Journal of Clinical Oncology (JCO) Podcast

Guest Dr. John Wingard and host Dr. Davide Soldato discuss JCO article, "Randomized Non-inferiority Trial of a Liberalized Diet Versus the Neutropenic Diet in Hematopoietic Stem Cell Transplant and Acute Leukemia Patients," the reason behind the trial, its design, methodology, results, and the implications for future dietary approaches in hematology.
LINK TO FULL TRANSCRIPT

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 platforms, with the DIRECT study developing an independent, fully open-source phased-variant ctDNA assay. This has been released on GitHub. In contrast, the HOVON 902 study utilized PhasED-seq by Foresight Diagnostics, which is currently the only proprietary and commercially available phased-variant assay for lymphoid malignancies.
Interestingly, despite the differences in platforms and the primary end points, the results were remarkably consistent. The DIRECT study found a highly significant difference in the 2-year TTP rate of 96% in those with undetectable ctDNA MRD at the end of treatment compared to 45% in those with detectable ctDNA, with a hazard ratio of 15. Similarly, the HOVON 902 study found a significantly superior 3-year PFS of 85% in those with undetectable ctDNA compared to 17% with detectable ctDNA, with a hazard ratio of 10.
Crucially, both studies found end-of-treatment ctDNA MRD significantly outperformed PET response assessment for long-term PFS. In fact, for the end point of PFS in both trials, the baseline IPI lost all statistical significance in both univariate and multivariable analysis when accounting for ctDNA MRD and PET status at the end of treatment.
While both studies demonstrate the superiority of ctDNA MRD compared to PET in predicting survival, interestingly, the combination of both tests appeared to be complementary in identifying the highest-risk group. The HOVON 902 study identified 13 patients who were double positive, ie, they were positive with end-of-treatment PET and detectable ctDNA MRD. Every single one of these patients progressed over a 3-year period with a dismal overall survival of 17%. The DIRECT study mirrored these findings with the same double-positive group having a 2-year time to progression rate of 23%. Given consistency in identifying the poor outcome of this double-positive population in both studies, this is clearly a group that would benefit from trial-based approaches like consolidation or, alternatively, frequent surveillance for clinical relapse.
On the other hand, the best-performing group was the double negative, ie, those who had achieved PET negative and ctDNA undetectable at the end of treatment. The double-negative group had a 2-year time to progression of 97% in the DIRECT study and a 3-year PFS of 88% in the HOVON 902 trial. This is quite impressive. Based on these findings, we can anticipate that ctDNA may complement rather than wholly replace PET at the end of treatment for response assessment.
Perhaps the most critical finding from both studies challenged current NCCN-recommended ctDNA MRD sensitivity threshold of achieving less than one part per million. While phased-variant assays can theoretically detect this, this is under optimal conditions, specifically 120 nanograms of input cell-free DNA. In both trials, only 3% of samples could achieve this sensitivity, with the vast majority limited to a sample-specific LOD95 of approximately 1 in 100,000 informative reads. The primary constraint was simply limited plasma volume collected, a denominator problem of input cell-free DNA. For example, the HOVON 902 study had a median plasma volume of 5 mL, yielding 20 nanograms of input DNA. The DIRECT study elegantly demonstrated bridging the gap to attain the NCCN standard of LOD95 of less than 1 part per million is practically impossible. This would require greater input DNA, attained through a 20- to 30-milliliter collection of plasma rather than the standard 10 milliliters, and a massive 20- to 40-fold increase in sequencing depth.
With the current real-world sensitivity of roughly 1 in 100,000 in both these studies, the negative predictive value is already nearly at 90%. There is going to be diminishing returns for further analytical sensitivity. This strongly suggests that the NCCN guidelines should be updated to prioritize achievable sample-specific LOD95 rather than assay-specific theoretical limits.
Collectively, these studies validate the real-world utility of ctDNA MRD as an independent predictor of long-term outcomes following first-line therapy of large B-cell lymphoma. Finally, after two decades of the default R-CHOP for all, the field of aggressive large B-cell lymphoma is taking leaps and bounds by integrating ctDNA MRD with the current wave of bispecific and cellular therapies.
I want to now leave you with my five key clinical takeaways from both these studies.
●        Firstly, ctDNA MRD is a more potent independent predictor of outcome than end-of-treatment PET/CT and baseline IPI.
●        Second, ctDNA MRD in first-line large B-cell lymphoma is already reshaping clinical trial space with therapeutic escalation and de-escalation strategies based on ctDNA kinetics during treatment, as well as identifying candidates with persistent ctDNA at the end of treatment for consolidation approaches.
●        Thirdly, this technology is ready for prime time. Whether this is through Foresight's PhasED-seq assays or the open-source method released by the DIRECT group, academic centers can now operationalize this in routine clinical care.
●        Fourth, biology clearly provides a ceiling. Current sensitivity goals of less than one part per million as recommended by the NCCN are limited by the actual amount of cell-free DNA we can extract from a patient's blood, not just the assay's technology. I believe these two studies will inform the NCCN's next revision to move away from theoretical assay limits to a more realistic sample-specific LOD95 of approximately 1 in 100,000.
●        Finally, it appears that the end-of-treatment ctDNA MRD test may be complementary to PET/CT rather than a replacement. Clearly, the best outcomes are seen in double-negative patients, while double-positive results, ie, positive end-of-treatment PET and detectable ctDNA at the end of treatment, identify a group with an extremely high risk of early progression who may need early intervention.
Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries, and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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 trial, and they couldn't have had a prior upper tract urothelial cancer.
The other point about the observational trial design is I think a really important one. Part of our engagement work also asked patients about their willingness to randomize. There is a ton of literature in our history of trials that failed to accrue well when they were comparing a large-scale surgical intervention with a more conservative management strategy. What we found is only about 10% of patients would be willing to randomize when the clinical comparison is between radical cystectomy and bladder-sparing therapy. So it was very clear that an observational study design was the only way we were going to get evidence to inform clinical care when one of the key comparators was radical cystectomy. And so that is why we utilized the observational trial design.
Dr. Davide Soldato: Starting to go deeper into the results, you mentioned before that the endpoint you chose for this trial was really centered on what patients thought was more important to them. In particular, the primary endpoint of the study was physical function as measured by the EORTC QLQ-C30 questionnaire. I just wanted to understand: first, did you have a solid hypothesis regarding how physical function could be impacted by either radical cystectomy or bladder-sparing treatments? And second, what were the key results of the study?
Dr. John Gore: We figured that at 12 months after enrollment, given the burden and morbidity of a radical cystectomy, that patients in the radical cystectomy arm would have worse self-reported physical functioning than patients in the bladder-sparing therapy arm. We did hypothesize that some of our secondary outcomes might potentially be better after radical cystectomy, such as recurrence-free survival and potentially some other cancer-specific outcomes, because it is a more definitive management strategy. For our primary endpoint, however, we hypothesized that it would be worse.
What we found, and the key finding of our study, is that at 12 months after enrollment, physical functioning was not different between patients undergoing radical cystectomy and patients undergoing bladder-sparing therapy, which is just important in terms of clinical counseling because it just means that you can tell your patients, "Gosh, if we could fast-forward your life six to nine months after this procedure, your physical functioning would be similar to as if you had been able to keep your bladder."
Dr. Davide Soldato: And you mentioned that there were some key secondary endpoints of the study, which included both other dimensions of quality of life and also hard clinical outcomes. We mentioned metastasis-free survival, for example. Going a little bit into the key secondary quality of life outcomes, we know that radical cystectomy can impact physical functioning, but we also know that bowel, sexual symptoms, and also genitourinary symptoms might potentially be impacted by this type of treatment. We also know that, especially in a system like the US, financial toxicity can be a significant burden for patients. Considering the two different approaches, was radical cystectomy better also in other key secondary quality of life outcomes, and was financial toxicity different between the two arms?
Dr. John Gore: Thank you for highlighting some of the really important secondary outcomes that I think are really important to trying to figure out what's best for your patients. Some of the main ones were some of the bladder cancer-specific quality of life outcomes you highlight. Urinary quality of life was worse at enrollment in patients in the radical cystectomy arm but was no different 12 months after. What is unique about how we measure that is we used an instrument called the Bladder Cancer Index because we're comparing a population of patients who have lost their bladder with a population of patients who have retained their bladder, and there are different considerations by gender. And so that instrument is agnostic to urinary diversion status and gender.
We found that bowel function and sexual function were worse in the radical cystectomy arm. It appeared that bowel functioning was getting better to the point of near equivalence at 12 months in the radical cystectomy arm but was still inferior to bladder-sparing therapy, and that probably relates to the fact that we use the bowel as part of the urinary diversion, and that causes some transient disruption in bowel function.
Financial toxicity is an outcome we weren't initially planning on having as part of the CISTO study, but based on that patient feedback, we made that one of our key secondary outcomes. That actually demonstrated superiority in the radical cystectomy arm. I think it's important that we remember that when we do bladder-sparing therapy, those patients are predisposed to a number of visits to our office, whether they're for instillational therapies or cystoscopy surveillance visits. Sometimes that involves the patient themselves, and sometimes that involves a caregiver. We live in an area with a very large geographic catchment, so sometimes that involves overnight hotel stays and airfare. It can be a particular burden, as you made mention, especially in our healthcare system.
Dr. Davide Soldato: Going back to the quality of life dimensions and especially considering the different treatments, 50% of the patients received radical cystectomy with robotic surgery. Did you look a little bit into whether the type of surgery that they received might potentially impact on these dimensions of quality of life?
Dr. John Gore: These are some questions that a lot of urologists have asked us in the surgical arm, related to surgical approach, so robotic versus open, and urinary diversion type. We sometimes reconstruct the urinary tract with an incontinent diversion called an ileal conduit where the urine drains tonically into a bag, and we sometimes do a continent diversion where someone typically will have a neobladder, where you reconstruct a sphere reservoir out of intestines and sew it to the urethra. About 20% of patients in the radical cystectomy arm in CISTO had a neobladder.
We have not yet looked at specific surgical factors and some of those outcomes. That is one of the secondary analyses that we have planned, but we have not drilled into how different surgical approach factors can affect some of our outcomes. Fortunately, we have about 200 patients in the radical cystectomy arm, so it's enough patients that hopefully we can look at some of those factors in the future.
Dr. Davide Soldato: Going back to the clinical endpoints, you mentioned that several of these were measured. There was metastasis-free survival, cancer-specific survival, and progression-free survival. We now have the data at 12 months. I am just wondering if you can comment on those when comparing the radical cystectomy with the bladder-sparing techniques.
Dr. John Gore: I think importantly, bladder cancer-specific survival was very high in both arms, over 95% at one year. So both patient populations do very well in terms of cancer-specific and overall survival at one year. You know, when you take out the bladder, you're taking out a big source of recurrences. Not surprisingly, there was a marked reduction in recurrences in the radical cystectomy arm, so they had better recurrence-free survival.
There actually was worse progression-free survival in the radical cystectomy arm, but there is a big asterisk to that. As you noted, it is an observational study, and one of the areas of imbalance in the study is that we had higher cancer severity in the radical cystectomy arm. So there was about a 20% rate of progression at the time of radical cystectomy to muscle-invasive and node-positive disease. Of those progressions, the overwhelming majority of them were progressions at the time of radical cystectomy, which I think speaks to a couple of important factors. Number one is the challenge in staging these patients. Our staging of non-muscle-invasive bladder cancer is very reliant on our resection. And so there is this risk of understaging our patients. Number two is just the challenge of decision making, that we fear losing our window of cure in this patient population, which is why we try to steer some patients toward radical cystectomy, and that progression figure kind of speaks to that.
Dr. Davide Soldato: Also, one of the factors that was most common in the patients who received radical cystectomy was the presence of other high-risk features. For example, non-urothelial histology, which I think is something that in clinical practice we tend to fear a little bit in terms of recurrence, and so it might potentially bias a little bit towards proposing more strongly radical cystectomy to the patient.
Another thing that I wanted to have a comment on, so this is not really in the paper, but I think it speaks a little bit to how the data will evolve over time. Do you imagine these clinical outcomes changing over time, and do you think that with higher maturity of these endpoints, this study might be even more informative when counseling patients regarding what they are obtaining with a radical cystectomy versus the other type of treatments?
Dr. John Gore: You know, I think in this cancer universe, 12-month outcomes are great, but I think we all want to see two-year and five-year outcomes. We're very fortunate to supplement the work that we've done in the initial CISTO study, we're very fortunate that we've gotten supplementary funding from the National Cancer Institute to get long-term outcomes in this patient population. So we are continuing to follow all of our CISTO study patients to get two-year and five-year outcomes.
What we expect to find is the accrual of new events in the bladder-sparing therapy arm. About 7% of patients in the bladder-sparing therapy arm underwent cystectomy in the first year, but that number will probably go up either as they have recurrences or progression events. We definitely expect the recurrence-free survival to continue to have superiority in the cystectomy arm, but we probably will see the progression events equilibrate as more progression events accrue in the bladder-sparing therapy arm. Maybe by five years, we hypothesize that we'll see clinical superiority in the radical cystectomy arm. By then, we might also see mortality events that separate bladder cancer-specific survival and overall survival between the two arms potentially. But we don't know. Hypothetically, cystectomy has its own downstream risks. It is a major reconstruction with some metabolic sequelae and renal functional sequelae, and so there may be some general medical events that accrue in the cystectomy arm that are also impactful.
Dr. Davide Soldato: One other thing that I think should be complimented on this study is that you also looked at several other endpoints that might be important for patients. For example, anxiety symptoms and depression symptoms.
Dr. John Gore: Yeah, I think one of the other key secondary outcomes we looked at were mental health outcomes. We utilized the PROMIS domains of anxiety and depression. Not unexpectedly, our radical cystectomy arm patients exhibited higher anxiety symptoms and higher depression symptoms at enrollment. What we found is at 12 months, they actually had significantly lower anxiety and depression than patients in the bladder-sparing therapy arm.
We hypothesized in this paper that that actually relates probably mostly to cancer-specific anxiety. You know, when you experience this cavalcade of recurrences, it just breeds an anxiety about adverse cancer-specific outcomes, and by taking out the bladder, you kind of eliminate this prevalent source of anxiety. We followed up the study with a qualitative piece where we interviewed 50 patients and 20 caregivers. Based on those interviews, and that's just a sample of the patient population, it did seem to be cancer-specific anxiety that was driving a lot of those responses.
Dr. Davide Soldato: I would like to end with a methodological consideration on your part because we said that this was an observational study. Frequently we tend to think that observational studies come with a lot of bias, and so we tend to downgrade a little bit the results. But I think that a lot of the merit that goes in the CISTO study that was published in the JCO, and I think it also speaks to the fact that this is very high-quality data, comes with the fact that the methodology behind this study was really robust in terms of informing us. Even with this observational study that, as you said, was the only one that we could perform considering the patient population. So just a comment on your part also to speak to the solidity of the data that was published.
Dr. John Gore: Importantly, you know, if you look at ClinicalTrials.gov or other sources, CISTO is the only trial that has radical cystectomy as a major comparator. In many ways, this study is our only source of evidence for radical cystectomy. So we'd rather have flawed observational evidence than no evidence at all. We all experience flaws of our RCTs as well. They tend to be these narrowly defined patient populations that may not match the patient in front of you. So I think there are unrecognized flaws on the other side as well.
The way that we try to counterbalance that, and none of these techniques are perfect, but we used a strategy called 'targeted maximum likelihood estimation'. Like many methods, such as propensity scores or instrumental variable analysis, what we're trying to do theoretically is coax randomization from non-randomized data. And TMLE, which is the technique we use, tends to be pretty robust to that. So it's the best available way that we can try to counterbalance the bias based on age and clinical severity between the two patient arms. I also think what's important about this is that even when there are biases, I think we are able to infer those out and still extract meaningful details from the data. So even with the biased data, I think we all glean some really important clinical learnings from it.
Dr. Davide Soldato: Absolutely, but I would also say that in terms of observational data, the work that you have done is really something that makes us quite confident about what you found in the CISTO study.
So with this, I would like to thank you again for joining us today.
Dr. John Gore: Thank you so much, and thank you for highlighting the CISTO study. We are very excited about the data.
Dr. Davide Soldato: So Dr. Gore, we appreciate you sharing more on your JCO 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."
If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest Disclosure
Dr. Gore:
Consulting or Advisory Role: Astellas Pharma

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 the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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.
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