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