Adjuvant Study of Immune Checkpoint Blockade in Patients with Urothelial Carcinoma - Matthew Galsky
February 19, 2021
First Results from the Phase 3 CheckMate 274 Trial of Adjuvant Nivolumab vs Placebo in Patients Who Underwent Radical Surgery for High-Risk Muscle-Invasive Urothelial Carcinoma were presented at ASCO GU 2021 and are the topic of discussion between Matthew Galsky, MD and Alicia Morgans, MD, MPH. CheckMate274 is a phase 3, randomized, double-blind, multicenter trial comparing nivolumab and placebo in a 1:1 randomized fashion among patients with high-risk muscle-invasive urothelial carcinoma (with primary tumor sites including bladder, ureter, or renal pelvis) after radical surgery.
The primary outcomes of interest were disease-free survival (DFS) in all randomized patients (ITT population) and in patients with tumor PD-L1 expression ≥ 1%. Assessment of DFS was stratified by nodal status, receipt of prior neoadjuvant cisplatin, and PD-L1 status. A key secondary endpoint was non–urothelial tract recurrence-free survival (NUTRFS) among ITT patients and among those with PD-L ≥ 1%. Further, safety is an exploratory endpoint.
Biographies:
Matthew Galsky, MD is Professor of Medicine (Hematology and Medical Oncology) and Acting Chief of the Division of Hematology and Medical Oncology for the Mount Sinai Health System. Dr. Galsky also serves as Director of Genitourinary Medical Oncology, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and Associate Director for Translational Research at The Tisch Cancer Institute.
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.
The primary outcomes of interest were disease-free survival (DFS) in all randomized patients (ITT population) and in patients with tumor PD-L1 expression ≥ 1%. Assessment of DFS was stratified by nodal status, receipt of prior neoadjuvant cisplatin, and PD-L1 status. A key secondary endpoint was non–urothelial tract recurrence-free survival (NUTRFS) among ITT patients and among those with PD-L ≥ 1%. Further, safety is an exploratory endpoint.
Biographies:
Matthew Galsky, MD is Professor of Medicine (Hematology and Medical Oncology) and Acting Chief of the Division of Hematology and Medical Oncology for the Mount Sinai Health System. Dr. Galsky also serves as Director of Genitourinary Medical Oncology, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and Associate Director for Translational Research at The Tisch Cancer Institute.
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'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago. I'm so excited to have here with me today as part of our GU ASCO 2021 coverage, Dr. Matt Galsky, who is a professor of medicine and the acting chief of the division of hematology and medical oncology at Mount Sinai. Thank you so much for being here with us today, Dr. Galsky.
Matthew Galsky: Thank you. Glad to be here.
Alicia Morgans: Great. Thank you, Matt. We're so excited to hear you talk to us a little bit about CheckMate 274, which was presented by Dean Bajorin. I know you two have a long standing relationship, but really I think that this data is so interesting, so important and informative. I'd love to hear you tell us a little bit about who was in the study, what were you assessing and what did you find?
Matthew Galsky: Thank you. Yes. It was really a pleasure to see Dean present this data. For those of you who haven't been in the field a very long time, Dean was my fellowship director and my mentor many, many years ago, so really a pleasure to work with him on this study and to see him present the results.
CheckMate 274 was an adjuvant study of immune checkpoint blockade in urothelial cancer, including upper tract disease and bladder cancer. It's an adjuvant study that's a bit different than adjuvant studies that have been done in the past in our field because it enrolled patients who had received prior neoadjuvant chemotherapy and had residual pathologic evidence of disease T2 or higher, or patients who didn't have neoadjuvant chemotherapy but were cisplatin ineligible.
We talk about this as an adjuvant study, but really it's different than the adjuvant studies that have been done in the past with chemotherapy. The study randomized patients one-to-one, stratified based on PD-L1 expression based on prior neoadjuvant chemotherapy or not to receive one year of adjuvant nivolumab. That was given at the every two week schedule for a year versus placebo infusions every two weeks for a year.
The primary endpoints of this study were disease free survival in the all comer population and then disease free survival in patients with a high expression of PD-L1 in their tumors. Remember, each of these immune checkpoint inhibitors uses a different assay. This is the 288 antibody clone measuring PD-L1 on tumor cells with a cutoff of greater than or equal to 1% and that's defined high.
That was the primary endpoint. Secondary endpoints are overall survival and non-urothelial tract recurrence free survival. That endpoint's important because disease-free survival includes patients with second primary tumors, quote unquote, or urothelial tract recurrences. Remember, if someone has a nephroureterectomy, they can have a bladder tumor down the line and vice versa. Those are counted as events for DFS in these studies if the tumors are invasive and so important to have another endpoint that removes those recurrences and includes everything else, pelvic recurrences outside of the urothelial attractor distant recurrences.
At ASCO GU this year, the co-primary endpoints were presented, so disease-free survival in the all comer group and then disease-free survival in patients with tumors with high PD-L1 expression. I should mention that using this assay in this cutoff in this patient population, about 40% of patients had a high PD-L1 expression. The study showed a significant improvement with adjuvant nivolumab for DFS in the all-comer population with a hazard ratio of around 0.7. And in patients with high PD-L1 expression, and improvement in DFS with a hazard ratio of 0.53.
The secondary endpoints non-urothelial tract recurrence-free survival, and the endpoint of metastasis-free survival showed very similar effect sizes.
Alicia Morgans: Let's dig into this a little bit because I think that we had an opportunity to talk just before recording a little bit about the nuances of these particular endpoints. Can you tell us a little bit about what you make of the disease-free survival data in the all-comers population, certainly an improvement, but how do you interpret the clinical meaning of this?
Matthew Galsky: Disease-free survival is obviously in part a radiographic endpoint. I should've mentioned that key secondary endpoint of this study is overall survival, but it wasn't a primary endpoint. I should also mention that all of these time [inaudible 00:04:42] endpoints were event driven and so no overall survival data was shown not because we didn't want to show it. It was not shown because the number of events haven't been reached to actually look at that data yet. This is a blinded study, placebo controlled. No one's seen that data yet. The significance, the clinical significance of a DFS endpoint is in part related, I think, to the effect size. If you see a small improvement in DFS, that could be viewed differently than in terms of the clinical impact than a large effect size on DFS. It's in part related to the natural history or the treated history of the disease upon recurrence and not to minimize the impact of recurrence in any other solid tumor or the risk of recurrence, but we are talking about urothelial cancer here where the risk of recurrence in this patient population's about 60%. It's not a breast cancer study, again, not to minimize the impact of recurrence on those patients. I'm simply making a point about the effect size and the risk of recurrence. Sometimes those studies are looking at risks of recurrence in the five to 10% range. We're talking about 60%. You can't improve survival, I don't think, in this setting based on most of the mechanisms of our drugs without improving DFS first. I think we're part of the way there. One could look at the data in counsel patients, and you have to ask yourself today, "Does my patient sitting in front of me half the time to wait for overall survival data based on the effect size, or do we make a decision based on the assumption that it might be beneficial in terms of OS as well?"
Alicia Morgans: I think I completely agree with that. I think that this is almost could also be compared to the MFS or metastasis free survival endpoint that we have in prostate cancer, that when that MFS prolongation became significantly longer in the non-metastatic CRPC setting, for example, with the AR antagonist agents, the FDA even said, "Hey, that's not a survival endpoint overall survival endpoint," but that's such a, like you said, the effect size is so large that the duration of prolongation is so large, the hazard ratio was so large that this is meaningful. It's meaningful to patients and so drugs were approved on an MFS endpoint. It will be really interesting to see how this particular effect size, particularly in the PD-L1 positive patients, or those patients with a PD-L1 over the [inaudible 00:07:18] of one that what the thought will be on this particular endpoint.
I wanted to get your thoughts too, on not necessarily from this study, but in general, when patients have recurrence from urothelium carcinoma, this is not something that they don't notice. In most cases, at least in my clinic, these are very clinically meaningful events that are very clinically relevant in terms of symptoms, pain control, other issues and complications that patients experience. What are your thoughts on that?
Matthew Galsky: I completely agree with that. I do think that the issue about whether or not DFS is a clinically meaningful endpoint, I think we need to hear from patients about that as well, not only clinicians because this position that recurrence doesn't matter I think is a very nuanced position that we really need to hear from patients about whether or not it matters to them.
I would also say that we don't have full quality of life or patient reported outcome data from this study presented yet, but Dean did present the QLQ-C30 data showing that at least based on the overall study population and the PU.1 high defined population, there was no deterioration in quality of life with this adjuvant approach. Clearly this decision-making about adjuvant therapies, because the adjuvant space is a very difficult space, of course, when you can't see any cancer on a scan and you're giving someone a treatment, so it needs to be a treatment that's well tolerated. It needs to be a treatment that's relatively safe, such that those risks and benefits align. Both the toxicity data consistent with what we know about immune checkpoint blockade and the limited quality of life data that was presented, I think do contribute to that bigger decision-making situation.
Alicia Morgans: I agree. The one final point that I would want to raise is that, say starting a therapy at the time of identification of metastatic disease is equally effective. Let's assume that that's the situation. I still think that, or at least I know from studies, that patients fall off line of therapy and a line of therapy. Even if on average we can capture patients at that recurrence at a time that's going to allow us to make a meaningful intervention, there will be patients in practice who don't come to their scan or who for whatever reason are not there to identify that earlier state of recurrence, or maybe because of the way that their diseases are progressing so rapidly, that they don't have the opportunity to get treatment. I think that the opportunity to capture patients early, particularly in urothelial carcinoma, maybe a really critical aspect of caring for them.
Matthew Galsky: I think that's a great point in the frequency of monitoring on this study certainly is such that one could imagine that in clinical practice, the risk of patients progressing and not being able to proceed with treatment is much higher.
Alicia Morgans: Great. Well, thank you for going through all of this. Congratulations to you and the team for some exceptional work. Before I get to your concluding remarks, I would just like to hear a tricky question, hopefully a great answer on this one. What are your thoughts for patients who may be enrolled in adjuvant studies that may be getting different agents? I'm not going to name specific studies or specific agents, but there are adjuvant trials that are out there. Should clinicians think about moving those patients off of whatever agent they're on? Should there be conversations? I know what I think, which is that there should always be conversation. I'll give you that part of a bit of an answer. But what are your thoughts?
Matthew Galsky: I think it's important to have a discussion that these data have come out and the potential relevance of these data in the context of the clinical trials that the patients are enrolled in. That said, I think one can say a number of things. One, the data haven't been published yet. Two, se don't do it quite as commonly in oncology, but there is that notion in medicine that we really should have a few randomized trials showing benefit to really feel comfortable about practice. As far along as some of these trials are, I do think it's really important to get those completed. I think it's a difficult situation, but in the absence of published data in the fact that some of those trials are near completion, as long as a balanced discussion has had, I think it's important to try and get those studies done.
Alicia Morgans: Thank you. That was a very balanced answer. I always appreciate your thoughts on those kinds of things. Thank you. If you had to summarize your findings from CheckMate 274 and really give a message to clinicians and to patients who are trying to kind of sort through all of the things that we've learned at GU ASCO 2021, what would that message be?
Matthew Galsky: I would say with regards to CheckMate 274 specifically, it met it’s co-primary endpoints of improvement in disease-free survival in the all-comer population and in the population of patients with tumors with high PD-L1 expression, all of the secondary endpoints, except for OS, which hasn't been shown because it hasn't been looked at yet, are trend in the exact same direction. I think these data warrants a discussion with patients and in the context of the difficulty explaining Kaplan-Meier curves, I do think visualizing those curves and explaining what they mean could play an important role in decision-making.
Alicia Morgans: Thank you so much. Congratulations again to you and the investigators and to the patients who put the time and the energy into completing this work. This is really, I think, quite an exciting study. As always, I always enjoy talking with you. Thank you so much for your time, Dr. Galsky.
Matthew Galsky: Thank you. Great to talk to you.
Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago. I'm so excited to have here with me today as part of our GU ASCO 2021 coverage, Dr. Matt Galsky, who is a professor of medicine and the acting chief of the division of hematology and medical oncology at Mount Sinai. Thank you so much for being here with us today, Dr. Galsky.
Matthew Galsky: Thank you. Glad to be here.
Alicia Morgans: Great. Thank you, Matt. We're so excited to hear you talk to us a little bit about CheckMate 274, which was presented by Dean Bajorin. I know you two have a long standing relationship, but really I think that this data is so interesting, so important and informative. I'd love to hear you tell us a little bit about who was in the study, what were you assessing and what did you find?
Matthew Galsky: Thank you. Yes. It was really a pleasure to see Dean present this data. For those of you who haven't been in the field a very long time, Dean was my fellowship director and my mentor many, many years ago, so really a pleasure to work with him on this study and to see him present the results.
CheckMate 274 was an adjuvant study of immune checkpoint blockade in urothelial cancer, including upper tract disease and bladder cancer. It's an adjuvant study that's a bit different than adjuvant studies that have been done in the past in our field because it enrolled patients who had received prior neoadjuvant chemotherapy and had residual pathologic evidence of disease T2 or higher, or patients who didn't have neoadjuvant chemotherapy but were cisplatin ineligible.
We talk about this as an adjuvant study, but really it's different than the adjuvant studies that have been done in the past with chemotherapy. The study randomized patients one-to-one, stratified based on PD-L1 expression based on prior neoadjuvant chemotherapy or not to receive one year of adjuvant nivolumab. That was given at the every two week schedule for a year versus placebo infusions every two weeks for a year.
The primary endpoints of this study were disease free survival in the all comer population and then disease free survival in patients with a high expression of PD-L1 in their tumors. Remember, each of these immune checkpoint inhibitors uses a different assay. This is the 288 antibody clone measuring PD-L1 on tumor cells with a cutoff of greater than or equal to 1% and that's defined high.
That was the primary endpoint. Secondary endpoints are overall survival and non-urothelial tract recurrence free survival. That endpoint's important because disease-free survival includes patients with second primary tumors, quote unquote, or urothelial tract recurrences. Remember, if someone has a nephroureterectomy, they can have a bladder tumor down the line and vice versa. Those are counted as events for DFS in these studies if the tumors are invasive and so important to have another endpoint that removes those recurrences and includes everything else, pelvic recurrences outside of the urothelial attractor distant recurrences.
At ASCO GU this year, the co-primary endpoints were presented, so disease-free survival in the all comer group and then disease-free survival in patients with tumors with high PD-L1 expression. I should mention that using this assay in this cutoff in this patient population, about 40% of patients had a high PD-L1 expression. The study showed a significant improvement with adjuvant nivolumab for DFS in the all-comer population with a hazard ratio of around 0.7. And in patients with high PD-L1 expression, and improvement in DFS with a hazard ratio of 0.53.
The secondary endpoints non-urothelial tract recurrence-free survival, and the endpoint of metastasis-free survival showed very similar effect sizes.
Alicia Morgans: Let's dig into this a little bit because I think that we had an opportunity to talk just before recording a little bit about the nuances of these particular endpoints. Can you tell us a little bit about what you make of the disease-free survival data in the all-comers population, certainly an improvement, but how do you interpret the clinical meaning of this?
Matthew Galsky: Disease-free survival is obviously in part a radiographic endpoint. I should've mentioned that key secondary endpoint of this study is overall survival, but it wasn't a primary endpoint. I should also mention that all of these time [inaudible 00:04:42] endpoints were event driven and so no overall survival data was shown not because we didn't want to show it. It was not shown because the number of events haven't been reached to actually look at that data yet. This is a blinded study, placebo controlled. No one's seen that data yet. The significance, the clinical significance of a DFS endpoint is in part related, I think, to the effect size. If you see a small improvement in DFS, that could be viewed differently than in terms of the clinical impact than a large effect size on DFS. It's in part related to the natural history or the treated history of the disease upon recurrence and not to minimize the impact of recurrence in any other solid tumor or the risk of recurrence, but we are talking about urothelial cancer here where the risk of recurrence in this patient population's about 60%. It's not a breast cancer study, again, not to minimize the impact of recurrence on those patients. I'm simply making a point about the effect size and the risk of recurrence. Sometimes those studies are looking at risks of recurrence in the five to 10% range. We're talking about 60%. You can't improve survival, I don't think, in this setting based on most of the mechanisms of our drugs without improving DFS first. I think we're part of the way there. One could look at the data in counsel patients, and you have to ask yourself today, "Does my patient sitting in front of me half the time to wait for overall survival data based on the effect size, or do we make a decision based on the assumption that it might be beneficial in terms of OS as well?"
Alicia Morgans: I think I completely agree with that. I think that this is almost could also be compared to the MFS or metastasis free survival endpoint that we have in prostate cancer, that when that MFS prolongation became significantly longer in the non-metastatic CRPC setting, for example, with the AR antagonist agents, the FDA even said, "Hey, that's not a survival endpoint overall survival endpoint," but that's such a, like you said, the effect size is so large that the duration of prolongation is so large, the hazard ratio was so large that this is meaningful. It's meaningful to patients and so drugs were approved on an MFS endpoint. It will be really interesting to see how this particular effect size, particularly in the PD-L1 positive patients, or those patients with a PD-L1 over the [inaudible 00:07:18] of one that what the thought will be on this particular endpoint.
I wanted to get your thoughts too, on not necessarily from this study, but in general, when patients have recurrence from urothelium carcinoma, this is not something that they don't notice. In most cases, at least in my clinic, these are very clinically meaningful events that are very clinically relevant in terms of symptoms, pain control, other issues and complications that patients experience. What are your thoughts on that?
Matthew Galsky: I completely agree with that. I do think that the issue about whether or not DFS is a clinically meaningful endpoint, I think we need to hear from patients about that as well, not only clinicians because this position that recurrence doesn't matter I think is a very nuanced position that we really need to hear from patients about whether or not it matters to them.
I would also say that we don't have full quality of life or patient reported outcome data from this study presented yet, but Dean did present the QLQ-C30 data showing that at least based on the overall study population and the PU.1 high defined population, there was no deterioration in quality of life with this adjuvant approach. Clearly this decision-making about adjuvant therapies, because the adjuvant space is a very difficult space, of course, when you can't see any cancer on a scan and you're giving someone a treatment, so it needs to be a treatment that's well tolerated. It needs to be a treatment that's relatively safe, such that those risks and benefits align. Both the toxicity data consistent with what we know about immune checkpoint blockade and the limited quality of life data that was presented, I think do contribute to that bigger decision-making situation.
Alicia Morgans: I agree. The one final point that I would want to raise is that, say starting a therapy at the time of identification of metastatic disease is equally effective. Let's assume that that's the situation. I still think that, or at least I know from studies, that patients fall off line of therapy and a line of therapy. Even if on average we can capture patients at that recurrence at a time that's going to allow us to make a meaningful intervention, there will be patients in practice who don't come to their scan or who for whatever reason are not there to identify that earlier state of recurrence, or maybe because of the way that their diseases are progressing so rapidly, that they don't have the opportunity to get treatment. I think that the opportunity to capture patients early, particularly in urothelial carcinoma, maybe a really critical aspect of caring for them.
Matthew Galsky: I think that's a great point in the frequency of monitoring on this study certainly is such that one could imagine that in clinical practice, the risk of patients progressing and not being able to proceed with treatment is much higher.
Alicia Morgans: Great. Well, thank you for going through all of this. Congratulations to you and the team for some exceptional work. Before I get to your concluding remarks, I would just like to hear a tricky question, hopefully a great answer on this one. What are your thoughts for patients who may be enrolled in adjuvant studies that may be getting different agents? I'm not going to name specific studies or specific agents, but there are adjuvant trials that are out there. Should clinicians think about moving those patients off of whatever agent they're on? Should there be conversations? I know what I think, which is that there should always be conversation. I'll give you that part of a bit of an answer. But what are your thoughts?
Matthew Galsky: I think it's important to have a discussion that these data have come out and the potential relevance of these data in the context of the clinical trials that the patients are enrolled in. That said, I think one can say a number of things. One, the data haven't been published yet. Two, se don't do it quite as commonly in oncology, but there is that notion in medicine that we really should have a few randomized trials showing benefit to really feel comfortable about practice. As far along as some of these trials are, I do think it's really important to get those completed. I think it's a difficult situation, but in the absence of published data in the fact that some of those trials are near completion, as long as a balanced discussion has had, I think it's important to try and get those studies done.
Alicia Morgans: Thank you. That was a very balanced answer. I always appreciate your thoughts on those kinds of things. Thank you. If you had to summarize your findings from CheckMate 274 and really give a message to clinicians and to patients who are trying to kind of sort through all of the things that we've learned at GU ASCO 2021, what would that message be?
Matthew Galsky: I would say with regards to CheckMate 274 specifically, it met it’s co-primary endpoints of improvement in disease-free survival in the all-comer population and in the population of patients with tumors with high PD-L1 expression, all of the secondary endpoints, except for OS, which hasn't been shown because it hasn't been looked at yet, are trend in the exact same direction. I think these data warrants a discussion with patients and in the context of the difficulty explaining Kaplan-Meier curves, I do think visualizing those curves and explaining what they mean could play an important role in decision-making.
Alicia Morgans: Thank you so much. Congratulations again to you and the investigators and to the patients who put the time and the energy into completing this work. This is really, I think, quite an exciting study. As always, I always enjoy talking with you. Thank you so much for your time, Dr. Galsky.
Matthew Galsky: Thank you. Great to talk to you.