patients did you enroll in and what did you find?
Samuel Funt: That's exactly right. It was a multicenter study. We enrolled patients within the Memorial Sloan Kettering Alliance, including our main center, Lehigh Valley, and Hartford, as well as NYU and Ohio State University. We enrolled 44 patients and treated 44 patients. Five of those patients were inevaluable because they received less than two cycles of therapy and were removed from the study for non-treatment-related toxicity or withdrawal of consent. And so we had 39 response evaluable patients. And we found that the downstaging rate, which was the primary endpoint, so downstaging to less than non-muscle invasive disease, or less than pT2 node-negative disease was 69%, which made it a positive study and compares quite favorably to what we see with gemcitabine/cisplatin monotherapy. We also found a complete pathologic response rate of 44%, which also compares favorably with gemcitabine and cisplatin monotherapy. We found that the regimen was overall well-tolerated or what is to be expected with immunotherapy and chemotherapy, the toxicities were in line with the individual components. So chemotherapy, we saw neutropenia, thrombocytopenia, and we did see some patients with immune-related adverse events, which is to be expected when you use these agents.
Alicia Morgans: And that's definitely true. Was the rate of immune-related adverse events what you expected? Was it similar, on the same level, or was it more, or less?
Samuel Funt: So with regard to immune-related adverse events, there were six patients with grade three immune-related adverse events, so 14% of the study population. And of those six, two required high-dose systemic steroids, so prednisone 40 milligrams or greater. There was one patient with hepatitis and one with immune-related nephritis, and actually, the immune-related nephritis was discovered after radical cystectomy. So, that we feel is in line with prior studies.
Alicia Morgans: It sounds that to me, for sure. So as you think about this and the path CR rate, which is actually like you said, it's quite a nice path CR rate, similar perhaps to some prior work with gemcitabine and cisplatin alone. How are you planning to move forward with your future studies? Are you using this combination in a larger randomized trial or are there other plans for the future on this?
Samuel Funt: It's a really good question. And I just want to highlight one additional important finding from the study. We know from studies with chemotherapy, with cisplatin-based chemotherapy, that those patients that are downstaged to less than muscle-invasive disease experience really excellent outcomes, excellent overall survival and a very low rate of relapse. And it's important to note that we found that as well. There were 36 patients that went to surgery out of the 39. Two patients actually progressed to metastatic disease prior to surgery, and one patient refused surgery. All three of those patients were considered non-responders. But of the 36 patients that went to surgery, of the patients that were found to be downstaged, none subsequently relapsed and of the non-responders, four subsequently relapsed or progressed to metastatic disease.
So that is a really important finding from this study, and in terms of the future of neoadjuvant therapy for cisplatin eligible patients, there are a number of ongoing phase three studies. There is the KEYNOTE-866 study, which is evaluating pembrolizumab, again, using that gemcitabine and cisplatin backbone and comparing it to gemcitabine and cisplatin. There is the ENERGIZE study with nivolumab and linrodostat. There's the NIAGARA study looking at durvalumab in combination with gemcitabine and cisplatin.
Now, with regard to all of these studies, they are important studies, but they do include on the backend after surgery, additional adjuvant immunotherapy, irrespective of whether or not patients have responded. And so I think to a certain extent because we've seen time and time again that patients are downstaged, the patients that are downstaged have excellent outcomes. We have to be careful to try and minimize toxicity in those patients and not expose them unnecessarily to therapy.
So, in terms of where the field is moving, I think these studies are important, but I also feel it's important to minimize the burden of toxicity. For example, there are a number of ongoing studies looking at the presence of DNA damage repair mutations in the pre-treatment tumor, which we know really seem to predict excellent responses. These studies, including an ongoing Alliance study, are looking at avoiding cystectomy in those patients and in patients with DDR mutations and a good clinical response, watching them instead of removing the bladder. And so I think it's important to incorporate genomic profiling, novel agents, and try and maintain efficacy while minimizing toxicity.
Alicia Morgans: I couldn't agree more. I think it's phenomenal too, that we are moving muscle-invasive bladder cancer into a space where we can think about avoiding over-treatment because I think we all know that was not a concern years ago, particularly when we had fewer options to potentially decrease the rate of complications and certainly decrease adverse events that patients feel and experience are impacting their daily life. So, wonderful goal.
And then just to your point about biomarkers, were there subsets? Did you guys look for PD-L1 status within this work? Was there an association between that and response? You know, it's not the best biomarker that we have to use in this situation, and so we don't always see it. So I'm just curious about this particular study, what you found.
Samuel Funt: Yes, that's a really good question because looking to identify patients who either are responders or who are going to be resistant to the therapy ahead of time is a really important effort. And PD-L1 staining by immunohistochemistry is perhaps the most well-known biomarker for trying to predict immunotherapy response. And we did perform PD-L1 immunohistochemistry using the VENTANA SP142 Assay, and we did all the staining centrally. We did it using standard procedures, we didn't let the slide sit for a prolonged period of time. They needed to be stained within 60 days. The majority of slides were stained significantly sooner. And despite all that, we actually only found four patients that were PD-L1 positive, which is a rate of about 10%, which is much lower than what has been reported in other studies in patients with metastatic disease and in muscle-invasive disease using the same Assay.
So it's just what we found. All four patients who were PD-L1 positive were responders, but then if you look at the non-responders and put it all together, it's not predictive of response in our study. And therefore we are now in the process of really delving into these tumors, interrogating these tumors using next-generation sequencing, whole-exome sequencing, doing RNA sequencing, and trying to better determine who is responsive and who is going to be resistant to these therapies.
Alicia Morgans: I'm glad that you're doing that. I really do look forward to hearing more about these patients, because you did have a great CR rate. And as you said, there are multiple phase threes that are exploring similar approaches, so we will continue to learn more. If you could just give us a bottom-line summary statement for this trial to the listeners, what would that be?
Samuel Funt: In terms of a bottom line for this study, the addition of atezolizumab to gemcitabine and cisplatin was safe and associated with a 69% pathologic downstaging rate and a 44% complete response rate in patients with muscle-invasive bladder cancer. And therefore this combination really compares favorably with historical data and should be investigated further. There are ongoing phase three studies looking at the gemcitabine and cisplatin combination with PD-1 or PD-L1 blockade, we are beginning to incorporate novel agents. And it's really important that we look for genomic biomarkers of response and resistance beyond PD-L1.
Alicia Morgans: I could not agree more. Thank you so much for taking the time to explain this and congratulations to you and the team, and of course, congratulations to the patients and thank you to them for doing such excellent work, and really serving to move the field forward. We appreciate it.
Samuel Funt: Absolutely. Thank you for having me and I also echo thanking my co-investigators, the other sites, and of course, the patients and their families for participating in the study.
Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the US. I'm so excited to have here with me today, Dr. Sam Funt, who is a GU Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York. Thank you so much for being here with me today.
Samuel Funt: Thank you for having me.
Alicia Morgans: Wonderful. I wanted to talk with you a little bit about your recent presentation at ASCO 2021, where you talked about the use of atezolizumab, in addition to gemcitabine and cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. This was a phase two study. Can you tell us a little bit about it?
Samuel Funt: Yes, absolutely. As you may be aware, neoadjuvant cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive bladder cancer, who are cisplatin eligible. And we are looking to improve upon the efficacy of gemcitabine and cisplatin, which is the standard of care and used widely as a neoadjuvant regimen. And we elected to combine gemcitabine and cisplatin with the immune checkpoint inhibitor, atezolizumab. And the rationale for that is threefold. We know that immunotherapy is active in patients with platinum-refractory disease in the metastatic setting and in fact atezolizumab is approved for patients with metastatic bladder cancer. And there is also a thought that chemotherapy might modulate the immune microenvironment, make it more permissive to anti-tumor immunity. And also we know now that immunotherapy, PD-1 blockade specifically, has efficacy as monotherapy in patients with muscle-invasive bladder cancer. So for those reasons we launched our phase two study evaluating atezolizumab, gemcitabine, and cisplatin as neoadjuvant therapy.
Alicia Morgans: Great. And that definitely makes sense. As I understand, this was although a single-arm trial, this was a multicenter study. How many patients did you enroll in and what did you find?
Samuel Funt: That's exactly right. It was a multicenter study. We enrolled patients within the Memorial Sloan Kettering Alliance, including our main center, Lehigh Valley, and Hartford, as well as NYU and Ohio State University. We enrolled 44 patients and treated 44 patients. Five of those patients were inevaluable because they received less than two cycles of therapy and were removed from the study for non-treatment-related toxicity or withdrawal of consent. And so we had 39 response evaluable patients. And we found that the downstaging rate, which was the primary endpoint, so downstaging to less than non-muscle invasive disease, or less than pT2 node-negative disease was 69%, which made it a positive study and compares quite favorably to what we see with gemcitabine/cisplatin monotherapy. We also found a complete pathologic response rate of 44%, which also compares favorably with gemcitabine and cisplatin monotherapy. We found that the regimen was overall well-tolerated or what is to be expected with immunotherapy and chemotherapy, the toxicities were in line with the individual components. So chemotherapy, we saw neutropenia, thrombocytopenia, and we did see some patients with immune-related adverse events, which is to be expected when you use these agents.
Alicia Morgans: And that's definitely true. Was the rate of immune-related adverse events what you expected? Was it similar, on the same level, or was it more, or less?
Samuel Funt: So with regard to immune-related adverse events, there were six patients with grade three immune-related adverse events, so 14% of the study population. And of those six, two required high-dose systemic steroids, so prednisone 40 milligrams or greater. There was one patient with hepatitis and one with immune-related nephritis, and actually, the immune-related nephritis was discovered after radical cystectomy. So, that we feel is in line with prior studies.
Alicia Morgans: It sounds that to me, for sure. So as you think about this and the path CR rate, which is actually like you said, it's quite a nice path CR rate, similar perhaps to some prior work with gemcitabine and cisplatin alone. How are you planning to move forward with your future studies? Are you using this combination in a larger randomized trial or are there other plans for the future on this?
Samuel Funt: It's a really good question. And I just want to highlight one additional important finding from the study. We know from studies with chemotherapy, with cisplatin-based chemotherapy, that those patients that are downstaged to less than muscle-invasive disease experience really excellent outcomes, excellent overall survival and a very low rate of relapse. And it's important to note that we found that as well. There were 36 patients that went to surgery out of the 39. Two patients actually progressed to metastatic disease prior to surgery, and one patient refused surgery. All three of those patients were considered non-responders. But of the 36 patients that went to surgery, of the patients that were found to be downstaged, none subsequently relapsed and of the non-responders, four subsequently relapsed or progressed to metastatic disease.
So that is a really important finding from this study, and in terms of the future of neoadjuvant therapy for cisplatin eligible patients, there are a number of ongoing phase three studies. There is the KEYNOTE-866 study, which is evaluating pembrolizumab, again, using that gemcitabine and cisplatin backbone and comparing it to gemcitabine and cisplatin. There is the ENERGIZE study with nivolumab and linrodostat. There's the NIAGARA study looking at durvalumab in combination with gemcitabine and cisplatin.
Now, with regard to all of these studies, they are important studies, but they do include on the backend after surgery, additional adjuvant immunotherapy, irrespective of whether or not patients have responded. And so I think to a certain extent because we've seen time and time again that patients are downstaged, the patients that are downstaged have excellent outcomes. We have to be careful to try and minimize toxicity in those patients and not expose them unnecessarily to therapy.
So, in terms of where the field is moving, I think these studies are important, but I also feel it's important to minimize the burden of toxicity. For example, there are a number of ongoing studies looking at the presence of DNA damage repair mutations in the pre-treatment tumor, which we know really seem to predict excellent responses. These studies, including an ongoing Alliance study, are looking at avoiding cystectomy in those patients and in patients with DDR mutations and a good clinical response, watching them instead of removing the bladder. And so I think it's important to incorporate genomic profiling, novel agents, and try and maintain efficacy while minimizing toxicity.
Alicia Morgans: I couldn't agree more. I think it's phenomenal too, that we are moving muscle-invasive bladder cancer into a space where we can think about avoiding over-treatment because I think we all know that was not a concern years ago, particularly when we had fewer options to potentially decrease the rate of complications and certainly decrease adverse events that patients feel and experience are impacting their daily life. So, wonderful goal.
And then just to your point about biomarkers, were there subsets? Did you guys look for PD-L1 status within this work? Was there an association between that and response? You know, it's not the best biomarker that we have to use in this situation, and so we don't always see it. So I'm just curious about this particular study, what you found.
Samuel Funt: Yes, that's a really good question because looking to identify patients who either are responders or who are going to be resistant to the therapy ahead of time is a really important effort. And PD-L1 staining by immunohistochemistry is perhaps the most well-known biomarker for trying to predict immunotherapy response. And we did perform PD-L1 immunohistochemistry using the VENTANA SP142 Assay, and we did all the staining centrally. We did it using standard procedures, we didn't let the slide sit for a prolonged period of time. They needed to be stained within 60 days. The majority of slides were stained significantly sooner. And despite all that, we actually only found four patients that were PD-L1 positive, which is a rate of about 10%, which is much lower than what has been reported in other studies in patients with metastatic disease and in muscle-invasive disease using the same Assay.
So it's just what we found. All four patients who were PD-L1 positive were responders, but then if you look at the non-responders and put it all together, it's not predictive of response in our study. And therefore we are now in the process of really delving into these tumors, interrogating these tumors using next-generation sequencing, whole-exome sequencing, doing RNA sequencing, and trying to better determine who is responsive and who is going to be resistant to these therapies.
Alicia Morgans: I'm glad that you're doing that. I really do look forward to hearing more about these patients, because you did have a great CR rate. And as you said, there are multiple phase threes that are exploring similar approaches, so we will continue to learn more. If you could just give us a bottom-line summary statement for this trial to the listeners, what would that be?
Samuel Funt: In terms of a bottom line for this study, the addition of atezolizumab to gemcitabine and cisplatin was safe and associated with a 69% pathologic downstaging rate and a 44% complete response rate in patients with muscle-invasive bladder cancer. And therefore this combination really compares favorably with historical data and should be investigated further. There are ongoing phase three studies looking at the gemcitabine and cisplatin combination with PD-1 or PD-L1 blockade, we are beginning to incorporate novel agents. And it's really important that we look for genomic biomarkers of response and resistance beyond PD-L1.
Alicia Morgans: I could not agree more. Thank you so much for taking the time to explain this and congratulations to you and the team, and of course, congratulations to the patients and thank you to them for doing such excellent work, and really serving to move the field forward. We appreciate it.
Samuel Funt: Absolutely. Thank you for having me and I also echo thanking my co-investigators, the other sites, and of course, the patients and their families for participating in the study.