Journal of Clinical Oncology (JCO) Podcast

In this episode of JCO Article Insights, host Dr. Ash Gurumurthi summarizes JCO articles, "Phased Variant–Supported Circulating Tumor DNA as a Prognostic Biomarker After First-Line Treatment in Large B-Cell Lymphoma: Findings From the DIRECT Study" and " Prospective Validation of Circulating Tumor DNA Measurable Residual Disease After First-Line Therapy in Large B-Cell Lymphoma" TRANSCRIPT Ash Gurumurthi: Hi and welcome to JCO Article Insights. I'm your host, Ash Gurumurthi, and today we will be discussing two articles, both published in the Journal of Clinical Oncology, on the real-world utility of circulating tumor DNA (ctDNA) MRD in newly diagnosed large B-cell lymphoma. The first study is the article "Phased-Variant-Supported Circulating Tumor DNA as a Prognostic Biomarker After First-Line Treatment in Large B-Cell Lymphoma: Findings From the DIRECT Study" by Dr. Joanna Krupka and colleagues in the United Kingdom. For the sake of convenience, I'll refer to this as the DIRECT study. The second study is "The Prospective Validation of Circulating Tumor DNA Measurable Residual Disease After First-Line Therapy in Large B-Cell Lymphoma" by Dr. Steven Wang and colleagues in the Netherlands, referred to as the HOVON 902 study. By way of background, I wanted to talk about MRD in hematolymphoid malignancies. Nodal diseases have lacked a robust biomarker for end-of-treatment response. They have relied historically on PET scans interpreted using the semiquantitative Deauville 5-point scale, which has a high negative predictive value but a limited positive predictive value. The poor positive predictive value for survival results in extended follow-up with serial imaging for risk stratification with unnecessary and invasive biopsies. There have been recent revolutionary advancements in ctDNA MRD in B-cell lymphoma. The use of ctDNA in lymphoma began with CAPP-seq, which tracked single nucleotide variants that were tumor specific but was limited by excessive background sequencing noise with false negatives. To overcome this, Dr. Kurtz and colleagues developed the proprietary PhasED-seq assay. This tracks well-recognized phased mutations on the same DNA strand in cis configuration within hypermutated regions that are unique to B-cell lymphoma. Using this method, they pushed their limit of detection at 95%, the so-called LOD95, to 0.7 parts per million under optimal circumstances with 120 nanograms of input cell-free DNA from plasma. Based on the use of the PhasED-seq assay in trials of newly diagnosed large B-cell lymphoma with the use of investigational agents, the NCCN currently recommends consideration of ctDNA MRD assay with a detection limit of less than 1 part per million if biopsy is not feasible for a positive end-of-treatment PET. However, I believe this threshold needs reconsideration given it is based on an ideal assay LOD95 under optimal circumstances rather than sample-specific LOD95. Real-world validation of the role of end-of-treatment ctDNA and appropriate thresholds for sample-specific LOD95 were lacking until the publication of these two studies. The DIRECT and the HOVON 902 studies were multicenter, prospective trials using real-world cohorts of newly diagnosed large B-cell lymphoma treated with standard anthracycline immunochemotherapy, ie, R-CHOP chemotherapy. They validated end-of-treatment ctDNA MRD response measured on a phased-variant platform and found them to be strongly prognostic for relapse and survival. This was independent of PET imaging or baseline clinical prognostication like the International Prognostication Index, the IPI. They also demonstrated a threshold with an LOD95 of approximately 1 in 100,000 is necessary for clinical utility. Both trials recruited over a similar period between 2020 to 2023, with the DIRECT study conducted within the National Health Service in the United Kingdom and the HOVON 902 as a national study in the Netherlands. For survival analysis, only patients who reached the landmark event of end of treatment with an available ctDNA MRD sample without progressive disease or death at that time point were included. These studies evaluated similar-sized cohorts with 134 patients for HOVON 902 and 151 patients for the DIRECT study. As expected, their baseline demographics are reflective of a real-world population of newly diagnosed cases with large B-cell lymphoma. Although both used comparable statistical methodologies with time-to-event analysis, the primary outcomes vary, making headline comparisons quite challenging. The DIRECT study utilized the time to tumor progression, censoring death unrelated to disease. This was done to isolate the molecular impact of detectable ctDNA at the end of treatment. In contrast, the HOVON 902 study used progression-free survival, which counts all-cause mortality as an event. This naturally results in lower event-free rates for PFS compared to TTP in the DIRECT study. The trials differed in their choice of phased-variant platform

Guest Dr. John Gore and host Dr. Davide Soldato discuss JCO article, "12-Month Results from the CISTO Study Comparing Radical Cystectomy Versus Bladder-Sparing Therapy for Recurrent Non-Muscle Invasive Bladder Cancer," which compares radical cystectomy and bladder sparing therapy for patients with recurrent high-grade non-muscle invasive bladder cancer. Dr. Gore and Dr. Soldato focus on the study's patient-centered approach, eligibility criteria, and quality of life after treatment. 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 author Dr. John Gore, urologist at Fred Hutch Cancer Center and professor of urology at University of Washington School of Medicine. Today, we will be discussing the article titled, "Twelve-Month Results From the CISTO Study Comparing Radical Cystectomy Versus Bladder-Sparing Therapy for Recurrent High-Grade Non-Muscle-Invasive Bladder Cancer." Thank you for speaking with us, Dr. Gore. Dr. John Gore: Thank you so much for having me. Dr. Davide Soldato: So, I just want to jump right in. We know that patients who are diagnosed with recurrent high-grade non-muscle-invasive bladder cancer can be treated with two different approaches. So, one is radical cystectomy, and the other is bladder-sparing therapy. I just wanted to understand: what was the gap that you were trying to fill with this study? In particular, one point that is very important is that this study is very centered on the preference of the patients. Why did you choose this endpoint instead of going for more solid oncology-based endpoints? Dr. John Gore: Yeah, so CISTO was a study that was derived really organically from patient engagement. I think as a clinical gap in care, making a decision about when to pursue radical cystectomy for patients with non-muscle-invasive bladder cancer is a tough decision for us as clinicians. We did some engagement work partnered with the Bladder Cancer Advocacy Network and my partner Angela Smith, and found that it is also a huge gap for patients. You know, they are very anxious about recurrences, and the decision about when to take out the bladder is a very difficult one. We did an evidence synthesis and found that evidence guiding this decision is fairly limited. The reason we chose more of a patient-reported endpoint is several-fold. One is that we, as part of our engagement work, also worked with our patient survey network to identify outcomes that were important to patients. Some of those are the same outcomes that we care about as clinicians - recurrence-free survival and metastasis-free survival - but several outcomes came out that were more patient-centered. These were patient-reported outcomes such as the burden on my finances, the burden on my caregiver or loved one, and the ability to return to physical activities that are important to them. Part of what is unique about CISTO is that this was a contract with PCORI where we knew we would only have about 12-month outcomes for the majority of our patients. That is too early to really derive a lot of the clinical outcomes, but we are able to answer that patient-centered question of, "Am I going to be able to return to physical activities that are important to me?" And that was the genesis of that as the primary endpoint. Dr. Davide Soldato: So, who were the patients that were eligible to participate in the CISTO trial? What were the key eligibility criteria? This is very particular to this study because this was actually an observational study. Why did you think that such a pragmatic approach still can inform us on what is the best treatment approach for these patients? Dr. John Gore: The intent of CISTO was not necessarily to focus on the tightly defined BCG-unresponsive patient population. That is a clearly important patient population, but every day we are all faced in our real-world practice with patients with challenging, high-grade recurrences that don't fit neatly into that BCG-unresponsive box. The reason we chose a broader inclusion was to help doctors and patients answer these same questions they have when it doesn't fit nicely into this BCG-unresponsive category. You know, maybe their BCG exposure was two years ago, but now they are having a recurrence after intravesical chemotherapy. That is no less challenging a clinical conundrum, and we wanted to be able to enroll those patients. Other key inclusions were that all of the patients in CISTO had to have BCG at some point, and they had to have recent exposure to some adjuvant instillational or intravenous therapy like pembrolizumab. We also had some exclusions that were important. They couldn't be participating in a phase 2 clinical tri

In this episode of JCO Article Insights, host Dr. Melis Canturk summarizes the article, "Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial," by Harter et al. TRANSCRIPT Melis Canturk: Hello, and welcome to the JCO Article Insight. I'm your host, Melis Canturk, and today we will be discussing the JCO article, "Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial." While integrating immune checkpoint inhibitors has revolutionized the treatment of various gynecologic cancers, these agents have historically shown limited single agent activity in ovarian cancer. Despite a strong biological rationale for combining immunotherapy with chemotherapy and bevacizumab to enhance T-cell infiltration and normalized tumor vasculature, several phase III trials have failed to demonstrate a significant survival benefit in this setting. The AGO-OVAR 2.29/ENGOT-ov34 trial was launched to definitely evaluate whether adding the PD-L1 inhibitor atezolizumab to this combination could improve long-term outcomes for patients experiencing early relapse. This international, double-blind, randomized phase III trial enrolled 574 patients with epithelial ovarian, fallopian tube, or peritoneal cancer. Eligible participants had to be in their first or second relapse within 6 months of completing platinum therapy or in their third relapse regardless of the treatment-free interval. All patients received bevacizumab and an investigator selected chemotherapy backbone, either paclitaxel or doxorubicin. They were randomly assigned to receive either 840 mg of atezolizumab or a placebo every 2 weeks until disease progression or for a maximum of 2 years. The study population was an all-comer group, though patients were stratified by their PD-L1 status, previous bevacizumab use, and the number of prior treatment lines. The trial did not meet its primary end points, as the addition of atezolizumab failed to significantly improve overall survival or progression-free survival in the intention-to-treat population. For the primary end point of overall survival, the median was 14.2 months with atezolizumab compared to 13 months with the placebo. Progression-free survival was similarly insignificant, with a median of 6.4 months in the experimental arm versus 6.7 months in the control arm. Furthermore, the objective response rates were nearly identical between the groups, recorded at 40% for atezolizumab and 44% for the placebo. Interestingly, exploratory subgroup analyses revealed potential signals of benefit in specific populations, even though the overall trial was negative. Patients who had been previously treated with bevacizumab appeared to derive a greater benefit from the addition of atezolizumab than those who were bevacizumab-naïve. Additionally, outcomes seemed more favorable for patients receiving a paclitaxel chemotherapy backbone compared to those receiving doxorubicin. However, PD-L1 status did not appear to be a predictive marker for success, as hazard ratios for survival were similar regardless of whether the tumor was PD-L1 positive or negative. The safety profile of the triple combination was consistent with the known toxicities of the individual drugs. Grade 3 or higher adverse events occurred in 73% of the atezolizumab group and 70% of the placebo group. While the experimental arm saw higher incidences of immune-mediated events, such as thyroid-related issues, these were generally manageable. Serious adverse events were more frequent in the atezolizumab arm than in the placebo arm, but discontinuation rates due to toxicity were relatively low and comparable between the two groups. In conclusion, the AGO-OVAR 2.29 trial confirms that adding atezolizumab to bevacizumab and nonplatinum chemotherapy does not provide a statistically significant survival advantage for patients who receive nonplatinum chemotherapy for recurrent ovarian cancer. This study contributes to the growing body of evidence showing that immune checkpoint inhibitors have yet to find a definitive role in the standard treatment of recurrent ovarian cancer. Future research will likely focus on more sophisticated molecular stratification and the use of novel agents, such as bispecific antibodies, to overcome the challenging tumor microenvironment of low-grade serous ovarian cancer. Thank you for tuning into JCO Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. 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

In this episode of JCO Article Insights, host Dr. Melis Canturk summarizes the article, "Phase 2 Trial of Ribociclib plus Letrozole in Women with Recurrent Low-Grade Serous Cancer of the Ovary, Fallopian Tube, or Peritoneum: A GOG Partners Trial," by Slomovitz et al. TRANSCRIPT Melis Canturk: Hello, and welcome to JCO Article Insights. I'm your host, Melis Canturk, and today we will be discussing the JCO article, "Phase 2 Trial of Ribociclib plus Letrozole in Women with Recurrent Low-Grade Serous Cancer of the Ovary, Fallopian Tube, or Peritoneum: A GOG Partners Trial." Building on the fact that more than 95% of low-grade serous carcinoma are estrogen receptor positive and often exhibit abnormalities in the CDK4/6 signaling pathway, researchers launched the GOG 3026 trial. This study investigated the effectiveness of pairing the CDK4/6 inhibitor ribociclib with letrozole, an aromatase inhibitor, adapting a therapeutic approach that has already transformed the treatment landscape for hormone receptor-positive metastatic breast cancer. Low-grade serous ovarian cancer is a rare malignancy characterized by its hormonally driven nature and relative resistance to traditional platinum-based chemotherapy. While it's associated with longer survival than high-grade serous carcinoma, recurrent disease presents a significant clinical challenge due to low response rates to standard treatments. The GOG 3026 trial was an open-label, single-arm, multicenter, phase 2 study that enrolled 51 women with measurable, recurrent, low-grade serous ovarian cancer. To ensure diagnostic accuracy, all cases underwent central pathology review. Participants were required to be at least 18 years old with an ECOG performance status of 0 to 2. While there was no limit on the number of prior therapies, patients were excluded if they had previously used CDK4/6 inhibitors. Prior endocrine therapy was permitted only if the patient had discontinued it at least 6 months before the study and had not experienced disease progression while on that specific therapy. Additionally, women with intact ovarian function were required to undergo ovarian suppression. The treatment regimen consisted of 600 mg of oral ribociclib daily for the first 21 days of a 28-day cycle, paired with a continuous daily dose of 2.5 mg of letrozole. The trial's primary endpoint was the investigator-assessed objective response rate. The results were clinically meaningful. The confirmed overall response rate was 30.6%, which included one complete response and 14 partial responses. The clinical benefit rate, which includes stable disease, reached 84%. These outcomes are particularly notable given the heavily pretreated study population, where nearly 40% of patients had received three or more prior lines of systemic therapy. Durability and survival data further underscored the potential of this combination. Among those who responded to treatment, the median duration of response was 21.2 months. The median progression-free survival was 14.5 months, and the median overall survival reached 44.5 months. In terms of safety, the profile was consistent with previous CDK4/6 inhibitor studies. The most common grade 3 and 4 adverse event was neutropenia, occurring in 47% of patients. However, it was asymptomatic and managed through dose modification. Only 4% of patients discontinued the trial due to adverse events, and no dose-limiting toxicities were observed. When comparing these results to other therapeutic benchmarks, the ribociclib-letrozole combination demonstrated more favorable outcomes than historical endocrine monotherapy. It yields response rates of only 13% to 14%. Furthermore, while MEK inhibitors like trametinib or the combination of avutometinib defactinib show similar response rates, the ribociclib-letrozole regimen displayed significantly better tolerability. Specifically, only 4% of patients in this trial discontinued the therapy due to adverse events, compared to much higher discontinuation rates seen with MEK inhibitor strategies. In conclusion, the GOG 3026 trial successfully establishes ribociclib plus letrozole as a clinically active and well-tolerated regimen for recurrent low-grade serous ovarian cancer. By achieving durable disease control in a heavily pretreated, relatively chemoresistant population, this combination may redefine the therapeutic paradigm for this rare cancer. These findings support the continued evaluation of CDK4/6 endocrine strategies as a preferred chemotherapy-sparing option that prioritizes both disease control and patients' quality of life. Thank you for tuning into JCO Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. 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

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 and the importance of PSA doubling time as a prognostic factor, 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 sta

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

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, t

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

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 e

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 immunot

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 li

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

In this episode of JCO Article Insights, host Dr. Lauren Shih summarizes the article, "Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study" by Bourhis, et al published September 03, 2025 TRANSCRIPT

Host Dr. Shannon Westin and guest Dr. Giancarlo Di Guiseppe discuss the JCO article "Long-Term Dynamic Financial Impacts Among Adolescents and Young Adults With Cancer: A Longitudinal Matched-Cohort Study" TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hi everybody and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts that are published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, social media editor of JCO and gynecologic oncologist extraordinaire. I'm so very excited to talk to you today. We're going to speak about "Long-Term Dynamic Financial Impacts Among Adolescents and Young Adults With Cancer: A Longitudinal Matched-Cohort Study." And I'm joined today by Dr. Giancarlo Di Giuseppe. He has a PhD in epidemiology that he actually just defended with this very work you're going to hear about today at the Dalla Lana School of Public Health at the University of Toronto. He is now a research fellow at the Hospital for Sick Children. Welcome, Dr. Di Giuseppe. It's so exciting to have you. Dr. Di Giuseppe: Thank you so much for having me. Dr. Shannon Westin: So we'll get right to it. Let's level set. Can you talk a little bit about the financial impact of cancer on survivors in general? I think this has been a growing area of interest and research, certainly. Dr. Di Giuseppe: Yeah, and I think that's a very important question, and I'm so happy that this research is now becoming more popular in the research world because it really addresses a critical issue that cancer survivors and their families must face. You know, you're diagnosed with cancer, and now you need to take time off work because you're hospitalized for chemotherapy. You're going back and forth to the hospital, and that all requires time away from your employment, and as a result of that, that has a significant financial strain, both on you and your family. And that's during therapy. Now, in survivorship, in the years after you've survived your cancer, you still need to deal with all the late effects associated with your treatment and your disease, and that can be psychological, physical, and that impacts your workability as well. So, it's not just exclusive to individuals undergoing treatment but also in survivorship afterwards. It really gets the financial strait that you face as a cancer survivor because you're time away from work and your lost productivity. Dr. Shannon Westin: Yeah, that makes sense. Then I think it would be great to talk a little bit specifically about the patient population that you studied in this particular manuscript. Can you talk a little bit about the adolescent young adult cohort, you know, why you singled out this particular group of people? Dr. Di Giuseppe: Absolutely. Adolescents and young adults, or AYAs, which I'll now refer to them as - I'm one of them - we're at a unique crossroads of our life and in our developmental stage of life. We are finishing our post-secondary education. We're entering the workforce. We're forming romantic relationships, and we're really achieving financial autonomy. It's because of this unique developmental stage in life where we've become quite susceptible to health shocks such as cancer. Really, does a cancer and the associated negative financial impacts affect our long term trajectory? So, I'm just finishing my PhD. If I was diagnosed with cancer, I would require a year or two away from my studies. I may or may not finish my education that could then impact my employment and then my financial outcomes later on in life. So it's really this unique population who are going through so many transitions and changes in their lives. How does that cancer really impact that life course trajectory? I think it's unique from an adult who might have, you know, large savings where they can bear the brunt of their cancer financial impacts, whereas AYAs may not have that same financial stability, provide a safety net for the financial impact resulting from their disease. Dr. Shannon Westin: You broke my heart a little bit. I realized I'm no longer in that group, so I guess it's time to move on. Okay. So, let's talk a little bit about the overall design of the study. Can you just kind of walk us through how you set everything up? Dr. Di Giuseppe: Yeah, absolutely. So it's a matched cohort study at the population level here in Canada. We have large national administrative databases, and we have this really unique set of data at the national level through Statistics Canada that we can link our cancer registry to tax records. It really provides this unique opportunity to longitudinally follow individuals from their disease forward in time. The main overall design is the matched cohort study. At the time of diagnosis of a cancer case, they're matched to someone from the population on certain characteristics. I follow these individuals from the index date of their cancer case forward in t

In this JCO Article Insights episode, Dr. Ece Cal interviews Dr. Martin Wermke, author of the JCO article, "Phase I Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-Like T-Cell Engager Obrixtamig (BI 764532) in Patients With Delta-Like Ligand 3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas." TRANSCRIPT The disclosures for guests on this podcast can be found in the transcript. Dr. Ece Cali: Welcome to this episode of JCO Article Insights. This is Dr. Ece Cali, JCO editorial fellow, and today I am joined by Dr. Martin Wermke, Professor for Experimental Cancer Therapy at Dresden University of Technology, to discuss the manuscript "Phase 1 Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-like T-Cell Engager Obrixtamig in Patients with DLL3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas." Obrixtamig is a bispecific T-cell engager that binds to DLL3 on tumor cells and CD3 on T-cells. This manuscript presents the phase 1A dose escalation results of Obrixtamig in patients with DLL3+ small cell lung cancer and neuroendocrine carcinomas. In this study, 168 patients were treated with Obrixtamig across four different dosing regimens. 49% of the patients had small cell lung cancer, 42% had extrapulmonary neuroendocrine carcinoma, and 8% had large cell neuroendocrine carcinoma of the lung. Patients received a median of two prior lines of therapy. 33% of the patients had brain metastases at baseline. Of note, this trial did not mandate baseline brain imaging. Maximum tolerated dose was not reached. 88% of the patients experienced a treatment-related adverse event, however, only 3.6% of the patients had to discontinue treatment due to treatment-related AEs, and dose reduction due to treatment-related AEs was documented in 2.4% of the patient population. Similar to the other DLL3-targeted bi-therapies, the most common adverse events included CRS in 57%, dysgeusia in 23%, and pyrexia in 21% of the patients. CRS events were mostly mild. They occurred more frequently in the first two to three doses. 9% of the patients experienced ICANS, of which 3% were graded as Grade 3 or higher. And let's review the efficacy results. Responses were only seen in patients who received 90 microgram per kg or more once weekly or once every three weeks dosing. The objective response rate in patients who received an effective dose was 28%. If we review by tumor type, 21% of the small cell lung cancer patients, 27% of the extrapulmonary neuroendocrine carcinoma patients, and 70% of the large cell neuroendocrine carcinoma patients had objective response. Median duration of response was 8.5 months, though this data is immature due to short follow-up. Dr. Wermke, DLL3-targeted bispecific T-cell engagers are reshaping the treatment landscape of small cell lung cancer. This trial investigates Obrixtamig in other high-grade neuroendocrine tumors as well. Can you put this trial into context for us and explain why it may represent an important step forward? Dr. Martin Wermke: Yeah, thank you for providing me with the opportunity to discuss our data today. I think the data with Obrixtamig in small cell lung cancer are largely similar to what has been observed with other bispecific T-cell engagers such as tarlatamab with respect to the response rate and duration. It has, however, been to be mentioned that BI 1438001 had a bit more liberal inclusion criteria than other trials around. You already mentioned the fact that we allowed the inclusion of patients without mandatory brain imaging, which led to some patients having their brain mets been diagnosed during the treatment with obrixtamig and then adding to the progressive disease patients. That is something which was not the case with the tarlatamab trials where you really had to have a brain imaging before, and in the Phase 1 trial you were even required to treat the brain mets before you included the patient. So it is a bit different, more poorest patient population. I think the trial adds on existing data by being the first trial to also include non-SCLC neuroendocrine carcinoma of other origin, for example from the gastrointestinal tract, and also by including large cell neuroendocrine carcinoma of the lung, which is a really hard to treat pulmonary neoplasm which currently lacks any standardized treatment. So that is really a step forward which we will build on in the future. Dr. Ece Cali: And one thing I would note in this trial, only patients with tumor expressing DLL3 were enrolled. Can you tell us a little bit more about this target, DLL3 in the context of neuroendocrine tumors, and does DLL3 expression predict clinical outcomes after treatment with DLL3 BiTEs, or do we actually need other predictive biomarkers for these novel agents? Dr. Martin Wermke: Yeah, thank you. That's a pretty interesting question. First of all, DLL3 is an atypical notch ligand, which is expressed by the majority of neuroendocrine carcinomas, virtually absent on healthy adult tissues. The

Host Dr. Shannon Westin and guest Dr. Hani Babiker discuss the JCO article "Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study." TRANSCRIPT TTFields in Locally Advanced Pancreatic Adenocarcinoma Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that have been published in the Journal of Clinical Oncology. I am your host, gynecologic oncologist Shannon Westin, social media editor at the JCO, and just excited to be here to learn today about pancreatic cancer. None of our participants have conflicts of interest related to this podcast, and it is my honor to introduce Dr. Hani Babiker. He is an associate professor of medicine, consultant in oncology at the Mayo Clinic in Jacksonville, Florida. Welcome, Dr. Babiker. Dr. Hani Babiker: Hi, Dr. Westin. Thank you for the great opportunity to discuss our trial, and thank you for having me here. I really appreciate it, and I am excited. Dr. Shannon Westin: All right, so are we. So we are going to be talking about "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: A Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study." This was simultaneously published and presented in the JCO and at the annual meeting of ASCO on 5/31/2025. So, let's level set. Can you speak to us just a little bit about pancreatic cancer? What is the survival, and what is the typical treatment for locally advanced disease? This gynecologic oncologist has not kept up in this field. Dr. Hani Babiker: Absolutely, Dr. Westin, and thank you for that question. Pancreatic adenocarcinoma is a lethal cancer. When I first started my career, the 5-year survival, per the Surveillance, Epidemiology, and End Results, was at 4.5%. I always, whenever I was giving talks, say that I really hope that I will see it in the double digit. Now, the 5-year survival for all pancreatic adenocarcinoma is 13.3%. And the 5-year survival, and although it is a double digit, I still hope that I will see it in a higher double digit in the future. It is even worse in patients with metastatic cancer, about 3% 5-year survival for metastatic pancreatic cancer. It is a dismal diagnosis. I really hope in the future we will find a better therapeutic approach to this lethal cancer. Dr. Shannon Westin: Yes, I just lost a very dear friend and colleague to this disease, so I completely agree with you. Well, now that we are settled kind of with the basics here, I would love to talk a little bit about kind of the primary piece of this intervention, the Tumor Treating Fields. So, how does this work? And what diseases has it gotten indications in as yet? Dr. Hani Babiker: Absolutely. So, Tumor Treating Fields is alternating frequency electrical fields that have been studied preclinically and shown that it abrogates cancer cell proliferation. Earlier on, we knew that it inhibits polymerization of tubulin, and hence, it affects cancer cells from proliferating. Later, we are learning that there are multiple mechanisms of action. It affects permeability, allowing for better drug delivery. It also inhibits cancer cell proliferation through affecting autophagy mechanisms that pancreatic cancer cells will use for proliferating and becoming more aggressive. There is also some early data preclinically in colorectal cancer cell lines and lung cancer cell lines and in vivo models showing that it potentially could activate the microenvironment to make it more pro-immunogenic. We recently published papers showing that it could also affect the nanomechanical properties of the tumor microenvironment within pancreatic cancer, hinting towards affecting, potentially, the stroma. So, there are multiple mechanisms to Tumor Treating Electric Fields. It is a new, novel therapeutic approach. Sometimes when I speak with my trainees, I say, "Well, we have surgery, we have radiation and chemotherapy, and this is something new." Tumor Treating Fields initially was studied in refractory GBM and got an indication there. Subsequently, frontline treatment of GBM in a randomized clinical trial, and then malignant pleural mesothelioma and non-small cell lung cancer. We have studied it in pancreatic cancer. Dr. Shannon Westin: I don't think I have ever heard it described so perfectly. That was brilliant. So thank you, and I hope everyone listening knows that you just got a masterclass on this mechanism. You know, they dabbled in it a little bit in ovarian cancer and it didn't quite make the grade, so I was a little definitely disappointed. But very excited about the data we're going to talk about today. So let's get into the PANOVA-3 study. Can you highlight the overall design and also the key eligibility criteria that would be helpful for our listeners? Dr. Hani Babiker: Absolutely. So, it started off with preclinical work in

JCO fellow Dr. Ece Cali speaks with JCO Associate Editor Dr. Thomas E. Stinchcombe to discuss the JCO article "Phase 2 Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B)", that was simultaneously released at the IASLC 2025 World Conference on Lung Cancer. TRANSCRIPT Dr. Ece Cali: Hello, and welcome to our series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's most important oncology meetings. I am your host, Dr. Ece Cali, JCO editorial fellow, and I am joined by Dr. Tom Stinchcombe, JCO associate editor, to discuss the Journal of Clinical Oncology article and 2025 World Conference on Lung Cancer abstract presentation, "Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non–Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations." The WU-KONG1B trial is a multinational, phase II study that investigated the efficacy and safety of different doses of sunvozertinib in patients with metastatic non-small cell lung cancer and EGFR exon 20 insertion mutations after progression on platinum based chemotherapy. Tom, before we dive into the results, could you walk us through the rationale for this study, and how does it fit into the current treatment options for patients with EGFR exon 20 insertion? Dr. Tom Stinchcombe: Thank you, Dr. Cali. I think the clinical context is always important. We have known that EGFR exon 20 insertions exist and that they are resistant to our currently available EGFR tyrosine kinase inhibitors, and I think there have been attempts in the past to develop a tyrosine kinase inhibitor, but there is a very narrow therapeutic window between the dose you need to inhibit the EGFR mutation in the cancer and the EGFR receptor on normal tissues, most notably the mucosa, the gut, and the skin. And so, our previous attempts have failed largely because the dose required was not tolerable for patients and they could not really stay on the drug for a long time or they were not very active. And so, I think there was a real desire to develop an EGFR tyrosine kinase inhibitor, and then, historically, the standard had been a platinum based doublet as the standard of care. And more recently, platinum based doublet with amivantamab has proven to be superior to platinum based chemotherapy alone. I think the context is also important that amivantamab is not necessarily available in all the countries, and so, there are patients who do not have access to amivantamab. Going to the rationale, I think that this drug had shown preliminary promise of having activity but without that being encumbered by those EGFR wild type toxicities, and, therefore, it was really explored in this larger study. Dr. Ece Cali: And what are some key findings from this trial? Dr. Tom Stinchcombe: So, I think that we should look at the study design. It is a little quirky, for lack of a better term, in that there is a randomization to 200 versus 300 mg, and then, there was a nonrandomized cohort of 300 mg. So, when you look at the study, if you are a purist, you will just look at the randomized patients. If you are sort of an aggregator, you look at all patients. So, it shows reporting on three cohorts, but I think the key findings are that the 200 mg and the 300 mg treatments had similar toxicities in terms of response rate, duration of response, and progression free survival. And as you know going through the review, there was a lot of queries from the reviewers as to which would be the preferred dose, and to me, I think this really illustrates a dose finding component to a trial design because there is a lot of debate about what the minimal effective dose is or the optimal dose. And in this case, having the two dose cohorts did provide us some valuable efficacy and toxicity information. And then, when I look at the study, I want to make sure it reflects my patient population, and about a quarter of patients had brain metastases, and about 15% had previous amivantamab, and about 5% to 10% had another EGFR tyrosine kinase inhibitor. Dr. Ece Cali: And what is the objective response rate and the duration of response? These are pretty good numbers for this patient population. Dr. Tom Stinchcombe: In the 200 mg cohort, it was about 46%. The duration of response was around 11 months, and the PFS was around 8 months. The 300 mg cohort was 46%, duration of response 9.8, and the median PFS is 6.9 months, and I think that this is greater activity than we have seen with our previous attempts at EGFR tyrosine kinase inhibitors. Dr. Ece Cali: And based on these data, FDA granted accelerated approval for sunvozertinib very recently at 200 mg once daily dosing in this setting. So, that is a major step forward for our patients. Dr. Stinchcombe, how does this impact your clinical practice, and what side effects should oncologists be watching for if they