Journal of Clinical Oncology (JCO) Podcast

Host Dr. Davide Soldato and guests Dr. David Einstein and Dr. Ravi Madan discuss JCO article, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations," underscoring the need for a consensus on clinical trial designs implementing novel endpoints in this population, the importance of PSA doubling time as a prognostic factor and with an emphasis on treatment de-escalation to limit toxicity and improve patient outcomes.
TRANSCRIPT
The disclosures for guests on this podcast can be found in the show notes.
Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy.
Today, we are joined by JCO authors Dr. David Einstein and Dr. Ravi Madan. Dr. Einstein is a medical oncologist specializing in genitourinary malignancy working at Beth Israel Deaconess Medical Center, part of the DFCI Cancer Center, and an assistant professor at Harvard Medical School. Dr. Madan is a senior clinician at the National Cancer Institute (NCI), where he focuses on conducting clinical research in prostate cancer, particularly in the field of immunotherapy.
Today, we will be discussing the article titled, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations."
So, thank you for speaking with us, Dr. Einstein and Dr. Madan.
David Einstein: Thanks for having us. This is a great pleasure.
Ravi Madan: Appreciate being here.
Davide Soldato: So, I just want to start from a very wide angle. And the main question is why did you feel that there was the need to convey a consensus and a working group to talk about this specific topic: biochemically recurrent prostate cancer? What has been the change in current clinical practice and in the trial design that we are seeing nowadays? And so, why was it necessary to convey such a consensus and provide considerations on novel clinical trials?
David Einstein: Yeah, so I think it's very interesting, this disease state of biochemically recurrent prostate cancer. It's very different from other disease states in prostate cancer, and we felt that there was a real need to define those differences in clinical trials. Years ago, metastatic castration-resistant prostate cancer was the primary disease state that was explored, and over time, a lot of things shifted earlier to metastatic disease defined on a CAT scan and bone scan to an earlier disease state of metastatic castration-sensitive prostate cancer. And the clinical trial principles from late-stage could be applied to MCSPC as well.
However, BCR is very different because the patients are very different. And for those reasons, there are unique considerations, especially in terms of toxicity and treatment intensity, that should be applied to biochemically recurrent prostate cancer as opposed to just using the principles that are used in other disease states. And for that reason, we thought it was very important to delineate some of these considerations in this paper with a group of experts.
Davide Soldato: Thanks so much. So, one of the main changes that have been applied in recent years in clinical practice when looking at biochemically recurrent prostate cancer is the use of molecular imaging and particularly of PSMA PET. So, first of all, just a quick question: was the topic of the consensus related on which threshold of PSA to use to order a PET scan to evaluate this kind of patient?
David Einstein: Yeah, thanks for that question. It's a super important one. The brief answer is that no, we did not address questions about exactly when clinicians would decide to order scans. We were more concerned with the results of those scans in how you define different disease states.
But I think as a broader question, I think a lot of folks feel that finding things on a scan equates that with what we used to find on conventional scans. And fundamentally, we actually sought to redefine that disease space as something that's not equivalent to metastatic disease, and rather coined the term "PSMA-positive BCR" to indicate that traditional BCR prognostic criteria and factors still apply, and that these patients have a distinct natural history from those with more advanced metastatic disease.
Ravi Madan: And if I may just add that the National Cancer Institute is running a trial where we're prospectively monitoring PSMA-positive BCR patients. And that data is clearly showing that, much like what we knew about BCR a decade ago, PSMA findings in BCR patients do not change the fact that overall, BCR is an indolent disease state.
And the findings, which are usually comprised of five- to seven-millimeter lymph nodes, do not endanger patients or require immediate therapy. And so, while PSMA is a tool that we can be using in this disease state, it doesn't really change the principal approach to how we should manage these patients. And as Dr. Einstein alluded to, there is a drive to create a false equivalency between PSMA-positive BCR and metastatic castration-sensitive prostate cancer, but that is not supported by the data we're accumulating or any of the clinical data as it exists.
Davide Soldato: One thing that it's very important and you mentioned in your answer to my question was actually the role of PET scan and conventional imaging, so CAT scan and bone scan that we have used for years to stage patients with metastatic prostate cancer. And you mentioned that there is a distinction among patients who have a positive PET scan and a BCR, and patients who have a positive conventional imaging. And yet, we know that sometimes the findings of the PET scan are not always so clear to interpret. So, I just wanted to understand if the consensus reached an agreement as to when to use conventional imaging to potentially resolve some findings that we have on PET scan among thess patients with BCR?
David Einstein: Yeah, I think there's a number of questions actually buried within that question. One of which is: does PSMA PET result in false positives? And the answer has definitely been yes. There's a known issue with false-positive rib lesions. And so, first and foremost, we need to be very careful in calling what truly is suspicious disease and what might actually not be cancer or might be something that is totally separate. So I think that's the first part of the answer to that question.
The second is to what extent do we need to use paired PET and conventional imaging to define this disease state? In other words, do you have to have positive findings on one and negative findings on the other in order to enter this definition? The challenge there, as we discussed, is that logistically, oftentimes it's hard to get patients to do multiple sets of scans to actually create that definition. Sometimes it's difficult to get insurers to pay for such scans. And finally, it's hard to sometimes blind radiologists to the results of one scan in reading the other. So, we did have some deliberations about to what extent you could use some of the CAT scan portion of a PSMA PET in order to at least partially define that. We also talked about using bone scans to confirm any bone findings seen on PET. But I think another important part of this is not just the baseline imaging, but also what's going to be done serially on a study in order to define responses and progression. And that's sort of a whole separate conversation about to what extent you can interpret changes in serial PET.
Ravi Madan: And just to pick up on the key factor here, I think that the PSMA PET in BCR is pretty good at defining lymph node disease, and that's actually predominantly 80 to 90 percent of the disease seen on these findings. It might be pretty good at also defining other soft tissue findings. The real issues come to bone findings.
And one thing the group did not feel was appropriate was to just define only PSMA-positive bone findings confirmed on a CT bone window. There's not really great data on that, but the working group felt that, when in the rare situation, because it is relatively rare, a PSMA-positive finding is in a bone, a bone scan should be done. And it's worth noting that Phu Tran, who is a co-author and a co-leader of this working group, his group has already defined that underlying genomics of conventionally based lesions, such as bone scan, are more aggressive than findings on next-gen imaging, such as PSMA. So, there is also a genomic underlying rationale for defining the difference between what is seen on a PET scan in a bone and what is seen on a bone scan.
Davide Soldato: Coming back to this issue of PET PSMA sometimes identifying very small lesions where we don't see any kind of correlates on conventional imaging or where we see only very little alteration on the bone scan or in the CT scan, was there any role that was imagined, for example, for MRI to distinguish this type of findings on the PET scan?
Ravi Madan: So, I think that, again, what can be identified on a PSMA frequently cannot be seen on conventional imaging. We didn't feel that it was a requirement to get an MRI or a CT to necessarily confirm the PSMA findings. I think that generally, we have to realize that in this disease state, that questionable lesions are going to be seen on any imaging, including PSMA. We've actually probably put way too much faith in PSMA findings thus far, as Dr. Einstein alluded to with some of the false positives we're seeing.
So, I think that these false positives are going to have to be baked into trials. And in terms of clinical practice, it highlights the need to again, not overreact to everything we see and not necessarily need to biopsy everything and put patients' health in jeopardy to delineate a disease that's indolent anyway.
Davide Soldato: Thanks so much. That was very clear. So, basically, the main driver was really also the data showing that if we have a BCR, so a patient with a biochemically recurrent disease that is positive on the conventional imaging, this is usually associated with a different aggressiveness of the disease.
But coming back to a comment that you made before, Dr. Madan, you said that even if we talk about PSMA-positive BCR, we are still talking about BCR and the same criteria should apply. So, what we have used for years in this space to actually try to stratify the prognosis of patients is the PSA doubling time, so how quickly the PSA rises over time. So, coming back to that comment, was the consensus on the PSA doubling time basically retained as what we were using before, so defining patients with a doubling time less than 12 months, 10 months, 9 months, as patients with a higher risk of progressing in terms of developing metastatic disease?
Ravi Madan: Yes, so that's a very important point. And the working group defined high-risk BCR as a PSA doubling time less than six months. And this really comes from Johns Hopkins historical data, which shows that if your doubling time is three months or less, there's about a 67 percent chance of metastasis at five years. If it's between three and six months, it's 50 percent. And if it's over six months, if it's between six and nine months, it's roughly only 27 percent. There are trials that are accruing with eligibility criteria that they may describe as high-risk that are beyond six months, but the data as really it's been defined in the literature highlights that truly high-risk BCR is less than six months. And the working group had a consensus on that opinion, and that was our recommendation.
David Einstein: And I think an important follow-on to that is that's regardless of PET findings, right? And so, we present a couple of case studies of patients with positive PET findings who have a long doubling time, in whom the disease is in fact indolent, as you would have expected from a traditional BCR prognostic standpoint. Obviously, there are patients in whom they have fast doubling times, and even if they do not have PET findings, that doesn't make them not high-risk.
Ravi Madan: And just to follow up that point, I will let you know a little bit of a free preview that my colleague Melissa Abel from the NCI will be presenting PSMA findings in the context of PSA doubling time at ASCO GU if that data is accepted.
Davide Soldato: Looking forward for those data because I think that they're going to clarify a lot of the findings that we have in this specific population.
And coming back to one of the points that we made before, so PET PSMA has a very high ability to discriminate also a very low burden of disease, which we currently refer to as oligometastatic biochemically recurrent prostate cancer, which is not entirely defined as an entity.
But what we are seeing both in some clinical trials, which use mainly conventional imaging, but also what we're starting to see in clinical practice, is that frequently we use the metastasis-directed therapy to treat these patients. So, just a little bit of a comment on the use of this type of strategy in clinical practice and if the panel thought of including this as, for example, a stratification criteria or mandated in the design of novel clinical trials in the field of BCR?
David Einstein: Yeah, I think that's an incredibly important point. You know, fundamentally, there's a lot of heterogeneity in practice where some folks are using local salvage approaches, some are using systemic therapies, in some cases surveillance may be reasonable, or some combination of these different strategies. We certainly have phase two data from multiple trials suggesting that met-directed therapy may help buy patients time off of treatment until subsequent treatments are started. And that in and of itself may be an important goal that we can come back to in discussing novel endpoints.
I think what our panel acknowledged was that, in some sense, the clinical practice has gotten even farther ahead than where the data are, and this is being offered pretty routinely to patients in practice. And so, what became clear was that we, in developing clinical trials, cannot forbid investigators from doing something that would be within their usual standard of care, even if it might not be supported by the most robust data. But at minimum, it definitely should be used as a stratification factor, or in some trial designs, you can do met-directed therapy after a primary endpoint is assessed. And that offers a compromise between testing, say, the effect of a systemic therapy but also not excluding patients and investigators from doing what they would have done had they not been on a study.
Ravi Madan: And I would just like to follow up your phrasing in the question of "oligometastatic prostate cancer." We have a figure in the paper and it highlights the fact that, unfortunately, that term in prostate cancer is imaging agnostic. And we've already discussed in this podcast, as well as in the paper, that imaging used to define a metastatic lesion, whether it's PSMA or conventional imaging, carries with it a different clinical weight and a different prognosis.
So, we feel in the working group, that the correct term for this disease state of PSMA-positive BCR is just that: PSMA-positive BCR. We also have to realize that when we talk about oligometastatic disease, while it's imaging agnostic, it seems to be numerically based, whether it's five or three or 10 depending on the trial. But PSMA-positive BCR does not have a limit in terms of the number of lesions. And so again, we just feel that there is an important need to delineate what we're seeing in this disease state, which again is PSMA-positive BCR, and that should be differentiated frankly from oligometastatic disease defined on other imaging platforms.
David Einstein: Right, and that also makes clear that patients can have polyfocal disease on PET that still is not what we would consider metastatic, but goes beyond the traditional definition of oligometastatic. So, in other words, just because someone has PET-detected disease only, that does not automatically equate with oligometastatic.
Davide Soldato: Thanks so much.
So, you were speaking a little bit, Dr. Einstein, about the different types of treatment that we can propose or not propose to this patient because you mentioned, for example, that in clinical practice MDT, so metastasis-directed therapy, is becoming more and more used. For these patients, we can potentially use systemic treatments, which include androgen deprivation therapy, which can be given continuously or in an intermittent fashion.
And recently, we can also use novel systemic therapies, for example, enzalutamide, to treat this type of patient. So, given that the point of the consensus was really to provide consideration for novel clinical trials in this space, what was the opinion on the panel regarding the control arm? So, if we're looking at a novel therapy in the BCR space, does the control arm need to include a therapy or not? And if so, which therapy?
David Einstein: Yeah, this is a super important question and one that's subject to a lot of discussion, especially in light of recent data from EMBARK. What we came to a consensus around was the fact that neither MDT nor systemic therapy should be required as a control arm on BCR trials. And we can talk about a number of reasons for that. There's also the pragmatics of what investigators might actually accrue patients to and what they would consider their standard of care, and that's important to factor in, too.
I think that one of the major goals of our working group was outlining what kinds of trials we would like to see in the future and where the limitations of the current data stand. For example, EMBARK proposes a strategy of a single treatment discontinuation and resumption at a predefined threshold indefinitely. That's probably not how most people are practicing. Most folks are probably using some version of intermittent therapy as they would have before this trial, but we actually don't have any data supporting that. Moreover, we don't have data comparing different intermittent strategies to one another. We don't know what the right thresholds are, we don't know how much time we buy patients off treatment, and we don't know to what extent MDT modifies that.
And so, those are all really important questions to be asking in future versions of these trials. I'd say my second point would be that a lot of drug development is happening with novel therapies that are not hormonal, trying to bring them into this space. And when you think about trying to compare one of those types of therapies to a hormonal therapy on short-term endpoints, the hormonal therapy is always going to win. Hormonal therapy is almost universally effective, it will bring down PSAs, and it will prolong, quote-unquote, "progression." The downside of that is that hormonal therapy doesn't actually modify the disease, it suppresses it, and it tends to have fairly transient effects once you remove it. And so, part of our goal was in trying to figure out some novel endpoints that would allow these novel types of therapies to be examined head-to-head against a more traditional type of hormonal therapy and have some measurement of some of the more long-term impacts.
Davide Soldato: So, jumping right into the endpoints, because this is a very relevant and I think very well-constructed part of the paper that you published. Because in the past we have used some of these endpoints, for example, metastasis-free survival, as potentially a proxy for long-term outcomes. But is this the right endpoint to be using right now, especially considering that frequently this outcome is measured using conventional imaging, but we are including in these trials patients who are actually negative on conventional imaging but have a positive PSMA when they enter this type of trial?
David Einstein: Yeah, there's a number of challenges with those types of endpoints. One of which is, as you say, we're changing the goalposts a little bit on how we're calling progression. We still don't exactly understand what progression on PET means, and so that's something that is challenging. That said, we're also cognizant of the fact that many times investigators are likely to get PET scans in the setting of rising PSA, and that's going to affect any endpoint that relies purely on conventional imaging. So, there's some tension there between these two different sets of goalposts.
One thing that we emphasize is that not only are there some challenges in defining those, but also there're challenges in what matters to a patient. So, if a progression event occurs in the form of a single lesion on a PET scan or even a conventional image, that might be relevant for a clinical trial but might be less relevant for a patient. In other words, that's something that, in the real world, an investigator might use serial rounds of metastasis-directed therapy or intermittent therapy to treat in a way that doesn't have any clinical consequences for the patient necessarily. In other words, they're asymptomatic, it's not the equivalent of a metastatic castration-resistant disease progressing. And so, we also need to be cognizant of the fact that if we choose a single endpoint like PFS, that there's going to be many different versions of progression, some of which probably matter clinically more than others, and some of which are more salvageable by local therapies than others.
Ravi Madan: So I think the working group really thoughtfully looked at the different options and underscored perhaps strengths and weaknesses, and I think that's presented as you mentioned in the paper. But I think it's also going to depend on the modality, the approach of the therapeutic intervention. In some cases if it's hormone-based, then maybe PSA is providing some early metrics, maybe metastasis-free survival is more relevant in a continuous therapy, but intermittent therapies might have a different approach. There's emerging immunotherapy strategies, radiopharmaceutical strategies, they might have some more novel strategies as well.
I think we have to be open-minded here, but we also have to be very clear: we do not know what progression is on a PSMA scan. Just new lesions may not carry the clinical significance that we think, and we may not know what threshold that ultimately becomes clinically relevant is. So, I do think that there was some caution issued by the working group about using PSMA as an endpoint because we still do not have the data to understand what that modality is telling us. Again, I'm optimistic that the National Cancer Institute's prospective data set that we've been collecting, which has over 130 patients now, will provide some insights in the months and years ahead.
Davide Soldato: So, just to ask the question very abruptly, what would you feel like the best endpoint for this type of trials is? I understand that is a little bit related to the type of treatments that we're going to use, whether it's intermittent, whether it's continuous, but do we have something that can encapsulate all of the discussion that we have up until this point?
David Einstein: Yeah, so that's a perfect segue to the idea of novel endpoints, which we feel are very important to develop in these novel disease spaces. So, one thing that we discussed was an endpoint called treatment-free survival, which conceptually you can think of as exactly what it sounds like, but statistically you actually have to do some work to get there.
And so essentially, you imagine a series of Kaplan-Meier curves overlaid: one about overall survival, one time to next therapy, one time on initial therapy. You can actually then take the area under those curves or between those curves and essentially sum it up using restricted mean survival time analysis. And that can give you a guide about the longitudinal experience of a patient: time spent on treatment versus off treatment; time spent with toxicity versus without toxicity.
And importantly, each one of those time-to-event metrics can be adjusted depending on exactly what the protocol is and what is allowed or not allowed and what's prespecified as far as initiation of subsequent therapies. So, we felt that this was a really important endpoint to develop in this disease space because it can really capture that longitudinal aspect. It can really reward treatments that are effective in getting durable responses and getting patients off of therapy, because unfortunately, PFS-based endpoints generally reward more or longer systemic therapy versus shorter or no systemic therapy, and that's sort of an artificial bias in the way those endpoints are constructed.
So, I think that there are challenges of course in implementing any new endpoint, and some of the things that are really critical are collecting data about toxicity and about subsequent therapies beyond what a typical trial might collect. But I think in this kind of disease space, that longitudinal aspect is critical because these are really patients who are going to be going through multiple rounds of therapy, going to be going on and off treatments, they're going to be using combinations of local and systemic therapies. And so, any one single endpoint is going to be limited, but I think that really highlights the limitations of using PFS-based endpoints in this space.
Ravi Madan: I also think that in the concept of treatment-free survival lies one of the more powerful and, honestly, I was surprised by this, that it was so universally accepted, recommendations from the committee. And that was that the general approach to trials in this space should be a de-escalation of the EMBARK strategy as it's laid out with relatively continuous therapy with one pause.
And so, I think again, buried in all of this highlights the need for novel endpoints like treatment-free survival. We get to the fact that these are patients who are not at near-term clinical risk from symptoms of their disease, so de-escalating therapies does not put them at risk. And if you look at, for example, lower-volume metastatic castration-sensitive prostate cancer, it's become realized that we need to de-escalate, and there are now trials being done to look at that. Historically, we know that BCR is an indolent disease process for the vast majority of patients who are not at near-term risk from clinical deterioration. So, therefore, we shouldn't wait a decade into abundant BCR trials to de-escalate. The de-escalation strategy should be from the outset. And that was something the committee really actually universally agreed on.
David Einstein: And that de-escalation can really take multiple forms. That could be different strategies for intermittent therapy, different start-stop strategies. It could also mean actually intensifying in the short-term with the goal long-term de-intensification, kind of analogous to kidney cancer where we might use dual checkpoint inhibitors up front with some higher upfront toxicity but with the hope of actually long-term benefit and actually being able to come off treatment and stay in remission.
Those kinds of trade-offs are the types of things that are challenging to talk about. There's not a one-size-fits-all answer for every patient. And so, that's why some of these endpoints like treatment-free survival would be really helpful in actually quantifying those trade-offs and allowing each patient to make decisions that are concordant with their own wishes.
Davide Soldato: Thanks so much. That was very clear, especially on the part of de-escalation, because, as you were mentioning, I think that we are globally talking about a situation, a clinical situation, where the prognosis can be very good and patients can stay off treatment for a very long period of time without compromising long-term outcomes. And I think that well-constructed de-escalation trials, as you were mentioning and as the consensus endorsed, are really needed in this space also to limit toxicity.
This brings us to the end of this episode. So, I would like to thank again Dr. Einstein and Dr. Madan for joining us today.
David Einstein: We really appreciate the time and the thought, and I think that even starting these types of discussions is critical. Even just recognizing that this is a unique space is the beginning of the conversation.
Ravi Madan: Yeah, and I want to thank JCO for giving us this forum and the opportunity to publish these results and all the expert prostate cancer investigators who were part of this committee. We produced some good thoughts for the future.
Davide Soldato: We appreciate you sharing more on your JCO article titled, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations."
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Host Dr. Davide Soldato and guests Dr. Kerin Adelson and Dr. Maureen Canavan discuss JCO article "Association Between Systemic Anticancer Therapy Administration Near the End of Life with Health Care and Hospice Utilization in Older Adults: A SEER Medicare Analysis of End-of-Life Care Quality," highlighting adverse outcomes for patients who receive any type of systemic anticancer therapy(SACT) at EOL (end of life) and the need for better communication between oncologists and patients regarding expected risk and benefits of such treatments to properly align goals-of-care.
TRANSCRIPT
Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy.
Today, we are joined by JCO authors Dr. Maureen Canavan, epidemiologist and associate research scientist at Yale Cancer Outcomes, Public Policy and Effectiveness Research Center; and by Dr. Kerin Adelson, Chief Quality and Value Officer, medical oncologist, and clinical researcher on health services and clinical care delivery at MD Anderson Cancer Center.
In the manuscript "Association Between Systemic Anticancer Therapy Administration Near the End of Life With Health Care and Hospice Utilization in Older Adults: A SEER-Medicare Analysis of End-of-Life Care Quality." that you recently published in the JCO, you performed an analysis that included more than 30,000 older adults in the SEER-Medicare database, and you observed that 7.6% of these patients received any systemic anticancer medication within 30 days of death. So, I wanted you to explain why you thought that this was a priority right now, and whether there was any previous data that was published in the literature, and if you think that there was any significant gap in the literature that led you to the research you just published.
Dr. Kerin Adelson: We have published a series of articles looking at real-world trends  in patterns of care, particularly related to systemic anticancer therapy at the end of life. This has been gaining increasing focus in recent years because of the understanding that when patients stay on systemic anticancer therapy, that is often a surrogate for a lack of goal-concordant care.
So, patients who continue to receive systemic therapy have worse quality of life, are more likely generally to have a medicalized death, and less likely to use hospice. And what our prior work has shown is that more and more we are seeing patients using immunotherapies and targeted therapies towards the end of life. No prior work had really comprehensively examined whether these novel therapies were associated with those same patterns of care increases in acute care utilization and decreases in hospice.
Dr. Davide Soldato: So basically, the data that we had up until that point was mostly with cytotoxic chemotherapy, and the emergence of this new treatment, which frequently are thought to be less toxic and so less problematic also in the end of life, led to this research. Is that correct?
Dr. Kerin Adelson: Correct.
Dr. Maureen Canavan: I would also build on that. I think that as the landscape of cancer care changes, it is important to really understand the availability of treatments, but then also, as Kerin noted, it is important to focus on goal-concordant care. We have established literature, studies we have done and some other studies that have looked at cytotoxic chemotherapy, but with the emergence of these targeted therapies, we really did not know a few things. We did not know the rates of utilization in a large national population, and how that was associated with these elements of medicalized death like ED use, hospitalizations, acute care use.
So this was really a question that we had going into it. How can we expand the knowledge base so that both patients and providers can be more cognizant when thinking about goals of care conversations and ensuring that that is in place?
Dr. Kerin Adelson: And our work has kind of evolved to answer some critical questions. So, one of our early papers looked at different rates of systemic anticancer therapy at the end of life, and that is where we showed that we were seeing a lot more immunotherapy and targeted therapy. And then we asked the question, well, oncologists generally when they give these treatments, they are hoping that those treatments are going to work and help the patients live longer. So we did another paper where we actually looked at practices who were more aggressive near the end of life and whether they had better overall survival than practices that were less aggressive, accounting for the fact that there could be populations of patients who benefited.
And in fact, we showed there was no survival difference. So then this paper sort of answered the question: Well, if it is not having benefit, is this treatment actually doing harm? And this study gets at that question: What are the harms of continuing patients on therapy past the point of benefit?
Dr. Maureen Canavan: And I think building off of that, the use of the SEER-Medicare database is a quite robust database. So in this, we have very specific data we can track. We can track the exact type of treatment they had, you know, was it a targeted therapy? Was it immunotherapy? So looking at those subclasses of therapy. We were also able to directly link it within that time frame to the acute care utilization, a limitation that we had in some of our previous work that that data was not always available.
So it is more focused in the sense that we were looking at older adults, so patients 66 years of age and older, but we were able to get those individual metrics. So to Kerin's point, we did not see the survival benefit. What do we see then for these medicalized death elements? So the higher rates of all of them across the board.
Dr. Davide Soldato: So coming back to the cohort and to the data that you utilized, Dr. Canavan mentioned the use of the SEER system to analyze these data. You already mentioned that you included mostly older adults, so those aged 66 and more. And also there was a little bit of restriction regarding the fact that the patient needed to be covered by Medicare in the last year of death concerning Part A and Part B, and the last 30 days from death concerning Part D. So I just wanted to ask a little bit of a question regarding these findings and whether you think that we also need additional work, especially in the younger population because I think it is something that all of us who work in oncology have seen. The aggressiveness, and this is also something that you showed in your data, tends to increase as the age of the patient tends to decrease. So we tend to be more aggressive towards younger patients. So just a comment on that on the population and generalizability of the findings.
Dr. Maureen Canavan: Yeah, I will start with the data question element. Thank you. I think there are a few things to point out for that. So in terms of the restriction to ensure that they had continuous Part D coverage, that was necessary for us to track their oral medication use during that time. So kind of an easy response. The Part A, Part B requirement, it is actually pretty widely used in studies of SEER-Medicare data, and that is you want to establish the patient population, that they are not getting treated with another insurance provider in some way that you are not able to track.
So that ensures that we can track not only their systemic anticancer therapy use but also when we are trying to make sure that we are controlling for confounders like chronic conditions and stuff, we are able to track the presence of chronic conditions. So we wanted to make sure we were not biasing the data, so I think that was an important consideration.
You do point out very wisely that there are then limitations with the generalizability, and I think we would be lacking if we did not account for that. But I think it is important to establish this baseline relationship association, and then you can step out, we will say, to more diverse populations. So I think we could potentially maybe try to relax the timeline to see if people that might have influx in and out of the Medicare system are still seeing those same rates. I think it is likely they would.
But I think to the bigger point that you bring up is that establishing this within the older adults where, you know, we do see as they get older maybe less rates of systemic therapy, extending it to the younger population. There is a challenge with that in that just that data is not available to the robust level that SEER-Medicare is. Both Kerin and I have noted that there is the possibility to look within one specific insurance provider type. Again, recognizing the limitations of the generalizability, but always slowly pushing the needle, finding out more about younger adult populations.
And I think this is maybe in an ideal world, but setting the precedent that we really do need to track this on a national scale within younger adults because they do have the need. We do see these higher rates of utilization, and really making sure again with the mindset always of the best interest of patients and the most informative to providers in how we are looking at care.
So I think generalizability is definitely a goal. However, there are limitations of the availability of data for younger populations and I think that they are a necessary restraint that all researchers should acknowledge.
Dr. Kerin Adelson: Yeah, I think it is important for our audience to understand that health services research and large database research is really limited by what databases are available and what are the characteristics of those databases. So we have done a lot of work in an electronic health record database, and there you can get certain kinds of granularity that you may not be able to get in a payer or a claims-based database. But what you do not get is that comprehensive look at, say, what happens if a patient goes to another practice.
Claims-based databases offer you that, but research on US populations is limited by our payment system. So when you look at younger patients, there are so many different insurance companies that when you are trying to get that comprehensive view, it can be hard or very expensive actually. These commercial insurers will sell their data to different databases. So for us, the largest single payer in the United States is the US government, and that is for patients who are over age 65, and that is why you see lots of US-based studies done in the Medicare population.
Interestingly, a recent paper by a Canadian group showed very, very similar patterns. It was a significantly smaller study but, right, Canada is a single-payer system and so they were able to really look at all ages, and we did see the same patterns of care in a different payment system.
Dr. Davide Soldato: Going back a little bit to the type of treatments that were observed in your manuscript, so we start from a 7.6% of patients who received any type of systemic anticancer therapy within 30 days from death. And when we split the different categories that you analyzed, which I think is a very strong aspect of your manuscript, we see that more or less 50% of the patients received chemotherapy, 20% more or less received immunotherapy, more or less 20% targeted therapy, and then there is a combination of those agents. So just wanted to have a little bit of your opinion compared also to the data that you already published and that you mentioned before. Was this in line with previous data? Was there anything surprising about this? We saw a little bit of a raise in the use of immunotherapy and targeted therapy as you were saying, but still, there is a very high proportion of chemotherapy, 50%.
Dr. Kerin Adelson: So I think that really, really reflects the time period in which we studied where immunotherapies were gaining ground. There was tons of excitement and we were seeing this shift. I bet if we do the same study in five years that chemotherapy percent may even go down to half, and we are going to see more and more targeted and immunotherapies, and that is just reflecting the pattern of drug discovery that we are seeing.
Dr. Davide Soldato: Coming to the real question that you wanted to answer with this manuscript, so is systemic anticancer therapy associated with worse outcomes in terms of healthcare utilization and use of hospice resources? Was there any hint that for example immunotherapy was related to less of these adverse outcomes?
Dr. Kerin Adelson: So I will be honest, I was a little bit surprised that the combination of chemotherapy and immunotherapy was that much more strongly correlated with acute care use at the end of life. You know, I had really thought most likely that what we would see were similar rates. And we did. Each different type of systemic anticancer therapy was associated with significantly higher odds of ending up in the hospital, going to the ICU, dying in the hospital, going to the ED. But that group that got dual therapy was that much higher, you know, over three times the risk.
And that surprised me because what it suggested is that there is likely a component of treatment toxicity that is leading to some of the acute care use. It is not simply just a constellation of patients who have not yet transitioned towards hospice or palliative care or end-of-life care who are then more likely to end up in the hospital. But the fact that we see a difference between, say, single-agent immunotherapy and dual combination with chemotherapy does suggest that the treatments are actually contributing to some of what we are seeing.
Dr. Davide Soldato: But still, all of the treatments that you evaluated were still associated with higher healthcare utilization. Like there was no signal that, for example, giving immunotherapy at the end of life was not associated with these adverse outcomes. Correct?
Dr. Kerin Adelson: Correct. And you will find oncologists out there who will say, actually, these treatments are so good that they might actually lower rates of hospitalization because they keep patients healthy. And certainly, that may be true upstream or earlier in the course of disease, but at the end of life, any form of systemic anticancer therapy is really a surrogate marker for lack of transition towards what is likely appropriate end-of-life therapy.
And I just want to point out that time spent in the hospital, going back and forth to invasive procedures, going to the intensive care unit, even going back and forth to an infusion center, that is time that is not spent at home with loved ones for people who have very little time left to live.
Dr. Davide Soldato: Thank you very much. That was exactly the point that I wanted you to stress because I think it is really the most important message that we can get as oncologists from this manuscript. Like there is no treatment that is not associated with potentially harming our patient and, as you were saying, taking off time with loved ones in a critical period of the life of these individuals who have been diagnosed and treated for cancer.
So, basically what we saw in the paper was a 7.65% utilization of systemic anticancer therapy. And I might imagine that for some oncologists or for some hematologists that might not actually be that much. Like they could potentially say, "Okay, but it is like 7%, it is not that high. I would have expected something higher." So I just wanted a little bit of perspective regarding also quality metrics that we have available for these types of indicators at end-of-life care. What would be the appropriate percentage of people receiving any type of treatment within 30 days from death?
Dr. Maureen Canavan: A couple caveats, as a data person I always like to give those. This was among all cancer patients, so not necessarily patients that had been on active treatment. So I think that number was actually quite lower than when we looked in another study about patients that had chemo within the last year, so on, you know, active treatment. So I think that is an element to take into consideration is that those numbers will vary based on who your denominator population is. So that is important to consider.
Additionally, the National Quality Forum, they call for reducing rates of systemic therapy at end of life. But I think they, similar to how I would be, are cautious to point out this is the exact number, or it should be zero. Because there are cases where you have to go in line with patient preferences. And if a patient is very adamant that they want to continue treatment, that needs to be a decision that comes between them and their provider.
So, you know, the zero, though sounding ideal to us who want to encourage transitions and encourage goals of care conversation is a nice number, it is not a realistic. So, to evade your question completely, I do not think there is a set number. But the goal is to make sure that both patients, providers, everyone is informed and is making the best holistic decision. So there is this natural tendency, I think, to keep fighting both for the patient and the provider to try to beat something, but recognizing the point at which we are beyond a benefit of treatment and what would be most beneficial to the patient in terms of getting back to that idea of, you know, the time with their families and whatnot.
So is the number zero? No. Could it probably be lower than we have? I think yes, definitely.
Dr. Kerin Adelson: I completely agree with everything Dr. Canavan said. I think one of the other challenges is that this data isn't being tracked and publicly reported across the world. And so what that optimal rate is, is a little unclear. We see different rates also depending on the population included. So one of the things Dr. Canavan said is our database included patients who were likely treated long ago for cancer and cured of their cancer. So they were less likely to die on systemic therapy. But until everybody starts tracking and reporting, it is really hard to know where we are as a country or really as a global population, and then what are the bars that we want to achieve in driving down the rates.
I think some data shows that probably something in the range of 10% or below, you know, for patients who have more active cancer is probably where we should be going and driving towards. But until we have more public reporting of these metrics and consistency in how we measure them, it is really hard to come up with a single number.
Dr. Davide Soldato: I have the impression that sometimes there is also a little bit of difficulty for the oncologist or the hematologist to really understand who are the patients who are approaching end of life. So there has been some data and you also report some of them in the discussion of the manuscript regarding, for example, prompts inside of the electronic health records or the use of artificial intelligence to try to predict what is the disease course. So just wanted a little bit of perspective if you think that these tools could potentially be helpful and if you think that we will be able at a certain point to implement them in routine clinical care.
Dr. Kerin Adelson: I have been working on trying to do this actually at MD Anderson and coming up with a really reliable data tool that will tell us who are the patients who are going to die in short order after receiving systemic anticancer therapy. And it is not that easy, I will say. So, you know, I think we all want this amazing machine learning model that is incredibly reliable. But like any statistical test, there are problems, right? So a very sensitive test that is going to identify high, high risk of dying at the end of life is going to be compromised by false positives. And when an oncologist knows that the test might be a false positive, it becomes very hard for them to take action on it.
Similarly, you know, a very, very specific test is going to be compromised by false negatives. So in that case, you could end up having patients who are at risk for dying and still treating them with chemotherapy. And so, you know, I think in the end we need some tools. It will be great if machine learning becomes very reliable and we have the right structured data elements in our electronic health records to give these reliable prediction tools.
But I think there are some basic things that we all know, and those are the markers of chronicity of cancer. So patients who have had multiple lines of therapy already, right? Past the point of clinical trial benefit. Patients who have lost significant amounts of weight. Patients who are not getting out of bed and have worse performance status. Patients who are increasingly confused, right? And not mentally engaging the way they did previously. Those markers have been shown in numerous publications by a colleague of mine, David Hui and others, to really be pretty strong predictors, and they resonate with clinicians more than a machine learning score might. You know, I think when clinicians do not understand what the elements in a machine learning tool are, they are less likely to trust it and more likely to say, "Oh, it is a false positive or a false negative." But very few clinicians can argue against the fact that the patient who hasn't gotten out of bed in two weeks is somebody who is less likely to benefit.
Dr. Davide Soldato: Dr. Adelson, I would like to close this podcast and I would like to thank you again for joining us today.
Dr. Maureen Canavan: Thank you so much.
Dr. Kerin Adelson: Thank you so much for having us.
Dr. Davide Soldato: Dr. Canavan, Dr. Adelson, we appreciate you sharing more on your JCO article titled "Association Between Systemic Anticancer Therapy Administration Near the End of Life With Health Care and Hospice Utilization in Older Adults: A SEER-Medicare Analysis of End-of-Life Care Quality."
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 Disclosures
Kerin Adelson
Stock and Other Ownership Interests: Carrum Health
Consulting or Advisory Role: Abbvie, Quantum Health, Gilead Sciences
Patents, Royalties, Other Intellectual Property: Genentech
Other Relationship: Genentech/Roche

Employment: Emilio Health/Brightline Health(An Immediate Family Member)
Stock and Other Ownership Interests: Emilio Health/Brightline Health, Lyra Health (An Immediate Family Member)

Guests Dr. Andrea Necchi, Dr. Ashish Kamat and host Dr. Davide Soldato discuss JCO article "End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer," focusing on the evolving treatment landscape of MIBC (muscle-invasive bladder cancer) and the need to properly design novel trials investigating non-operative management while including the incorporation of biomarkers and patient perspectives in clinical trials.
TRANSCRIPT
The disclosures for guests on this podcast can be found in the show notes.
Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy.
Today we are joined by JCO authors Andrea Necchi, Associate Professor of Medical Oncology at University San Raffaele and Medical Oncology at Ospedale San Raffaele in Milan, Italy, and Ashish Kamat, Professor of Urologic Oncology and Cancer Research at University of Texas MD Anderson Cancer Center. Both Professor Necchi and Professor Kamat are internationally recognized experts in the field of genitourinary malignancy and particularly in bladder cancer.
Today we will be discussing the article titled "Endpoints for the Next Generation Bladder-Sparing Perioperative Trials for Patients with Muscle-Invasive Bladder Cancer."
So thank you for speaking with us, Professor Necchi and Professor Kamat.
Dr. Andrea Necchi: Thank you, Davide, and thank you JCO for the opportunity.
Dr. Ashish Kamat: Yeah, absolutely. It is a great honor and privilege to be discussing this very important article with you. So thank you for the invitation.
Dr. Davide Soldato: The article that you just published in JCO reports the results of a consensus meeting that was held among experts in the field of genitourinary malignancy and particularly for bladder cancer. So the objective was really to define endpoints for a novel generation of trials among patients diagnosed with muscle-invasive bladder cancer. So my first question would be: what is the change in clinical practice and in clinical evidence that we have right now that prompted the start of such consensus in 2025?
Dr. Andrea Necchi: So, we are living so many changes in the treatment paradigm of patients with muscle-invasive bladder cancer. In general, patients diagnosed with bladder cancer or urothelial cancer today, thanks to the advent of immunotherapy or immunotherapy combinations, and today thanks to the advent of novel antibody-drug conjugates like enfortumab vedotin in combination with immunotherapy that are actually changing the landscape of treatment of patients with metastatic disease and also are entering quite fast into the treatment paradigm of patients with organ-confined disease with a lot of clinical trials testing these combination therapies, neoadjuvantly or adjuvantly, before or after radical cystectomy.
Having said that, by potentiating the efficacy of systemic therapy, an increasing number of patients that receive neoadjuvant therapy of any kind, at a certain point in time, result to have achieved a deep response to systemic therapy, evaluated radiologically with conventional imaging, CT scan or MRI, or with cystoscopy or with other urology-based techniques, urinary cytology, and so. And based on the fact that they achieve a complete response, so no residual viable disease after systemic therapy, they raise concern about the fact that they have to undergo surgery like radical cystectomy that is quite impactful for their quality of life and for the future of their lives after the surgery. So the point that the patients are raising, and the patients are raising this point, is primarily due to the efficacy of systemic therapy.
And we have seen so many cases fortunately achieving a deep response. So the question about what to do with the patient that at a certain point, at the start with the commitment to radical cystectomy, but at a certain point in time change their mind towards something else if possible, depending on the fact that they have achieved a deep response, is something that is a question and is a need to which we have to provide data, information, and guidance in general to the patients.
Dr. Davide Soldato: If we look at the population that the recommendations were formulated for, we are mainly speaking about patients who would be fit for cystectomy, and this is a very distinct population compared to those who are not fit for cystectomy, both from a medical oncology point of view but also from a urologic point of view in terms of surgery. So, can you explain a little bit to our listeners why you think that this distinction is critical and why you developed this recommendation especially for this population?
Dr. Ashish Kamat: That is a very important distinction that you made. To build upon what Professor Necchi mentioned earlier, this question that we get from patients after neoadjuvant therapy or systemic therapy is not a new question. It has been something that they have been asking us for the last 20 or 30 years. "Do I really need to have my bladder taken out?" And patients who are especially not fit for surgery will sometimes say, "Do I need to have my bladder taken out? And if I cannot have my bladder taken out, am I going to just not have anything done?" Because the eligibility for radical cystectomy is also a moving target.
Over the years with improvement in surgical technique, improvement in perioperative therapy, ERAS protocols, et cetera, it is really unusual for us to deny a patient the opportunity to have major surgery unless clearly they have very significant comorbid conditions. So I think this endeavor is more broadly encompassing of the patient population than what was evident in previous years.
And I really want to give a shout out to Professor Necchi because what we did was, as part of the International Bladder Cancer Group and Professor Necchi is an integral part of the scientific advisory board, we broached this topic broadly during one of our discussions. And of course, Andrea always does this, he picks on a topic and then he says, "Okay, we need to discuss this really in detail," put together a multinational, multicenter collaborative group, but the driving force was our patients. Because our patients are constantly asking, "Do I need to lose my organ? Do I need to have radiation therapy?" which again, also, has a lot of side effects.
So this was really to answer the question in today's day and age as to do we need to do local consolidation, and if so, in what way? It is not a new question, but we have newer therapies, newer technology, and better ways to answer this. So it is a much needed question that needs to be answered. And I think the distinction between non-surgical candidates and surgical candidates is a little bit blurred in today's day and age.
Dr. Davide Soldato: What about the eligibility, for example, for cisplatin-based chemotherapy? Because I think that that is a very fundamental part of this type of strategy that we apply to patients with muscle-invasive bladder cancer. So we know that there are some caveats for proposing such treatment. And also this population was specifically defined inside this recommendation.
Dr. Andrea Necchi: I think that the focus of our work is just to analyze what is happening after any type of systemic therapy the patient may get neoadjuvantly. So it is not actually a question of treatment eligibility or including cisplatin eligibility. This is an old question of today's practice and clinical trials. But regardless of what the patient received neoadjuvantly, the point that we have addressed in our consensus meeting was what to do next as a further step after systemic therapy or not.
So basically we are- the consensus guidance includes all-comers, so patients to get any type of systemic therapy. So really non-selected based on specific features that determine a special eligibility to a special or a particular therapy. But an all-comer approach is always the winning approach for the translation to be in practice, an all-comer approach just focusing on what has happened after treatment and that we are assessing by the use of conventional imaging, MRI or CT, cystoscopy, urinary cytology, and trying to merge all together this information, all these features in a unique, shared, reliable definition of clinical complete response that could be used as a biomarker for the selection of newer therapies instead of pathological response that has been historically used, and maybe surrogate for the outcome, the long-term outcome and survival of these patients.
Dr. Davide Soldato: A very specific point of the consensus was actually the definition of clinical complete response. As you were saying, this is actually a combination of several parameters including urinary cytology, the use of cross-sectional imaging, for example CT scan, but also the evaluation in cystoscopy of the bladder. Do you foresee any potential problems when applying this type of recommendation, not inside clinical trials, but in the context of routine clinical practice?
Dr. Ashish Kamat: Absolutely. And that was the whole reason we had this consensus meeting. What happens nowadays in daily practice, and we see this every day at our center, we see patients referred to us. This definition or this sort of attempt to define clinical complete response is an ongoing issue. And urologists, medical oncologists, radiation oncologists are always looking to see, does my patient have a complete response? That definition and those paradigms have changed and evolved over the years.
The FDA had a workshop many years ago looking at this very question. And it was to address the proposal that complete clinical response, which is a clinical definition, a clinical state, does this correlate with pathologic response? And with the technology and the systemic therapies we had then, the answer was 'no'. In fact, more patients got recurrent disease than did not get recurrent disease. And that is why, of course in the paper we mention the trials that looked at this question, the trials that evolved around this question.
And I think the distinction between a clinical trial and daily practice is extremely important when we are looking at this definition per se. Because essentially what happens with this issue is that if the patient is not appropriately counseled, and if the physician does not do the appropriate clinical complete response assessment as Professor Necchi mentioned, right, cystoscopy, cytology, imaging, use of markers that are still in evolvement, we risk doing harm to the patient. So we caution in the paper too that this definition is not ready for prime time use. It is something that needs to be studied. It is a rigorous definition and currently we are recommending it for clinical trials. I am sure eventually it will trickle down into clinical practice, but that guidance was not the purpose of this consensus meeting.
Dr. Davide Soldato: There are several parameters that are potentially evolving and could potentially enter inside of clinical practice. For example, you mentioned pelvic MRI and we have now very specific criteria, the VI-RADS criteria, we're able actually to diagnose and also to provide information. So along with these novel imaging techniques, we also know that there are novel biomarkers that could be explored, for example ctDNA and urinary DNA. So what I was wondering is, why were not these included inside the definition that you provide for clinical complete response? And do you think that, as we are designing these trials to potentially spare cystectomy for this patient, we should include these biomarkers very early so that we can actually provide better stratification for our patients and really propose this type of cystectomy-sparing strategy only to those where we are very confident that we have obtained a clinical complete response?
Dr. Andrea Necchi: I would say you have just to wait. So a follow-up is ongoing and hard work is ongoing. At the time we met, at the time we established the meeting in mid-December last year, we had no information on the ctDNA data from major trials, with only a few exceptions. So we were just at the beginning of a story that was more than likely to change but still without numbers and without data from clinical trials. Now in just nine months or 10 months time, we have accumulated important data and newer data will be presented during just a few weeks and a few days regarding the ctDNA, circulating tumor DNA in particular, as a prognostic marker assessed baseline or assessed after neoadjuvant therapy.
So the point is certainly well made and ctDNA is certainly well shaped to be incorporated in a future definition of clinical complete response. But you have to consider the fact that most of the data that we are accumulating related to ctDNA are about the post-cystectomy field or the metastatic field. So regarding neoadjuvant therapy, you know, we have neoadjuvant therapy in the context of bladder-sparing approach, basically we have no information.
And the point that is emerging in our daily practice when using these biomarkers or in clinical trials, and the impression in general, is that it is a very strong biomarker associated with survival, but we absolutely do not know what is the performance of the test in the prediction of superficial bladder relapses, high-grade pTa relapse in the bladder that is left untouched in the patient. We are considering, and maybe it will be just a matter of further discussion, not just what is happening within the immediate endpoint of clinical CR, but also what is happening later with other survival endpoints.
And for example, when looking at the type of events that we may see in this kind of bladder-sparing approaches, most of the events, also in the trials that have been published including the RETAIN study published in JCO, most of the events are related to superficial high-grade superficial non-muscle invasive relapses. So the ability to predict these types of events with ctDNA is completely unknown. Maybe, maybe other liquid biomarkers like urinary tumor DNA, utDNA, could be a bit better shaped in the prediction of this kind of events, you know. But we have still to build the story.
So the question is good. The answer is yes, we will likely, more than likely incorporate liquid biomarkers in the definition, but we have to wait at least more data and more robust data in order to translate this information in routine practice, you know. Another consensus meeting is organized by IBCG and the same folks for November. This meeting will be primarily focused on the liquid biomarkers, the interpretation and use and approval and so of liquid biomarkers including bladder cancer. And we will likely be able to address all these, most of these open issues, so most of these points in the next meetings.
Dr. Davide Soldato: In the consensus you say that probably clinical complete response is now ready to be included in early phase trials, so actually to test what is the efficacy of the regimens that is being evaluated inside of these trials. But you actually do very in-depth work of defining what are the most appropriate endpoints for later phase trials. So to be very specific, the phase three registrational trials that bring new regimens inside of this space. So I just wanted to hear a little bit about what was the definition for event-free survival, which you define as the most appropriate one for this type of trials. And as you were mentioning before, Professor Necchi, there is a very specific interest on the type of events that we observe, especially when we look at these superficial relapses inside of the bladder. So was this a very urgent matter of debate as we define which type of events should actually trigger event-free survival? And did you make a very thoughtful decision about why using this type of endpoint instead of others, for example metastasis-free survival?
Dr. Ashish Kamat: Yeah, this was a matter of intense debate as you might imagine. And again, this is a moving target. So as Professor Necchi mentioned, we tend to partner with each other, our organizations, on having definitions of clinical complete response, biomarker, retreats, and then using that as a marker, and you might imagine this definition of what is appropriate event-free survival, what events matter to the patient, is something we have been talking about for two years. It was not just something that came up at the retreat. But at the retreat there was intense discussion.
One of the things that we talked about was bladder-intact event-free survival because we are trying to spare the patient's bladder. And do we count bladder-intact event-free survival as something that is relevant? The patient advocates absolutely liked that, right? They wanted that. But then we also learned from some of the studies, for example from the RETAIN study, that the non-muscle invasive recurrences can actually lead to metastatic disease. It is not as benign when you have a patient with muscle-invasive bladder cancer that then develops a non-invasive tumor because maybe there is cancer growing underneath the surface that we don't detect when we look in the bladder.
So a lot of those discussions were held, debated. It was a consensus. I have to say it was not 100% agreement on that particular definition, but it was broad consensus. And Andrea, do you want to clarify a little bit as to how we came about that consensus? Because I think this is a very important point we need to make.
Dr. Andrea Necchi: We focused on a bit different definition of BI-EFS, Bladder-Intact Event-Free survival. Just stating EFS as an all-inclusive parameter including all type of high-grade relapse or progression or death that may happen to the patient. So that we were counting high-grade pTa, pT1, CIS relapses to the bladder and of course more deeper involvement in the muscle layer and so, and metastatic disease as a relapse. But the point is that as compared to the classical bladder-intact EFS definition of chemoradiation bladder-sparing approaches that is including muscle-invasive relapses only or death as events, we tried to be as inclusive as possible in order to be as much conservative as possible and to raise as higher the bar as possible for the success.
And this is actually what the patients are asking us. So they are asking, "Okay, I can save my bladder, sparing radical cystectomy, but at which cost?" So in order to provide an answer, we have to be very, very cautious and be on the right shape, on the right position to say, "Okay, we have accomplished the most, the safest points, you know, by which you can proceed with the bladder-sparing." This is the first point.
The other point is related to the MFS, metastasis-free survival that you have mentioned. For sure, it was recognized as a very important point for sure. But in the discussion was clear that our focus was in saving patients, curing the patient, and saving the bladder. Any single event, superficial event that may occur in the bladder-saving approaches of this kind may expose the patient to an extra risk of developing distant metastases, as it happened for example in the RETAIN study. So EFS defined as we have agreed and published, is actually a way of including or anticipating in a safest position the MFS. Because most or if not the entirety of the events of metastasis development in patients undergoing bladder-sparing after neoadjuvant systemic therapy were preceded by a superficial phase of disease relapse, you know.
So I remember very, very few, or we can count just on the finger of one hand, the cases that have been reported in the literature developing de novo metastatic disease in the similar bladder-sparing approaches, in particular when using a maintenance immunotherapy strategy, you know, after they reach TURBT. So this is the reason why with all the limitation that Ashish has mentioned, with all the uncertainties that are still there, the nervousness that is still there, EFS, as defined in the protocol, as put in the paper, is to us at the moment is the safest way to use a primary endpoint in potentially registration trials of this kind with perioperative systemic therapy and response-adapted surgery.
Dr. Ashish Kamat: And David, just to be absolutely clear for our listeners, right, so what was the event-free survival that we defined? Essentially it was a very inclusive definition. Event was defined as high-grade tumor persistence, recurrence, or progression during or after perioperative therapy, and receipt of any additional standard of care treatment including radical cystectomy, radiotherapy or even intravesical therapy. So this was done at the behest of our patient advocates because we really wanted to make a very robust definition that could be utilized appropriately as an adequate primary endpoint for both early and late phase bladder preservation trials.
Dr. Davide Soldato: I think that it really highlights one of the points that I liked the most about this consensus is that it really incorporated the patient vision and a sort of shared decision making process when we are deciding how we want to design these trials that will explore this bladder-sparing surgery.
And Professor Necchi mentioned something that I think will be also a very interesting question for trials that will be developed considering the activity of this combination that we are seeing right now, which is maintenance. Because right now our approach in the few cases where patients do not do any type of treatments after an induction with neoadjuvant treatments is basically represented by observation. So I was wondering if you think that the field will actually evolve to a sort of maintenance strategy even in patients that will achieve a complete clinical response?
Dr. Andrea Necchi: We just mentioned briefly in the paper, this is a very important point that was touched during the discussion, and in particular was raised and discussed by FDA people participating in the meeting. And when looking at the data from the trials that were available and are still available thus far, we could provide a suggestion that maintenance immune therapy is the preferred approach in this kind of approach as it currently stands, as the data currently stand. Because the cleanest data towards the successful part of this journey is related to the studies that provided a kind of maintenance therapy, like the study with nivolumab or the RETAIN-2 study with maintenance immune therapy instead of RETAIN study that was just stopping treatment until surgery with MVAC chemotherapy.
So in general the impression is that maintenance therapy may help in reducing the type of events, including the events that we incorporate in the EFS definition that we mentioned in the paper. The point that you mentioned is very important because on the other side we have a problem, a big problem of affordability and cost of the treatment. The de-escalation trials are an urgent need and represent a call for the studies. Unfortunately, as you mentioned, this is something that moves beyond the possibilities of this type of consensus because we don't have data and we have to accumulate data from clinical trials prior to saying, "Okay, certain patients could de-escalate therapy and stop therapy and some other not." So we are still at the very beginning. So we can do- we can discuss about this in the radical cystectomy paradigm but not in the bladder-sparing paradigm, you know. But this is for sure a point, a discussion point that will be taken, pretty well taken in one year or two year projection.
Dr. Davide Soldato: I was wondering if in the consensus, considering that patient advocates and patient associations were also involved, did you decide to actually suggest the inclusion of patient-reported outcomes or the evaluation of shared decision-making in the development of this trial really as endpoints that should matter as much or as much as possible as event-free survival and clinical complete response?
Dr. Ashish Kamat: Oh yeah, absolutely. We had patient advocates, we had the World Bladder Cancer Patient Coalition, Bladder Cancer Advocacy Network, patient representatives. And we always consider this. Shared decision-making is actually the impetus behind why these efforts have been launched, right? So it is the shared decision-making that is very, very important. It is the driving force behind what we do. And it is worth noting, for example, for the design of such studies, regulatory agencies consider response-based endpoints or overall survival as primary endpoints. But the patient advocates consider quality of life to be just as important, if not more important sometimes than overall survival numbers. Because patient advocates will say, "Well if I live longer but I'm miserable living longer, yes that works for regulatory agencies but doesn't work for us." So PROs clearly are very, very important. And, in fact, we just literally had a meeting in Houston, the IBCG meeting where PROs were a main point of what we discussed. So incorporating PROs in everything we do, not just this but everything we do, Dr. Necchi, myself, everybody involved in these fields realizes it is very, very important. So absolutely.
Dr. Davide Soldato: I want to thank again Professor Necchi and Professor Kamat for joining us today.
Dr. Andrea Necchi: Thank you.
Dr. Ashish Kamat: It is our pleasure.
Dr. Davide Soldato: Thanks again and we appreciate you sharing more on your JCO article titled "Endpoints for the Next Generation Bladder-Sparing Perioperative Trials for Patients with Muscle-Invasive Bladder Cancer."
If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO Editor-in-Chief Dr. Jonathan Friedberg is joined by colleagues Dr. Jennifer Woyach, Dr. Wojciech Jurczak, and Dr. Matthew Davids to discuss simultaneous publications presented at ASH 2025 on pertibrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia.
TRANSCRIPT
The disclosures for guests on this podcast can be found in the show notes.
Dr. Jonathan Friedberg: I'm Jonathan Friedberg, editor of Journal of Clinical Oncology, and welcome to JCO After Hours, where we are covering two manuscripts that were presented at the American Society of Hematology meeting 2025 in Orlando, Florida. I am delighted to be joined by colleagues on this call to discuss these pivotal manuscripts which cover the topic of pirtobrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia.
I will first just introduce our guests, Dr. Woyach.
Dr. Jennifer Woyach: Hi, my name is Jennifer Woyach. I am from the Ohio State University.
Dr. Wojciech Jurczak: Hello, I am Wojciech Jurczak, working at the National Research Institute of Oncology in Krakow, Poland.
Dr. Matthew Davids: Hi, I am Matthew Davids from Dana-Farber Cancer Institute in Boston.
Dr. Jonathan Friedberg: We are going to start by just learning a little bit about these two trials that were both large, randomized phase 3 studies that I think answered some definitive questions. We will start with your study, Jennifer. If you could just describe the design of your study and the patient population.
Dr. Jennifer Woyach: Absolutely. So this is the BRUIN CLL-314 study, and this is a phase 3 randomized trial of pirtobrutinib versus ibrutinib in patients with CLL or SLL who had not previously been treated with a covalent BTK inhibitor. The patients were both treatment-naive and relapsed/refractory, about one-third of the patients treatment-naive, the rest relapsed/refractory, and they were stratified based upon 17p deletion and the number of prior lines of therapy.
The primary objective was looking at non-inferiority of overall response rate over the entire treated population as well as the relapsed/refractory patient population. Key secondary objectives included progression-free survival in the intention-to-treat and the smaller relapsed/refractory and treatment-naive populations.
Dr. Jonathan Friedberg: And just comment a little bit on the risk of the patients.
Dr. Jennifer Woyach: This study was fairly typical of this cohort of patients. Within the relapsed/refractory patient population, there was a median of one prior line of therapy in each of the groups, up to nine prior lines of therapy in the patients included on the study. For the overall cohort, about two-thirds of the patients were IGHV unmutated, about 15% had 17p deletion, 30% had TP53 mutations, and about 35% to 40% had a complex karyotype, which is three or more abnormalities.
Dr. Jonathan Friedberg: And what were your findings?
Dr. Jennifer Woyach: Regarding the primary outcome, which is the focus of the publication, we did find that pirtobrutinib was indeed non-inferior and actually superior to ibrutinib for overall response rate throughout the entire patient population and in both the relapsed/refractory and treatment-naive cohorts. PFS is a little bit immature at this time but is trending towards also being significantly better in pirtobrutinib-treated patients compared with ibrutinib-treated patients. Probably most significantly, we found this to be the case in the treatment-naive cohort where there was a striking trend to an advantage of pirtobrutinib versus ibrutinib.
Dr. Jonathan Friedberg: And the follow-up that you have on that progression-free survival?
Dr. Jennifer Woyach: So we have about 18 months follow-up on progression-free survival.
Dr. Jonathan Friedberg: The second study, Wojciech, can you just go through the design and patient population that you treated?
Dr. Wojciech Jurczak: Thank you, Dr. Friedberg, for this question. So the BRUIN CLL-313 study was, in fact, the first phase 3 study with pirtobrutinib in exclusively untreated CLL patients. It was a randomized study where we challenged pirtobrutinib versus bendamustine-rituximab. At the time we designed the protocol, bendamustine-rituximab was an option as a standard of care, and Bruton tyrosine kinase monotherapy was used far more commonly than nowadays.
The primary target of the study was progression-free survival. We took all untreated patients except for those with 17p deletions. Therefore, it is a good representation for intermediate risk. We had about 60% of the population, 56 to be precise, which was unmutated, evenly distributed into two treatment arms. 17p deleted cases were excluded, but we had about 7% and 8% of TP53 mutated patients as well as about 11% and 7%, respectively, in the pirtobrutinib and bendamustine-rituximab arm of patients with complex karyotype.
The progression-free survival was in favor of pirtobrutinib and was assessed by an independent review committee. What is important is that the progression-free survival of the bendamustine-rituximab arm was actually similar to the other studies addressing the same questions, like the comparison with ibrutinib in the ALLIANCE study or zanubrutinib in the SEQUOIA study. What was different was the hazard ratio. In our study, it was 0.20. It was one of the longest effect sizes noted in the frontline BTK study. It represented an 80% reduction in progression-free survival or death. If we compare it to ibrutinib or zanubrutinib, it was 0.39 and 0.42 respectively.
Presumably, this great effect contributed towards a trend of overall survival difference. Although survival data are not mature enough, there is a clear trend represented by three patients we lost in the pirtobrutinib arm versus 10 patients lost in the bendamustine-rituximab arm. This trend in overall survival is becoming statistically significant despite the fact that there was a possibility of crossover, and effectively 52.9 patients, which means 18 out of 34 patients relapsing in the bendamustine-rituximab arm, were treated by pirtobrutinib.
Dr. Jonathan Friedberg: I am going to turn it over to Matt. The question is: why study pirtobrutinib in this patient population? And then with these two studies, how do you find the patients that were treated, are they representative of people who you see? And do you see this maybe being approved and more widely available?
Dr. Matthew Davids: I think in terms of the first question, why study this in a frontline population, we have seen very impressive data with pirtobrutinib in a very difficult-to-treat population of CLL patients. This was from the original BRUIN phase 1/2 study where most of the patients had at least two or three lines of therapy, often both a covalent BTK inhibitor and the BCL2 inhibitor venetoclax, and yet they were still responding to pirtobrutinib. The drug was also very well tolerated in that early phase experience. And actually, we have seen phase 3 data from the BRUIN 321 study comparing pirtobrutinib to bendamustine and rituximab in a relapse population as well. So I think that really motivated these studies to look at pirtobrutinib as a first therapy. You know, often in other cancers of course, we want to use our best therapy first, and I think these studies are an initial step at looking at that.
In terms of the second question around the patient population, these are pretty representative patient populations, I would say, for most frontline CLL studies. We see patients who are a bit younger and fitter than sort of the general population of CLL patients who are treated in clinical practice, and I think that is true here as well. Median age in the sort of mid-60s here is a bit younger than the typical patients we are treating in practice. But that is not different from other CLL frontline studies that we have seen recently, so I think it makes it a little bit easier as we kind of think across studies to feel comfortable that these are relatively similar populations.
Dr. Jonathan Friedberg: How do you see this either getting regulatory approval or potentially being used compared to current standard of care options?
Dr. Matthew Davids: So my understanding is that both of these trials were designed with registrational intent in the frontline setting, and they are both positive studies. That is certainly very encouraging in terms of the potential for an approval here. We have seen in terms of the FDA recently some concerns around the proportion of patients who are coming from North America, and my understanding is that is relatively low on these two studies. But nonetheless, the datasets are very impressive, and so I think it is certainly supportive of regulatory approval for frontline pirtobrutinib.
Dr. Jonathan Friedberg: I will ask Jennifer a question. The control arm in your study was ibrutinib, and I think many in the audience may recognize that newer, second-generation BTK inhibitors like acalabrutinib and zanubrutinib are more frequently used now if monotherapy is decided. How do you respond to that, and how would you put your results in your pirtobrutinib arm in context with what has been observed with those agents?
Dr. Jennifer Woyach: Yeah, that is a great question. Even though in the United States we are predominantly using acalabrutinib or zanubrutinib when choosing a monotherapy BTK inhibitor, this is actually not the case throughout the entire world where ibrutinib is still used very frequently. The head-to-head studies of both acalabrutinib and zanubrutinib compared to ibrutinib have shown us pretty well what the safety profile and efficacy profile of the second-generation BTK inhibitors is.
So even though we do not have a head-to-head study of acalabrutinib or zanubrutinib versus pirtobrutinib, I think, given the entirety of data that we have with all of the covalent BTK inhibitors, I think we can safely look at the pirtobrutinib arm here, how the ibrutinib arm compares or performs in context with those other clinical trials. And though we really can not say anything about pirtobrutinib versus acalabrutinib or zanubrutinib, I think we can still get a good idea of what might be the clinical scenarios in which you might want to choose pirtobrutinib.
Dr. Jonathan Friedberg: And Wojciech, do you agree with that? Obviously, I think you have acknowledged that chemoimmunotherapy is rarely used anymore as part of upfront treatment for CLL. So, I guess a similar question. If you were to put the pirtobrutinib result in your study in context with, I guess, more contemporary type controls, would you agree that it is competitive?
Dr. Wojciech Jurczak: Well, I think that that was the last study ever where bendamustine-rituximab was used as a comparator arm. So we should notice that smashing difference. Because if we look at the progression-free survival at two years, we have 93.4% in pirtobrutinib arm versus 70.7% in bendamustine-rituximab arm. Bendamustine-rituximab arm did the same as in the other trials, like ALLIANCE or SEQUOIA. Pirtobrutinib did exceptionally well, as pirto is not just the very best BTK inhibitor overcoming the resistance, but perhaps even more important for the first line, it is very well tolerated and is a very selective drug.
Now, if we look at treatment-related adverse events, the discontinuation rate, they were hardly ever seen. If we compared the adverse events in exposure-adjusted incidence, literally all adverse events were two or three times higher in bendamustine-rituximab arm except for the bleeding tendency, which however was predominantly in CTCAE grade 1 and 2 with just 0.7% of grade 3 hemorrhage. Therefore, I think that we should actually put the best and the safest drugs upfront if we may, and pirtobrutinib is, or should be, the first choice if we choose monotherapy.
Now, I understand that we are not presenting you the data of pirtobrutinib in combination with anti-CD20 or with BCL2 inhibitors, but that is to come.
Dr. Jonathan Friedberg: Matt, how would you envision, were regulatory approval granted and this were an option, using this in the upfront patient population? Is there anybody who you would preferentially use this or start on this treatment? Or would this be something that you would tend to reserve for second line?
Dr. Matthew Davids: So I would say that in general for most of my patients who would want to start with a continuous BTK inhibitor, I would still use a covalent BTK inhibitor, and I say that for a couple of reasons despite the very promising data from these studies. The first is that the follow-up for both of these phase 3 trials is still quite short, in the range of a median 18 to 24 months. And we know that CLL is a marathon, not a sprint, and these patients are going to probably be living for a very long time. And we do have much longer follow-up from the covalent BTK inhibitors, median of 10-year follow-up with ibrutinib and five to six years with zanubrutinib and acalabrutinib respectively. And you know, I do not think that the pirtobrutinib is going to fall off a cliff after two years, but on the other hand, I think there is a lot of value to long-term data in this disease, and that is why I think for most of my patients I would stick with covalent BTK inhibitors.
But the other important factor that we need to consider is patients who are younger and may have many different CLL treatments over the years. We have to be very careful, I think, about how we sequence these drugs. We know right now that we can start with covalent BTK inhibitors and then subsequently patients will respond well to the non-covalent inhibitor pirtobrutinib in later lines of therapy. But right now we do not have prospective data the other way around. So how will the patients on these studies who progress on pirtobrutinib respond to covalent BTK inhibitors? We do not know yet. There have not been a lot of progression events, which is great, but we would like to see some data in that respect to feel more comfortable with that sequence.
Now, I do think that particularly for older patients and those who have significant cardiovascular comorbidities, if they wanted to go on a continuous BTK inhibitor, I do think these data really strongly support using pirtobrutinib as the BTK inhibitor of choice in that population. In particular, the cardiovascular risks with pirtobrutinib seem to be quite low. I was very struck in the comparison with BR that the rate of AFib was equivalent between the two arms of the study. And that is really the first time we have seen that with any of these BTK inhibitors, no elevated risk of AFib in a randomized study. I think that is the population where it will get the most traction first, is the upfront, sort of older patient with significant cardiovascular comorbidities. And as the data from these studies mature, I think that we will start to see more widespread use of pirtobrutinib in the frontline setting.
Dr. Jonathan Friedberg: Jennifer, I am just curious if you have any personal experience or heard anecdotally about after progression on pirtobrutinib the use of other BTK inhibitors and whether there is a growing experience there.
Dr. Jennifer Woyach: I do not think that there is much clinical experience, you know, as Matt alluded to, it certainly has not been tested yet. There has been some data in relapsed CLL suggesting that in people who have resistance mutations to covalent BTK inhibitors after treatment with pirtobrutinib, sometimes those mutations go away. I think most of us are concerned that they are probably not actually gone but maybe in compartments that we just have not sampled, suggesting that sort of approach where you might sequence a covalent inhibitor after a non-covalent in somebody who had already been resistant probably would not work that well.
But, you know, in this setting where people had never been exposed to a covalent BTK inhibitor before, we really have no idea what the resistance patterns are going to be like. We assume they will be the same as what we have seen in relapsed CLL, but I think we just need some longer follow-up to know for sure.
Dr. Wojciech Jurczak: If I may confront Dr. Davids about the use of covalent BTK inhibitors upfront, well, I think that we should abandon the idea of using the first and the second and the third generation, at least if we don't have medical lines. If we endlessly block the same pathway, it is not going to be effective. So if pirtobrutinib gets approval in first, second line, we do not necessarily have to use it in the first line. I am not here in a position to defend that we should treat patients with pirtobrutinib upfront and not BCL2 time-limited regimen.
However, the way I look at CLL patients when choosing therapy is not just how should I treat them now, but what would be the best regimen in 5, 10 years if I have to re-treat them. And in some instances, the idea may be that in this setting we would like to have a BTK inhibitor upfront to have a BCL2 inhibitor later to make it time-limited. Although I understand and I agree with Matthew that if we have an elderly, fragile population, then the charm of having a drug taken once a day in a tablet with literally few cardiovascular adverse events might be an option.
Dr. Jonathan Friedberg: And I will give Matt the last word whether he wants to respond to that, and also just as a forward-looking issue, I know both investigators have implied that there will be future studies looking at combinations with pirtobrutinib, and if you have any sense as to what you would be looking for there.
Dr. Matthew Davids: The field really is heading toward time-limited therapy for most patients, I would say. There is a bit of a discrepancy right now in the field between sort of what we are doing in academic practice and what is done sort of more widely in community practice. And so right now we are going to see evolving datasets comparing these approaches. We are already seeing data now from the CLL17 study with ibrutinib comparing continuous to time-limited venetoclax-based therapy, and we are seeing similar efficacy benefits from these time-limited therapies without the need for continuous treatment. And so that is where I think some of the future studies with pirtobrutinib combining it with venetoclax and other partners are so important. Fortunately, several of these studies are already ongoing, including a phase 3 trial called CLL18, which is looking at pirtobrutinib with venetoclax, comparing that to venetoclax and obinutuzumab. So I am optimistic that we are going to be developing these very robust datasets where we can actually use pirtobrutinib in the frontline setting as a time-limited therapy as a component of a multi-drug regimen. So far, those early data are very promising.
Dr. Wojciech Jurczak: Perhaps last but not least, in a single center we have treated over 300 patients with pirtobrutinib. So eventually some of them relapsed. And I must say that our experience on BCL2 inhibitors, not just venetoclax but including sonrotoclax, are appealingly good. Therefore, by using pirtobrutinib even earlier, we do not block the efficacy of other compounds.
Dr. Jonathan Friedberg: All right.
Well, I want to thank all of our speakers. I also want to congratulate our two guests who presented these very influential papers at the ASH Annual Meeting, and chose to publish them in JCO, so we thank you for that, and Dr. Davids for your commentary - really appreciated.
That is this episode of JCO After Hours. Thank you for your attention.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
 
Disclosures

Dr. Wojciech Jurczak
Consulting or Advisory Role: BeiGene, Lilly, Abbvie/Genentech, Takeda, Roche, AstraZeneca
Research Funding: Roche, Takeda, Janssen-Cilag, BeiGene, AstraZeneca, Lilly, Abbvie/Genentech
Dr. Jennifer Woyach
Consulting or Advisory Role: Pharmacyclics, Janssen, AstraZeneca, Beigene, Loxo, Newave Pharmaceutical, Genentech, Abbvie, Merck
Research Funding: Company name: Janssen, Schrodinger, beone, Abbvie, Merck, Loxo/Lilly


Dr. Matthew Davids
Honoraria: Curio Science, Aptitude Health, Bio Ascend, PlatformQ Health, Plexus
Consulting or Advisory Role: Genentech, Janssen, Abbvie, AstraZeneca, Adaptive Biotechnologies, Ascentage Pharma, BeiGene, Lilly, Bristol-Myers Squibb, Genmab, Merck, MEI Pharma, Nuvalent, Inc., Galapagos NV, Schroedinger
Research Funding: Ascentage Pharma, Novartis, MEI Pharma, AstraZeneca

JCO Editorial Fellow Peter Li and author Dr. Jahanzaib Khwaja discuss the  ASH 2025 Simultaneous Publication article, "A New Validated Staging System for AL Amyloidosis With Stage lllC Defining Ultra-Poor Risk: AL International Staging System."
TRANSCRIPT
The disclosures for guests on this podcast can be found in the show notes.
Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO's Editorial Fellow, and today, I am joined by Dr. Jahanzaib Khwaja on a new validated staging system on AL amyloidosis with stage lllC defining ultra-poor risk, AL International Staging System. This is a simultaneous publication that will be presented at this year's ASH Conference. 
At the time of this recording, our guest has disclosures that will be linked in the transcript. 
So, Dr. Khwaja, let's start off first: What would you say is the significance of your study?
Dr. Jahanzaib Khwaja: Thank you very much. This is an important study in that, in the current treatment era, we have really improved outcomes of patients with systemic AL amyloidosis. Traditionally, the staging systems that have been employed, which are the Mayo 2012 and the European modification 2016, have been founded in eras where there were historic treatment protocols.
So the significance of this new staging system is looking at outcomes of patients in the modern treatment era. That is patients who are treated with daratumumab-based treatments in the first line. And this is kind of the largest study which is externally validating a new prognostic model in the current treatment era with modern outcomes.
Dr. Peter Li: Can you tell our listeners what is different about your new staging system?
Dr. Jahanzaib Khwaja: The traditional staging systems, the Mayo 2012 and the European modification of 2016, looked at outcomes of patients with systemic AL amyloidosis with historic treatment protocols. And we know that they looked at outcomes according to an NT-proBNP and troponin, and in the Mayo 2012, they looked at it with the addition of the dFLC, which is the difference in the involved and uninvolved free light chain.
Over the years, we have seen that outcomes have improved, and over decades, actually, outcomes are much better when we compare them to the previous decade. If we look at current treatment approaches, those traditional staging systems inadequately determine the poorest prognostic risk. So they are unable to tell us those who are going to perform poorly.
Our current new validated staging system looks at the traditional NT-proBNP and troponin but uses the addition of the longitudinal strain. This is an echocardiographic parameter, and it is used widely in treatment centers who treat amyloidosis. This really identifies those ultra-high risk patients, and these are the patients who will perform poorly in current treatment protocols.
And why is that important? Well, we need a robust staging system in the current treatment era which can stratify patients who will do well but also stratify those patients who do not do well. Because that is important for counseling patients, for risk stratification, for treatment approaches, and in the future, for designing clinical trials.
Dr. Peter Li: And that is referring to the longitudinal strain greater than  -9% and NT-proBNP greater than 8,500 and then the high-sensitivity troponins greater than 50, which will define the new staging system. Can you talk more about how you picked these cutoffs and also what that alludes to in terms of the outcomes that you have discovered in this age of daratumumab-based therapy?
Dr. Jahanzaib Khwaja: Yeah, that is a really excellent question because we have aimed to build upon traditional staging systems. So clinicians have used these traditional models for many, many years, and they have robustly underpinned our stratification of patients and how we counsel patients. So we didn't want to change some of these well-established thresholds, but we wanted to test them in the current treatment era. So the NT-proBNP of 8,500 and the high-sensitivity troponin of 50 were the traditionally used thresholds. And they actually stand the test of time.
But we found that longitudinal strain additionally and independently predicts outcome independent of these other biomarkers. It is independent actually as a continuous variable, so you can cut this at a number of different stratification points and find independence. But we wanted to determine and discriminate those with the poorest outcomes. So we validated a longitudinal strain threshold of greater than  -9% by deriving this from a dataset of patients with the traditionally highest risk. Those are with European stage lllB. And looked at the optimal threshold with time-dependent ROC analysis.
So we did this in our derivation cohort and then validated this externally in our external validation cohort amongst a number of centers in Europe, in the US, and in the UK. And it is important to note because longitudinal strain is an echocardiographic parameter, and traditionally the limitations are considered to be inter-vendor and inter-operator variability and intra-operator variability, and there are challenges with reproducibility of some of these measurements. So that is often cited as a limitation. But we found, when we have externally validated this across different centers using different platforms, actually the threshold of -9% is independently predictive of poorer outcomes independent of the traditional NT-proBNP and troponin thresholds, and it is robustly predictive of poorest outcomes.
We know that those with stage lllC have a median overall survival of 4 to 7 months in the modern treatment era. And if we sub-stratify these by patients treated with daratumumab, outcomes have improved, but still, even if we look at daratumumab-treated patients, one-year overall survival is still only around 50 percent. So these are a poor risk group in the modern treatment era.
Dr. Peter Li: Which kind of makes sense in a way because this kind of predicts whether they have amyloid-related cardiomyopathy. So I think this all tracks with our listeners. But given the poor outcomes even with daratumumab-based therapies, do you think this new staging system would change practice, if at all?
Dr. Jahanzaib Khwaja: Yeah, I think that is a really good point because I think it comes to the question of why we use a staging system. What are its applications? I think one of the key things we think about in the clinic is how do we counsel patients when we first talk to them about their diagnosis. So there is a lot of information, but predominantly people want to know, what is my outlook going to look like?
And as I say, in the bortezomib treatment era, 2010 to 2020, we used to say you have stage lllB, you have very poor outcomes, median survival maybe around six months. We have shown here that actually those with lllB have much better outcomes definitely over 12 months, up to 24 months in those with daratumumab-based therapies. So we need to counsel them in a different way.
We then also need to say, "Well, who are the ultra-high risk?" So we said those with the longitudinal strain of greater than -9% with the traditional NT-proBNP and troponin cutoffs. And those patients will have poor outcomes. We need to talk about palliation. We need to talk about alternate treatment approaches.
And then importantly for the community is about treatment and clinical trial design. So again, traditionally the traditional high-risk group lllB used to be considered an exclusion for all major trials. So these were excluded in the ANDROMEDA study, which led to the approval of daratumumab-based therapy, and multiple other trials. And we show here that actually patients with lllB should not be excluded from these studies because they do have good outcomes.
And I think we make the important point that those with lllC, who do have poor outcomes, they need a different treatment approach, and we need to think about stratifying these patients differently. So perhaps the next modality of treatment will be the anti-fibril antibodies or a mode of treatment which can clear antibodies or clear the amyloid fibrils from the organs and reduce the organ toxicity early on.
We know that those with lllC have poor outcomes particularly within the first year, and organ dysfunction really predominates here. So a different treatment approach is required, and we need to design trials specifically for these patients which look beyond anti-plasma cell clone therapy but also look at clearing the amyloid fibrils and improving organ function as this is predominantly the cause of death in these patients.
Dr. Peter Li: That's an excellent point right there. 
Do you foresee any limitations to this new staging system, or can you comment on is there potentially a better way to refine this staging criteria in the future?
Dr. Jahanzaib Khwaja: Yeah, I think that is a really excellent point to consider, that staging systems always need refining across treatment eras. So we have looked at the bortezomib era, and then we have validated this in the daratumumab-based era. We know that amongst different countries access to treatment varies. We know that there are a number of factors which determine your health-related outcomes. That's access to healthcare, speed of diagnosis, access to tertiary diagnostics, ability to biopsy, and then supportive care.
And I think our staging system highlights the importance of organ dysfunction predominantly causing death early on. And I think that as treatments improve this should be refined. So the expectation I think is, as we have better anti-plasma cell directed therapies, and as we hopefully develop anti-fibril antibodies and anti-fibril clearance drugs, that we will need to revalidate new models to effectively prognosticate in this treatment era.
And I also think that as we become a bit more sophisticated with our approaches, we know that this can be refined in the future looking at other prognostic factors with regards to healthcare outcomes. I would say one of the strengths, however, of this model is that it builds on the traditional model, and it's quite simple to use. You just have the NT-proBNP and the troponin, and then longitudinal strain, which is used quite frequently in amyloid centers, and an echocardiogram is used in essentially all patients for diagnosis. So I think it will certainly be quite practical.
But certainly I think, as you say, as treatment approaches change over time, and as we have further options in the future, we will need to refine prognostication.
Dr. Peter Li: For the listeners out there, let's say someone comes in our clinic and we diagnose them with stage lllC amyloidosis. Can you comment on what clinical trials are out there that potentially they can refer their patients to? You mentioned anti-fibril therapy, which I think would be the way of the future. Can you kind of comment what you know at this current stage and point listeners in the right direction?
Dr. Jahanzaib Khwaja: This is the challenge in amyloidosis. We don't have specific trials that are looking at those with the highest risk. And at present, even the ISA International Guidelines talk about risk according to the old treatment approaches and discuss attenuating our current chemotherapy approaches. And I think that for clinicians out there who identify those at the highest risk, it is really important to have a multidisciplinary approach, to consider palliation and palliative services early, and really work with your fellow cardiologists and renal physicians and neurologists to enable the best supportive care you have in order to deliver this anti-plasma cell directed therapy.
We know that actually you only need for most patients small amounts of doses of chemotherapy to get good clonal responses, and we have seen that even in the bortezomib era that actually they have good CR rates and more impressive CR rates with daratumumab. But because of the organ dysfunction, it can be really challenging to deliver these doses. And supportive care is going to be really important particularly for these challenging patients.
The future will be designing clinical trials that are appropriate for these patients. At present, we currently don't have available options, but I think the more we gather this data, the more we work collaboratively as a community, we will be able to mobilize our resources and get the best outcomes for these patients. 
Dr. Peter Li: First build the field of dreams and then hopefully more therapies will arrive in the future.
Thank you so much, Dr. Khwaja, for speaking about the JCO article, "A New Validated Staging System for AL Amyloidosis With Stage lllC Defining Ultra-Poor Risk: AL International Staging System," and for all your valuable input today.
Dr. Jahanzaib Khwaja: Thank you very much.
Dr. Peter Li: Make sure to check out the presentation at this year's ASH Conference taking place from December 6 to December 9. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcast.
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