Journal of Clinical Oncology (JCO) Podcast

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The Journal of Clinical Oncology podcast, hosted by Dr. Davide Soldato, presents analyses and discussions centered on the latest findings published in ASCO's esteemed Journal of Clinical Oncology. Through scholarly discourse and examination, this podcast is your resource for navigating oncological advancements and how they impact clinical practice. The JCO Podcast also features in depth summaries and interviews hosted by the year's fellows in the series, JCO Article Insights.

  1. NCI Working Group on Biochemically Recurrent Prostate Cancer

    5D AGO

    NCI Working Group on Biochemically Recurrent Prostate Cancer

    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

    28 min
  2. Association Between EOL SACT and Healthcare Utilization

    JAN 8

    Association Between EOL SACT and Healthcare Utilization

    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 y

    23 min

  3. 12/11/2025

    Milan Consensus Endpoints for Bladder Preservation in MIBC

    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

    27 min

  4. 12/09/2025

    JCO at 2025 ASH: Pirtobrutinib in Untreated CLL

    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

    20 min

  5. 12/07/2025

    JCO at ASH 2025: A New Validated Staging System for AL Amyloidosis: AL-ISS

    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 t

    15 min

  6. 11/24/2025

    JCO Article Insights: Simultaneous Durvalumab and CRT in Unresectable Stage III NSCLC

    In this episode of JCO Article Insights, host Dr. Ece Cali Daylan interviews author Dr. Jeffrey Bradley about the article, "Simultaneous Durvalumab and Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer" by Bradley, et al published October 13, 2025. TRANSCRIPT Dr. Ece Cali: Welcome to this episode of JCO Article Insights. This is Dr. Ece Cali, JCO Editorial Fellow. Today I'm joined by Dr. Jeffrey Bradley, Professor of Radiation Oncology at the University of Pennsylvania, to discuss the manuscript, "Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non-Small-Cell Lung Cancer: The Phase III PACIFIC-2 Study." The PACIFIC-2 study was a phase III, double-blind, randomized trial comparing the efficacy and safety of simultaneous durvalumab with concurrent chemoradiation followed by consolidation durvalumab to the concurrent chemoradiation followed by placebo in patients with unresectable stage III non-small cell lung cancer. The primary endpoint was progression-free survival by blinded independent central review. The secondary endpoints were overall response rate, overall survival, and safety. Three hundred twenty-eight patients were randomized 2:1 to durvalumab and placebo, respectively. Unfortunately, this trial did not meet its primary endpoint. There were no statistically significant differences in PFS or OS. The frequency of adverse events was similar between the two arms. Grade 3 or higher adverse events were observed in 53% of the patients in the durvalumab arm compared to 59% of the patients in the placebo arm. Of note, the frequency of pneumonitis was similar in the two arms. Approximately 28% of patients in each arm developed pneumonitis, and about 5% of the pneumonitis observed in each arm was grade 3 or higher in severity. Treatment discontinuation rates secondary to the adverse events were higher in the durvalumab arm, 25% compared to 12%. Adverse events leading to treatment discontinuation and death were more frequently seen in the durvalumab arm during the first four months of the treatment, which corresponds to the simultaneous administration of chemoradiation and durvalumab. Dr. Bradley, before we delve into the results, can you please explain the rationale for this study design and how this concept fits into the current treatment landscape? Dr. Jeffrey Bradley: Yeah, this trial came on the heels of PACIFIC after there was a progression-free survival benefit showed in PACIFIC that in the locally advanced unresectable population that consolidation immunotherapy, in this case durvalumab, had a progression-free survival benefit. A number of us in the clinical trial space thought to add concurrent immunotherapy in addition to consolidation immunotherapy that that would also improve outcomes for patients. So a number of trials were launched to follow up of PACIFIC. In this case, this is a phase III trial where the control arm was placebo. There was no overall survival results yet from PACIFIC, just a PFS benefit, and a number of countries across the world had not approved maintenance durvalumab in this space. So this trial looked at the experimental arm, which was concurrent immunotherapy, durvalumab, and chemoradiation followed by consolidation durvalumab versus placebo. Dr. Ece Cali: And if we were to focus on the safety profile first, an increased pneumonitis risk was a theoretical concern when immunotherapy is given concurrently with radiation. Do we see any major differences in the safety profile between the two arms in this trial? Dr. Jeffrey Bradley: No, and we were concerned about the addition of concurrent immunotherapy and chemoradiation, like you said, towards concern about increased pneumonitis rate, but we did not see increased pneumonitis in the experimental arm over placebo. And the grade 3 or higher, as you said, it was roughly 5%, more or less, in both arms, so we didn't see increase in pneumonitis toxicity with concurrent IO and chemoradiation. Dr. Ece Cali: But interestingly though, despite the lack of significantly increased toxicity with durvalumab, unfortunately, administering immunotherapy simultaneously with chemoradiation therapy did not improve survival. Lack of superiority of this treatment regimen, as you mentioned, is further confirmed across multiple similar negative trial readouts such as ECOG-ACRIN 5181 and CheckMate 73L. Dr. Bradley, in your view, what are some potential explanations for why this strategy did not pan out in clinical trials? Dr. Jeffrey Bradley: Regarding toxicity, let me go back and point out that we did see an increased number of immune-mediated adverse events. It was 34.7% in the concurrent immunotherapy arm versus 15.7% in the placebo arm. So that led to a higher number of discontinuations of immunotherapy which I think probably had an effect. So we didn't... there was an increased pneumonitis toxicity, but there were expected immune-mediated toxicities that caused people to stop giving immunotherapy. You can see that in the PFS curves. They were, you know, they crossed over after like a month, but initially there was lower PFS for the experimental arm, and then the experimental arm got better after we divided into four months, before four months and after four months. Dr. Ece Cali: For one reason or another, it looks like the simultaneous administration did not really improve outcomes. We now know that simultaneously giving them another concurrent radiation should really no longer be pursued in clinical trials for this patient population. Can you share with our audience what strategies are being studied in this setting and what trials to watch out for in the future? Dr. Jeffrey Bradley: Sure, I think when you add concurrent radiation to immunotherapy, there were more central tumors in this trial, I think you're killing lymphocytes and negating the effect of immunotherapy. So I think that's the smoking gun for this trial, for the ECOG trial, for the small cell trial that NRG reported, LU005, and other trials. So correct, I don't think there's any need to continue to pursue concurrent immunotherapy in this space of lung cancer. But that's not to say there aren't many other trials that are either ongoing, have accrued and awaiting results, or being planned for the next phase of clinical trials. We have a trial within NRG Oncology called NRG-LU008. It's a randomized phase III trial that is using an SBRT boost to a peripheral primary and chemoradiation to the nodes, because the primary tumor is the one that fails more often than the lymph nodes, and that's compared to PACIFIC in the control arm. PACIFIC-9 is another trial in the same line as the other PACIFIC trials. That one is using dual checkpoint inhibition versus the control arm being PACIFIC. So there are three arms in that trial, durva and oleclumab, durva and monalizumab versus the PACIFIC arm. And that trial is completed accrual, but we have no results from that study yet. Johnson & Johnson has a trial open looking at a nanoparticle. That's a radiosensitizer where bronchoscopy is used to inject the primary tumor and the lymph nodes with a radiosensitizer. That's a randomized phase ll trial that's ongoing. It's got three arms, two different doses of this radiosensitizing drug and then a control arm without injection at all. The control arm is again the PACIFIC arm. And then those of us within the NCI-based clinical trials evaluation program, CTEP, are proposing an intergroup trial that would compare induction chemo-immunotherapy followed by chemoradiation followed by maintenance immunotherapy versus PACIFIC in a phase III study. So I think there's other trials that are either completed, ongoing completed, or on the horizon to assess in this patient population. Dr. Ece Cali: Yeah, we definitely have an unmet need to improve survival outcomes for stage III patients, and it's great to hear that there are so many efforts looking at different strategies to improve outcomes for these patients.  Thank you so much, Dr. Bradley, for this informative discussion and for sharing your insights. Any last thoughts? Dr. Jeffrey Bradley: Yeah, we need something, you know. PACIFIC was first reported in 2017, and we really haven't made progress in terms of changing that standard of care control for the last eight years. So we need progress in this area. Dr. Ece Cali: Yep, definitely. Thank you so much for joining, Dr. Bradley.  And 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/podcasts. 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. Bradley Honoria: Mevion Medical Systems, Inc. Consulting or Advisory Role: Varian, Inc, Genentech, Inc. Research Funding: Varian Medical Systems Dr. Cali Research Funding Company: BeiGene, Nuvalent, Inc., Astra Zeneca

    11 min

  7. 11/20/2025

    Health Outcomes in Older Childhood Cancer Survivors

    Guest Dr. Rusha Bhandari and host Dr. Davide Soldato discuss JCO article "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study, " with a particular focus on mortality data, development of secondary malignancies and the importance of education for both patients and healthcare providers regarding long-term follow-up and care. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. 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 Policlinico San Martino in Genoa, Italy. Today, we are joined by JCO author, Dr. Rusha Bhandari, a Pediatric Hematologist-Oncologist and Assistant Professor in the Department of Pediatrics and Population Science at City of Hope, California. Today, we will be discussing the article titled "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study." So, thank you for speaking with us, Dr. Bhandari. Dr. Rusha Bhandari: Thanks so much for having me. Dr. Davide Soldato: So, I just want to go straight ahead in the paper and start from the title. So, we heard that you included in this study childhood survivors of pediatric cancer that were aged 50 years or higher. So, this is a very critical life stage when we know that there are a lot of aging-related comorbidities that can happen, also in the general population but potentially specifically in childhood cancer survivors. So, first of all, I wanted to ask you, why this specific study in this very specific population? Because I think that we had already some data in younger survivors, but now we are focusing specifically on patients aged 50 or more. Dr. Rusha Bhandari: Absolutely. So, to answer that question, I'll take a little bit of a step back in terms of where we are now and where we came from in terms of treatment for childhood cancers. So, thankfully, we now have great curative therapies and survival rates for many childhood cancers, including the most common ones. But this was not necessarily the case 50 or more years ago. So, we essentially are now seeing the first generation of older survivors who are 30, 40, or more years from completion of their cancer treatment. As you pointed out, we know from younger survivors that they have a markedly higher risk of malignancies and health conditions than the general population. You don't typically expect to see things like heart disease or diabetes, for example, in a young adult. But the question that remained was what the health status and risk of these conditions are in survivors who are entering this critical age, as you mentioned, 50 or older, when you do start to see these aging-related changes in the general population. And the question is whether we're still observing increased risks related to cancer treatment that was delivered 30 or more years ago in these survivors who are now entering ages 50 and beyond. Dr. Davide Soldato: Thanks so much. You used the data from a study that is called the Childhood Cancer Survivor Study. So, just a little bit of explanation for our listeners. How is the study conducted? What type of data are you collecting? And specifically for the interest of the study that was reported in this manuscript, which outcomes were really important for you and were so evaluated in the manuscript? Dr. Rusha Bhandari: Yes. So, the Childhood Cancer Survivor Study is a really excellent resource that combines information from children who were treated across North America at various different centers and sites. So it gives us a really good understanding of how different survivors are doing as they do progress through their survivorship journey. The Childhood Cancer Survivor Study includes a baseline questionnaire when participants are first eligible or first enter the study, and then includes a series of follow-up questionnaires to really understand how they're doing, like I mentioned, as they progress throughout their survivorship journey. And so for this study, we really wanted to take a global look at how these patients were doing as they entered that older age range. And so we wanted to look at outcomes ranging from mortality through the health conditions that we've seen from other survivorship studies, including subsequent malignant neoplasms, other health conditions, I mentioned earlier heart disease and other comorbidities we know survivors can be at increased risk for, and also things like frailty, which we know is, you know, the most widely recognized phenotype of aging. And we see that earlier on in our younger survivors. We want to see how this translated to these older survivors and then also other health outcomes like their health status. What is their self-report of their physical health, their mental health? Things like that. So we wanted a very comprehensive understanding of their health. Dr. Davide Soldato: This is a very comprehensive study. Right now it includes more than 30,000 patients that have been treated for childhood cancer, but specifically looking at the question of survivors aged 50 years or higher, you included more than 7,000 patients inside of this study. So, looking at the first outcome that you mentioned, which I think it's also one of the most important, you look specifically at mortality, and in this specific population, you saw a striking three-fold increase in mortality when comparing these survivors with the general population. I just wanted to dive in this result and ask you: What do you see as the main driver for this excess mortality in this population of survivors? And as you were mentioning, the study also collects information about the treatment received. So, was there any association with a specific kind of treatment that was received for curing these childhood cancers? Dr. Rusha Bhandari: I agree. I would say it's striking to see that mortality risk among the survivors relative to the general population. And we do know, again from prior studies, that survivors of childhood cancer do have an increased risk of mortality compared to the general population, but I think looking at those curves of the cumulative mortality risk was really quite striking as they diverge, and that's, you know, just so long past their initial diagnosis and treatment. We know that subsequent malignant neoplasms or secondary cancers are a really an important contributor to mortality among survivors. And I think it was important to note that even in these older survivors, it's still such an important contributor to mortality, and I think this really highlights the need for us to better understand what is driving specific secondary cancers and what are the differences in the biology and treatment approaches for some of these cancers? And how might that then be contributing to the mortality risk? Dr. Davide Soldato: Related to the treatment mortalities - because I think that one of the main forces of the study, as it is conducted, is that it contains a lot of information regarding radiotherapy, allogeneic transplant, surgery, type of chemotherapy received by these survivors - so, are we able right now with the data that we have to pinpoint which of these treatments can potentially lead to such increased risk of mortality? Dr. Rusha Bhandari: So, we weren't able to look at the comprehensive treatment exposures and mortality risk for this paper. So that might be one of the questions I would put on the side. We were able to look at that in relation to subsequent malignant neoplasms and health conditions though, as you mentioned. Dr. Davide Soldato: Another thing that I think is very important is that you were able to look at specific causes for mortality. So for example, you mentioned the increased rate of neoplasm in this population and specifically, more or less 7.6% of the patients that were included in the study developed another neoplasm after the ones they were cured for in the childhood period. So, you saw a wide range of cancer, for example, bone and soft tissue sarcomas, breast cancer, genitourinary cancer. And as you were mentioning, there were some associations for treatment modalities that were associated with a higher risk of developing this type of cancer. Can you expand a little bit on this? Dr. Rusha Bhandari: Absolutely. And so the key part here was that we really looked at any of these outcomes that occurred beyond age 50. What we found was there is still an increased risk of secondary cancers beyond that initial childhood cancer diagnosis, but when we really looked at that data, it was specifically among survivors who had a history of receiving radiation. And we did not necessarily see an association between different chemotherapy exposures and secondary cancers. And I think this speaks to what we're now learning in terms of the very long-term effects of radiation and how that impacts ongoing health risk even in patients who are 30 or more years out from their treatment. And I think it really highlights the importance of these- the efforts that have been made in the more recent decades to really try and reduce or eliminate radiation where possible, you know, as we've come to understand more about these long-term effects from it. Dr. Davide Soldato: A clear association with radiation therapy but no association when we look at specific types of chemotherapy that were used for curing this childhood cancer. Another thing that I think it's very interesting and you briefly mentioned before is that potentially when we look at these secondary malignant neoplasm that develop in this situation, we might also see some outcomes that are not comparable to the one of the general population, meaning that we managed to cure less this type of cancer when they devel

    21 min

  8. 11/13/2025

    Long-Term Remission After Cilta-cel in Patients With RRMM

    Guest Dr. Sundar Jagannath and host Dr. Davide Soldato discuss JCO article "Long-Term (≥5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma," and the efficacy of CAR-T cell therapy in patients with heavily pretreated RRMM (relapsed/refractory multiple myeloma). 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 author, Professor Sundar Jagannath, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and the Tisch Cancer Institute. He also serves as Network Director for the Center of Excellence for Multiple Myeloma, and he is an internationally recognized expert in the field of multiple myeloma. Today, we will be discussing the article titled, "Long-Term Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma." Thank you for speaking with us, Professor Jagannath. Dr. Sundar Jagannath: Thank you for having me, Dr. Davide Soldato. It is a pleasure to be here. JCO is a highly recognized journal among the oncologists, so I am very happy and privileged to be here today. Dr. Davide Soldato: Thank you so much for being with us. So, I wanted to start a little bit with the rationale of the study and the population that was included in the study. So, the trial that we are discussing, CARTITUDE-1, was already published before, and we observed very good results with a single infusion of cilta-cel. So we had previously reported a median progression-free survival of 30 months, and median overall survival was not reached. So, I just wanted to ask you if you could guide us a little bit into the population that was included in the study and also explain a little bit to our listeners what is the drug that we are discussing, cilta-cel. Dr. Sundar Jagannath: It is a CAR T-cell. This is a patient's own lymphocytes, which goes through apheresis and is sent to the company, where they modify it and introduce the B cell receptor. In this case, you know, there is a heavy chain gene receptor for the BCMA, and in cilta-cel, there are actually two receptor sites on each molecule, or there are two binding domains on each receptor molecule. So, it is considered to be quite efficacious. As you reported, the earlier results that the patients who participated, 97% of the patient responded. Now, you asked about the patients who participated in the clinical trial. This clinical trial was conducted between July of 2018 and October of 2019. At that time, this was a phase 1b/phase 2 trial, and the whole idea was to take patients who had relapsed all the available treatment regimen so that these patients were considered to have, in the unmet medical need situation. So, what does that entail? That means the patient should have been exposed to a proteasome inhibitor, to an immunomodulatory molecule, and to an anti-CD38 monoclonal antibody and should have received at least three or more prior lines of therapy and should be actually progressing on their last line of therapy. So with that requirement, if you look at it, the median number of prior therapy on the patients who participated was actually six. So patients were heavily pretreated. They had exhausted all available treatment options. So, they can participate in this clinical trial. And if not, there have been real-world evidence, such as LocoMMotion, which had reported what is the outcome for such a patient if they were treated outside of this clinical trial, if they were treated with the then available regimen. Their median progression free survival would have been only 3 months, and most patients would have lost their life within a year. So, this was truly an unmet medical need with patients in a very difficult clinical situation. Let's put it that way. So, those were the patients who participated in this particular trial. Dr. Davide Soldato: Thank you very much. And as we mentioned before, the results that were obtained in this clinical trial were really very interesting. And now, in this issue of the Journal of Clinical Oncology, you are reporting data with a longer follow up. So we are actually at more than 5 years of follow up for the patients included in this trial. So, I just wanted a little bit of insight into why you decided to report these long-term outcomes and what type of information do you think you could provide with this study to the medical community? Dr. Sundar Jagannath: This is very important because this was a clinical trial that was done in patients who were, as I said, in unmet medical need. Most of the patients had prior stem cell transplantation, had gone through a proteasome inhibitor. Many of them have had both Velcade and carfilzomib treatment. Most of them had been exposed to lenalidomide and pomalidomide. And as required, all of the patients had to have had prior exposure to anti-CD38 monoclonal antibody or daratumumab. So, the patients were heavily pretreated. Typically, TIL CAR T-cells came into the field at this particular moment, until then, we were developing small molecules, and they usually would have a PFS of 3 months and median life expectancy of a year, the overall response rate of 30%, and that is how, if you look back, that is how carfilzomib was approved, that is how pomalidomide was approved. So, the drugs which were approved, including daratumumab, you know, the response rate was in the same ballpark. So you would see that most agents, single agents, would have had a response rate in the neighborhood of 30%, the progression-free survival would have been between 3 to 5 months or 6 months at the most, and the life expectancy was short. And here comes a drug, and when I was following the patients at Mount Sinai, I found that there were a subset of patients, they got one-time treatment and they were in complete remission, no trace of cancer with annual evaluation with PET CT and bone marrow evaluation for MRD. So, I said this is remarkable, and this needs to be reported. And I went to the Janssen and company, and they agreed to review the entire experience. This is remarkable that 32 of the 97 patients, or one third of the patients, were alive and progression-free. This is unheard of for any clinical trial until now, that the patient will be progression-free, one third of the patients on a clinical trial will be progression-free, in the late stage of their disease. So that is the most important impact. And that is why this 5-year follow-up results were presented. Dr. Davide Soldato: Thank you very much. That was very clear. And as you said, we are speaking about a population that was heavily pretreated, that had exhausted all type of treatment options outside of a clinical trial. And as you said, one third of the patients was alive and progression-free after 5 years from being included and infused inside of the study. So, considering this population that, as we said, had received all treatment options, I was wondering if you observed any kind of differences in terms of disease characteristics when looking at these patients that had exceptional response, so, alive and progression-free at 5 years, and the patients that sadly had developed a progression after the infusion in the study. Dr. Sundar Jagannath: This is very important because we wanted to see who are the patients who are having this exceptional outcome. And we looked at all the 97 patients. If we look at all the patients, we saw that there were initially, out of the 97, 17 patients died earlier in the disease course due to treatment related complications, etc. But there were about 46 patients who had progression of disease and 32 patients, or one third, were alive without progression of disease. Then we looked at the 46 patients who had progression of disease. Of them, we found that 30 had disease progression and its complication, and there were actually 13 patients who were still alive even after progression of disease. So we decided to compare these 46 patients who had progression of disease versus 32 patients who had no progression of disease to see what is the difference. To our surprise, the age was similar, male, female distribution was similar. High-risk cytogenetics, which we would have thought, you know, that is why we say high-risk disease, the term, high-risk cytogenetics was equally distributed. That was really a surprise. Number of lines of prior therapy, number of exposure to drugs, all of that was the same. So that was also interesting. But a theme did emerge. Patients, in general, tend to have lower burden of disease who had the exceptional outcome. But there is one which we considered as bad, the extramedullary disease. Multiple myeloma being a blood cancer, it is usually in the bone marrow. When it starts growing outside of the bone marrow, the extramedullary disease, usually it portends poor prognosis. But we were surprised that actually there were an equal number of extramedullary disease patients even in the long-term survivor as those who had progressed of disease. So the most important takeaway was patients who had lower burden of disease, they had less number of myeloma cells in their bone marrow, percentage wise, and the soluble BCMA level was lower. Soluble BCMA is an indirect measure of the amount of plasma cells in the patient's body. It is like a tumor burden. So they were low. So, this was an important finding because it has future ramification, as you can understand. If this treatment is made available earlier in the disease course of the patients, where we are able to control the disease better, then more patients are likely to have such wonderful outcomes as one third of t

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The Journal of Clinical Oncology podcast, hosted by Dr. Davide Soldato, presents analyses and discussions centered on the latest findings published in ASCO's esteemed Journal of Clinical Oncology. Through scholarly discourse and examination, this podcast is your resource for navigating oncological advancements and how they impact clinical practice. The JCO Podcast also features in depth summaries and interviews hosted by the year's fellows in the series, JCO Article Insights.

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