Adjuvant Therapy for Improved Disease-Free Survival for Patients with Muscle-Invasive Urothelial Carcinoma Following Radical Surgery - Checkmate 274 - Petros Grivas

March 28, 2021

Adjuvant nivolumab could provide a treatment option for patients with muscle-invasive urothelial carcinoma to reduce the risk of recurrent cancers and death, the CheckMate 274 study finds. The standard-of-care treatment for muscle-invasive urothelial carcinoma is cisplatin-based neoadjuvant therapy followed by radical surgery. However, many patients are cisplatin-ineligible. 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. CheckMate 274 reported impressive disease-free survival benefit a the 2021 GU ASCO symposium and in this conversation with Alicia Morgans, MD, MPH, Petros Grivas, MD, PhD, details the findings of this study reported and look at the differences in this space between adjuvant nivolumab in CheckMate 274 and adjuvant atezolizumab in the IMvigor010 study. IMvigor010 is a phase III study of adjuvant atezolizumab vs observation in patients with muscle-invasive urothelial carcinoma. This conversation highlights and helps to answer a current question in the field: is that practice-changing, or do we want to wait for overall survival.


Petros Grivas, MD, PhD, Associate Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research 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.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a dear friend and colleague, Dr. Petros Grivas, Who's an associate professor of medicine and a GU medical oncologist at the University of Washington and the Fred Hutchinson Cancer Center. Thank you so much for being here with me today, Petros.

Petros Grivas: Thank you so much, Alicia, for having me. Always a pleasure to discuss with you.

Alicia Morgans: Always a pleasure to discuss with you, too. And I'm excited to talk today about two abstracts that really were key abstracts in urothelial carcinoma at GU ASCO 2021. Let's start with Checkmate 274. What are your thoughts? Can you describe the study for us once more, and then let us know what some of your thoughts and findings were?

Petros Grivas: Thank you, Alicia. I totally agree with you, Checkmate 274 was one of the major highlights at ASCO GU 2021 and Dr. Dean Bajorin of Memorial Sloan Kettering did a great job presenting the data, Dr.  Galsky, and others, many others were also involved. This is a purely adjuvant trial, so in the adjuvant setting, in patients with fully resected muscle-invasive urothelial cancer, either bladder or upper tract disease. And if you actually look at the makeup of the patients, about 21% were upper tract, so about 79% were bladder. And these patients were randomized to adjuvant nivolumab, [inaudible 00:01:22], versus placebo as a control arm. Neurological chemotherapy was allowed, but it was not mandatory. And these patients, if they had received neoadjuvant chemotherapy, YPT2 or higher stage was allowed. If they had never received neoadjuvant chemo, PT3 or higher stage was allowed, eligible, and of course, not a positive disease.

Petros Grivas: The primary point was disease-free survival, DFS, and the second point was overall survival. And there were, of course, different parameters to look at the pathologic states, the margins, and a number of nodes resected that were all, I think, interesting to look at as baseline factors. If you look at the make-up of the patients, the baseline characteristics, I think most of those patients, the vast majority had pathologic T3 or higher disease, only a small proportion having T2 or less, and probably those had either not both the disease or had neoadjuvant chemo. And as I mentioned before, about 21% had upper tract disease. The study met the primary endpoint of disease-free survival in all comers, the intent to treat population, which is regardless of PD-L1 expression. And also, in the co-primary endpoint of disease-free survival in those patients with PD-1 high tumors, the PD-1 high subset based on the particular assay that was used in that study.

Petros Grivas: The hazard ratio for DFS was 0.70, so a 30% reduction in the ratio of recurrence or death in all comers and a hazard ratio of 0.53 in patients with pilar high tumors. So even a higher degree of benefit in those, disease-free survival benefits in those with pilar high tumors. And even if you look at the median DFS, there was a striking difference in about 10 months or so in favor of nivolumab as adjuvant therapy. There were many details that were presented by Dr. Bajorin, but I think one of the main questions that the scientific community has since then is based on this really impressive disease-free survival benefit, is that practice-changing, or do we want to wait for overall survival? There was some interesting data that Dr. Bajorin presented looking at the recurrence-free survival outside the urinary tract, so non-urinary tract recurrence-free survival.

Petros Grivas: And also distant metastasis-free survival, but also showed benefit with Nivolumab, the adjuvant anti PD-1 therapy. So the overall survival data were not presented, and when we discussed that with the investigators, this was an event-driven endpoint, and there were not enough events to have a robust statistical analysis. The median follow-up, I think it was about 19 months or so if I remember correctly, was not very different than what we showed in [inaudible 00:04:22] trial, but again, based on the number of events, OS data were not presented. So I think the data is really, really, as I mentioned, a huge highlight, very impressive. There is a debate in the field, whether this is practice-changing or not. Some people believe that this striking impressive PFS benefit will translate to overall survival, some other people want to wait and see if that is the case or not.

Petros Grivas: And the same debate has to do with whether you change practice or not in the context of other ongoing trials, the adjuvant AMBASSADOR by Dr. Apollo, the adjuvant PROOF 302 with adjuvant infigratinib versus placebo by Dr. Pal and Dr. Daneshmand, and also in the context of the previous negative adjuvant trial with atezolizumab, the IMvigor 010. And because of these challenges and some different details in the forest plot, I think many folks may want to wait until the OS data come out, but I think it's going to depend on what regulatory agencies will do, and that's a big question. I think the bar is even higher in Europe with the EMA usually requiring overall survival, but we have to see. And I think if the regulatory agencies approve these agents, it's imaginable that this will start being used.

Petros Grivas: The last point is, is that going to affect or impact ongoing perioperative trials that span across neoadjuvant and adjuvant settings? I think we have to see that and I think it is difficult to answer this question right now, but if the ongoing trials keep accruing, and as I mentioned, we have to see what happens with regulatory approval or not of this agent in the adjuvant setting.

Alicia Morgans: Thank you so much for setting the stage here. And I agree that one of the most important questions that we are going to have to answer, and perhaps as you said, the regulatory bodies are going to have to answer is, what is the meaning of disease-free survival in urothelial carcinoma? And I think to me, I sort of see parallels with metastasis-free survival in prostate cancer. We had an initial drug that actually, there was an application for approval on that particular endpoint, denosumab, maybe a decade ago. And because the metastasis-free survival was only a number of months, a small number, I think it was two to four months, there was no approval in that setting. But when the metastasis-free survival benefit was so large, 22 months, really obviously, three agents were approved in that setting.

Alicia Morgans: From my perspective, and certainly, I don't have personal experience with urothelial carcinoma or, other than my patients have a family member with this disease, but this is a disease that causes suffering and symptoms when the cancer spreads, returns, recurs in many patients. And so, again, as a non-patient, but just as an advocate from a clinician's perspective, disease-free survival is, I think meaningful to me. And certainly, neither of us knows what the regulatory bodies are going to do, but what are your thoughts on that particular endpoint?

Petros Grivas: Alicia, you raise a great point, and I think in those discussions, we definitely should involve patient advocates. I think your point is exactly important because the voice that we need to hear is, what is a patient feeling about it? And I think patient advocates should be part of those decisions. There are pros and cons, I think, with disease-free survival, conceptually and philosophically.  If you ask me, what is the ideal endpoint in an adjuvant trial, I would answer to you, overall survival because we try to cure more patients, we try to make them live longer. And there is also potential toxicity and cost, physical toxicity, the potential of immune-related adverse events that can also have their own morbidity or early mortality. And of course, the cost in the healthcare system has to be balanced against the very important endpoint of the effects that you mentioned.

Petros Grivas: So I think ideally, OS, in the adjuvant setting, especially when a patient has no visible disease, of course, they may have micrometastases, micro scoping metastasis, but if the patient feels that they do not have the visible disease, I think the tolerance of a toxicity threshold may be lower and patients may have less enthusiasm to tolerate side effects. Having said that, I think that the degree of a difference in the magnitude of the difference is important, and I think the hazard ratio captures this, I think in a better way because it takes all the data points in the [inaudible 00:08:45] care. And to your point, the high degree of benefit, I think it's more relevant than a smaller benefit. So I do not think that there is a right answer.  I think it's different approaches and you are right, when the metastasis occurs, usually in the vast majority of patients, this is usually fatal and [inaudible 00:09:05]

Petros Grivas: So I think it's a lot of discussions to be made, and I would like to see, again, the regulatory agency's stance on this because I can see both pros and cons. There are different tumor types, that it is hard to compare apples and oranges. And there is also this debate about chemotherapy in the adjuvant setting in urothelial cancer, that for years if someone never received neoadjuvant, which is part of base chemotherapy which is level one evidence and comes to our clinics and they have PT3, PT4 [inaudible 00:09:33] disease and they can't get cisplatin and never got it before, are given it and I give it in the adjuvant setting, and I will probably keep doing that in those who never received neoadjuvant before.

Petros Grivas: And the debate has been, is this survival enough or overall survival? Because all the adjuvant chemotherapy trials were underpowered for overall survival. So I think that it is a long debate and I don't think that it is a clear-cut right answer, but I think the academic folks, many of them, would like to see overall survival. But you also mentioned if the drug gets approved, I think it's going to be used by many folks in practice.

Alicia Morgans: Yeah. And thank you for kind of talking that through with me, because I think that this is going to be one of the more interesting points as we try to sort through this data before the overall survival data is mature. And you also mentioned, of course, the IMvigor 010 study that really looked at atezolizumab but failed to show a benefit in the adjuvant setting, although there was this re-analysis at ESMO that looked at circulating tumor DNA. What are your thoughts? Why is there a potential difference here between these drugs?

Petros Grivas: That's another great question, Alicia. And just to add one more quick comment on the discussion about the efficient OS.  There has been a question of whether this disease-free survival is an adequate surrogate marker for overall survival? And we do not know the answer in the context of adjuvant immunotherapy, so that will be another interesting thing to see if that pans out in the neoadjuvant nivolumab trial, the Checkmate 274. Now you made a great point that the similar setting purely adjuvant trial with atezo versus observation, IMvigor 010 did not result in a difference in disease-free survival. And there is the question, why this happened. Is it a difference of the drugs, a difference of trial design, baseline characteristics of patients? It's hard to answer in a clear-cut way, but my personal take is, I do not think this is a drug difference.

Petros Grivas: I don't think this answers the whole question. I think mostly it may be clinical trial design and baseline characteristics of patients, patient populations. I think it would be interesting to go back and look line by line, category by category and see the different trials, of course, with the inherent caveat that you cannot compare perfectly across different trials.  There are many confounding factors and selection biases. Having said that, one of the striking differences in the design was the control arm, the observation in IMvigor010, and the placebo in Checkmate 274. And if you look, Alicia, in the actual performance of the control group, there was a striking difference. I think if I remember the numbers, on the top of my head, there was I think, 16.6 months of disease-free survival, medium disease-free survival in the atezo IMvigor010 trial.

Petros Grivas: And it was much less, it was about probably 10.9 or so median DFS in the Checkmate 274. So the control group did much worse in the Checkmate 274, nivolumab trial, and over-performed in the IMvigor 010. And we published that in a manuscript just a few months ago, where we were preparing for those trials to come up, we went back with Dr. Alexandra Drakaki at UCLA and other colleagues there, and we looked at the CIHR Medicare data from 2001 until 2013, and we tried to evaluate patients who, if I remember correctly, never received adjuvant chemo to see what the outcomes are in those patients. And we saw immediate disease-free survival of about 13.5 months in all comers, which is exactly in the middle of IMvigor010 that was 16.6, and the Checkmate 274 that was about 11 months.

Petros Grivas: So I think that difference, it may be meaningful because it can affect the hazard ratio in each individual trial. And one potential explanation that Dr. Galsky was commenting on that, if you have a dropout rate that was higher in IMvigor010, it was about 10% in the observation arm and it was about half of that in the Checkmate 274. If you have more patients dropping out from the atezo adjuvant trial, because of cumulative censoring, you have a potential risk that your control arm may look better because you do not capture those progression events, recurrence events. So this could be a potential difference, again, observational versus placebo. Many folks do not like a placebo in those trials, based on allocations, some other colleagues of ours, but it just raises a question, whether that may have played a role or not.

Alicia Morgans: Yeah. I love the way that you are thinking through this, and really, I always learn from you. So thank you so much for considering that and for talking that through, because I do think in the field, this is something that we are still trying to wrestle with. So as you think about Checkmate 274, any final thoughts? How do we consider this, what do we do with this data?

Petros Grivas: You know, I didn't answer you're great question though before, Alicia, I just realized, about circulating tumor DNA, I got into the detail of the comparisons. But I think to segue to your new question, I really like the idea of circulating tumor DNA. And just briefly for the audience, that it was an exploratory endpoint of the IMvigor010 trial and Professor Pal's SO data in a recent meeting that showed that, despite that IMvigor 010 was a negative trial with no difference between atezo and observation adjuvant setting, the patients with detectable positive circulating tumor DNA, those particular subsets of patients, they had a significant difference in DFS. And I think always with atezo versus observation, which raised the question, is circulating tumor DNA a potential predictive biomarker of benefit with atezolizumab in the adjuvant setting?

Petros Grivas: And obviously, this was an exploratory endpoint, so could not change practice, but the company already designed and launched a phase three adjuvant trial, the IMvigor011. And they take patients with positive, detectable circulating tumor DNA and randomized those patients to atezo or observation to confirm the exploratory finding in the IMvigor010. So I'm very excited about this study, to be honest with you. I think circulating tumor DNA has great potential as a tool. I think, in my opinion, this actually enriches a higher risk population with a higher chance of events, the higher chance of recurrence or death. And because in the urothelial population, you probably have a higher power to detect a difference. So I think this IMvigor011 trial is very interesting. I would like to see similar data from Checkmate 274, and I think that is another important point along with other biomarker work.

Petros Grivas: I want to see CDAP cell density in the cystectomy [inaudible 00:16:16] tissues that have been shown to be potentially prognostic. I want to see DNA repair gene mutations and see if there is a signal there. And I want to see also what happens, obviously, long-term with overall survival. And of course, I'm very excited about the Ambassador trial, Dr. Apollo is leading that from the NCI adjuvant pembro versus observation. We have a trial open and I'm accruing in this trial actively. I feel comfortable to accrue in this trial, Alicia. And also we have, as I mentioned, the adjuvant infigratinib placebo, called Proof 302. This is for patients with FGFR-3 mutation or fusion. And if they have a biomarker positive, they go on to Proof 302, if they are negative, they go on Ambassador.

Alicia Morgans: Yes, so I would agree with that. We have Ambassador open, I am following patients on that study right now. I think that we should all continue our enthusiasm to answer some of these questions. At this point in time, disease-free survival is a very intriguing endpoint, but for patients who feel comfortable potentially starting their checkpoint inhibitor when cancer comes back, if it comes back, these kinds of adjuvant studies that are ongoing like Ambassador are actually perfect opportunities for them to contribute to the science and see which one is really better.

Alicia Morgans: Because ultimately, as you've said, disease-free survival seems to be a great endpoint, yes. But if we can start the checkpoint inhibitor when we see evidence of disease in patients who are being closely monitored, particularly if they are on a clinical trial, and there is no difference, then we have saved that individual that duration of time that he or she did not have to endure treatment before the disease came back. So there is still so much for us to dig into, and as you said, it is all going to come down to the biology, and hopefully circulating tumor DNA will be one of those windows into understanding what is driving this disease and how we can differentiate those patients who are lower risks, versus the higher risk patients who will need additional therapy. So thank you so much for talking this through. I always, always learn from you and I appreciate your time today.

Petros Grivas: I also learn from you, Alicia. Thank you for a great discussion, and looking forward to more discussions together.