Journal of Clinical Oncology (JCO) Podcast

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JCO at ASCO Annual Meeting: Use of Low-Value Cancer Treatments in Medicare May 31, 2025

Show notes

JCO Editorial Fellow Dr. Lauren Shih and JCO Associate Editor Dr. Stephanie Wheeler discuss the ASCO 25 Simultaneous Publication paper "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare."

Transcript

The guest on this podcast episode has no disclosures to declare.

Dr. Lauren Shih: Hello, and welcome to our 2025 ASCO annual meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentations at this year's meeting. I'm your host, Dr. Lauren Shih, JCO editorial fellow, and I'm joined by JCO Associate Editor Dr. Stephanie Wheeler to discuss the Journal of Clinical Oncology article and abstract presentation "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare."

Let's start with the relevance of the article. Dr. Wheeler, can you explain this to our listeners?

Dr. Stephanie Wheeler: Thank you so much. Let's get right into it. So this article is really about understanding different types of Medicare plans and what we should expect to see in terms of their use of low-value treatments for cancer patients. So, as Medicare really is focused on trying to limit the use of low-value cancer treatments, we really need to better understand the drivers of variability. So we know that many cancer patients have multiple treatment options available to them. We also know that the vast majority of older adults beyond age 65 are insured by Medicare, and about half of them are on Medicare Advantage plans, which are serviced by private insurance. And private insurance companies in this case are receiving capitated payments for Medicare beneficiaries to manage their service utilization and reduce costs. So, with respect to Medicare Advantage versus the traditional fee-for-service Medicare, it's not really been known to what extent low-value treatments are differentially used by these types of plans for cancer patients. And so that was really the focus of this article.

What the authors found is that across six different types of treatments, in general, the folks who were enrolled in Medicare Advantage plans had reduced use of low-value treatment. So that's a good sign for Medicare beneficiaries. And although the relative difference in that use was somewhat low, this translates to a significant number of Medicare enrollees across the country not receiving these low-value treatments. And of course, this translates to considerable savings at the society level.

Dr. Lauren Shih: Are there any additional key results that we should review?

Dr. Stephanie Wheeler: Yeah. So I'll tell you just a little bit more about the methods and also their findings. So they looked at six different low-value treatments, and this was in, again, 100% of national Medicare enrollees from 2015 through 2021. So the six low-value treatments that they examined were the use of G-CSFs among patients receiving low-risk chemotherapy and denosumab for those who had castration-sensitive prostate cancer. Then they also looked at four high-cost treatments, including using nab-paclitaxel instead of paclitaxel for patients with breast or lung cancer; second, adding bevacizumab to carboplatin plus paclitaxel for ovarian cancer; third, using brand-name drugs instead of generics when generics were available; and fourth, using biologics instead of biosimilars when biosimilars were available. And these are all, by the way, non-recommended treatments according to a variety of guidelines, including NCCN and ASCO's Choosing Wisely guidelines.

So they used the Medicare claims data to examine use of these regimens. They also analyzed results by type of Medicare Advantage plan, whether people were enrolled in a health maintenance organization plan, or an HMO, or a preferred provider organization plan, or a PPO. They also looked at the largest Medicare Advantage insurers—including Aetna, Blue Cross Blue Shield, Cigna, Humana, and UnitedHealth—and limited their analyses to those that had complete encounter data. And what they found across the board is that the enrollees in Medicare Advantage plans generally had lower use of these low-value treatments. And the largest differences between Medicare Advantage and traditional Medicare plans were in the outcomes, including G-CSF use and using denosumab for castration-resistant prostate cancer, and then the combination of bevacizumab, carboplatin, and paclitaxel versus carboplatin and paclitaxel. And all of these had a change in use ranging from about 19% change to 24% change in use. This is significant as a field as we look at ways in which different plan organization can influence use of treatments, particularly given the excess cost of cancer care. This is something we really want to pay attention to.

So I'd encourage folks to look more closely at the results by treatment type as well as the results by plan type to see a little bit more about what was going on across different plan types.

Dr. Lauren Shih: Great. And are there any outstanding questions that need to be answered?

Dr. Stephanie Wheeler: Yes, there always are, of course. I think the study has several strengths that are worth noting.

First, they have 100% of Medicare enrollees, so there's national coverage there, which is, you know, quite outstanding. They also use an appropriate choice of analysis to help deal with some of the selection. So they use inverse probability of treatment weights, and they control for practice and county indicators to try to get some realistic adjustment for the selection that happens in terms of how patients are enrolled in different Medicare Advantage versus traditional fee-for-Medicare plans. These statistical approaches are a good idea, but they are limited by the observed variables that we can use for these kinds of adjustments. And so any unobserved—confounding or any unobserved factors that would influence selection in these plans aren't going to be captured well. So preferences, for example, that patients may have about different types of plans when they're insuring themselves and their families may not be captured.

Second, the data that are used are only encounter data from those plans with complete records. That may mean that smaller Medicare Advantage insurers or those that don't have as comprehensive records are not included. So this may not be reflective of their practice patterns. And then third, of course, this only looked at six different low-value cancer treatments. It remains to be seen whether this kind of finding extends to other types of low-value cancer treatments, and that's an opportunity for future study.

Finally, I would say that we don't exactly know why these patterns exist. It could be that Medicare Advantage plans have different approaches to prior authorization. They could have more in-house quality control and management to really understand, among their population for whom they're receiving Medicare Advantage payments, to really look at care quality and assess Choosing Wisely guidelines. We don't know exactly how that's playing out. And so we need additional data to really figure out what's working here and what are opportunities for future policy and payment innovations that can further reduce low-value care.

Dr. Lauren Shih: Great. Thank you so much, Dr. Wheeler, for speaking to us about the JCO article, "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare." We really appreciate your insights.

Dr. Stephanie Wheeler: Thanks for having me.

Dr. Lauren Shih: Join us again for the latest simultaneous publications from the ASCO 2025 Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO Article Insights: Double Hit Myeloma Correlates With Adverse Patient Outcome May 29, 2025

Show notes

In this JCO Article Insights episode, host Michael Hughes summarizes "Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma" by Kaiser et al, published February 18, 2025, followed by an interview with JCO Associate Editor Suzanne Lentzsch.

Transcript

Michael Hughes: Welcome to this episode of JCO Article Insights. This is Michael Hughes, JCO's editorial fellow. Today I have the privilege and pleasure of interviewing Dr. Suzanne Lentzsch on the "Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma" by Dr. Kaiser and colleagues.

At the time of this recording, our guest has disclosures that will be linked in the transcript.

The urge to identify patients with aggressive disease, which is the first step in any effort to provide personalized medical care, is intuitive to physicians today. Multiple myeloma patients have experienced heterogeneous outcomes since we first started characterizing the disease. Some patients live for decades after treatment. Some, irrespective of treatment administered, exhibit rapidly relapsing disease. We term this 'high-risk myeloma'.

The Durie-Salmon Risk Stratification System, introduced in 1975, was the first formal effort to identify those patients with aggressive, high-risk myeloma. However, the introduction of novel approaches in therapeutic agents—autologous stem cell transplantation with melphalan conditioning, proteasome inhibitors like bortezomib, or immunomodulatory drugs like lenalidomide—rendered the Durie-Salmon system a less precise predictor of outcomes.

The International Staging System in 2005, predicated upon the burden of disease as measured by beta-2 microglobulin and serum albumin, was the second attempt at identifying high-risk myeloma. It was eventually supplanted by the Revised International Staging System (RISS) in 2015, which incorporated novel clinical and cytogenetic markers and remains the primary way physicians think about the risk of progression or relapse in multiple myeloma.

Much attention has been focused on the canonically high-risk cytogenetic abnormalities in myeloma, typically identified by fluorescence in situ hybridization: translocation t(4;14), translocation t(14;16), translocation t(14;20), and deletion of 17p. Much attention also has been focused on the fact that intermediate-risk disease, as defined by the RISS, has been shown to be a heterogeneous subgroup in terms of survival outcomes. The RISS underwent revision in 2022 to account for such heterogeneity and has become the R2-ISS, published here in the Journal of Clinical Oncology first in 2022. Translocations t(14;16) and t(14;20) were removed, and gain or amplification of 1q was added. Such revisions to core parts of a modern risk-stratification system reflect the fact that myeloma right now is in flux, both in treatment paradigms and risk-stratification systems.

The field in recent years has undergone numerous remarkable changes, from the advent of anti-CD38 agents to the introduction of cellular and bispecific therapies, to the very technology we use to investigate genetic lesions. The major issue is that we're seeing numerous trials using different criteria for the definition of high-risk multiple myeloma. This is a burgeoning problem and speaks very much now to a critical need for an effort to consolidate all these criteria on at least cytogenetic lesions as we move into an era of response-adapted treatment strategies.

The excellent article by Kaiser and colleagues, published in the February 2024 edition of the JCO, does just that in a far-ranging meta-analysis of data from 24 prospective therapeutic trials. All 24 trials were phase II or III randomized controlled trials for newly diagnosed and relapsed/refractory multiple myeloma. The paper takes a federated analysis approach: participants provided summaries and performed prespecified uniform analyses. The high-risk cytogenetic abnormalities examined were translocation t(4;14), gain or amplification of 1q, deletion of 17p, and translocation t(14;16), if included in the original trials. All of these were collected into zero, single, or double-hit categories, not unlike the system currently present in diffuse large B-cell lymphomas. The outcomes studied were progression-free survival and overall survival, with these analyses adhering to modified ITT principles.

The authors also performed prespecified subgroup analyses in the following: transplant-eligible newly diagnosed myeloma, transplant non-ineligible newly diagnosed myeloma, and relapsed/refractory myeloma. They, in addition, described heterogeneity by the I2 statistic, which, if above 50%, denotes substantial heterogeneity by the Cochrane Review Handbook, and otherwise performed sensitivity analyses and assessed bias to confirm the robustness of their results.

In terms of those results, looking at the data collected, there was an appropriate spread of anti-CD38-containing and non-containing trials. 7,724 patients were evaluable of a total 13,926 enrolled in those 24 trials: 4,106 from nine trials in transplant-eligible myeloma, 1,816 from seven trials in transplant non-ineligible myeloma, and 1,802 from eight trials in relapsed/refractory disease. ISS stage for all patients was relatively evenly spread: stage I, 34.5%; stage II, 37%; stage III, 24%. In terms of high-risk cytogenetic lesions, double-hit disease was present in 13.8% of patients, and single-hit disease was present in 37.4%.

In terms of outcomes, Kaiser and colleagues found a consistent separation in survival outcomes when the cohort was stratified by the number of high-risk cytogenetic lesions present. For PFS, the hazard ratio was for double-hit 2.28, for single-hit 1.51, without significant heterogeneity. For overall survival, the hazard ratio was for double-hit disease 2.94, single-hit disease 1.69, without significant heterogeneity except in patients with double-hit disease at 56.5%. By clinical subgroups, hazard ratios remained pretty consistent with the overall cohort analysis. In transplant-eligible newly diagnosed myeloma, the hazard ratio for progression is 2.53, overall survival 4.17. For transplant non-ineligible, 1.97 progression, 2.31 mortality. Relapsed/refractory disease progression 2.05, overall mortality 2.21, without significant heterogeneity.

Of trials which started recruitment since 2015, that is to say, since daratumumab was FDA approved and thus since an anti-CD38 agent was incorporated into these regimens, analysis revealed the same results, with double-hit myeloma still experiencing worse survival by far of the three categories analyzed. Risk of bias overall was low by advanced statistical analysis. In terms of subgroup analysis, double-hit results for transplant-eligible newly diagnosed myeloma may have been skewed by smaller study effects, where the upper bound of the estimated hazard ratio for mortality reached into the 15 to 20 range.

In conclusion, from a massive amount of data comes a very elegant way to think about the role certain cytogenetic abnormalities play in multiple myeloma. A simple number of lesions - zero, one, or at least two - can risk-stratify. This is a powerful new prognostic biomarker candidate and, somewhat soberingly, also may confirm, or at least suggests, that anti-CD38 agents are unable to overcome the deleterious impact of certain biologic characteristics of myeloma.

Where do we go from here? This certainly needs further a priori prospective validation. This did not include cellular therapies. The very scale at which this risk-stratification system operates, agnostic to specific genetic lesion, let alone point mutations, lends itself also to further exploration. And to discuss this piece further, we welcome the one and only Dr. Suzanne Lentzsch to the episode. Dr. Lentzsch serves as an associate editor for JCO and is a world-renowned leader at the bleeding edge of plasma cell dyscrasia research.

Dr. Lentzsch, there are several new investigations which suggest that translocation t(4;14), for example, is itself a heterogeneous collection of patients. There are other studies which suggest that point mutations in oncogenes like TP53, which were not assessed in Kaiser et al., carry substantial detrimental impact. Is this classification system - no-hit, single-hit, double-hit - too broad a look at tumor genetics? And how do you think we will end up incorporating ever more detailed investigations into the genetics of multiple myeloma moving forward?

Dr. Suzanne Lentzsch: Michael, first of all, excellent presentation of that very important trial. Great summary. And of course, it's a pleasure to be here with JCO and with you to discuss that manuscript.

Let me go back a little bit to high-risk multiple myeloma. I think over the last years, we had a lot of information on what is high-risk multiple myeloma, and I just want to mention a couple of things, that we separate not only cytogenetically high-risk multiple myeloma, we also have functional high-risk multiple myeloma, with an early relapse after transplant, within 12 months, or two years after start of treatment for the non transplant patients, which is difficult to assess because you cannot decide whether this is a high-risk patient before you start treatment. You only know that in retrospective. Other forms of high-risk: extramedullary disease, circulating tumor cells/plasma cell dyscrasia, patients who never achieve MRD positivity, extramedullary multiple myeloma, or even age and frailty is a high risk for our patients. Then we have gene expression and gene sequencing. So there is so much information currently to really assess what is high-risk multiple myeloma, that is very difficult to find common ground and establish something for future clinical trials.

So what Dr. Kaiser did was really to develop a very elegant system with information we should all have. He used four factors: translocation t(14;16), t(4;14), gain or amplification of 1q, and deletion of 17p. Of course, this is not the entire, I would say, information we have on high risk, but I think it's a good standard. It's a very elegant system to really classify a standard single-hit, double-hit, high-risk multiple myeloma, which can be used for all physicians who treat multiple myeloma, and especially, it might also work in resource-scarce settings.

So, ultimately, I think that system is an easy-to-use baseline for our patients and provides the best information we can get, especially with a baseline, in order to compare clinical trials or to compare any data in the future.

Michael Hughes: Thank you, Dr. Lentzsch.

To the point that you made about this isn't the full story. There does, as you said, exist this persistent group of functional high-risk multiple myeloma where we see standard-risk cytogenetics, but these patients ultimately either exhibit primary refractory disease or very early relapse despite aggressive, standard aggressive treatment. How do you see risk-stratification systems incorporating other novel biomarkers for such patients? Is it truly all genetic? Or is next-generation sequencing, gene expression profiling, is that the answer? Or is there still a role for characterizing tumor burden?

Dr. Suzanne Lentzsch: Excellent question, Michael, and I wish I would have the glass ball to answer that question. I see some problems with the current approach we have. First of all, to do the cytogenetics, you need good material. You only detect and identify what you have. If the bone marrow is of low quality, you have mainly peripheral blood in your bone marrow biopsy, you might not really fully have a representation of all cytogenetic changes in your bone marrow. So I think with a low-quality sample, that you might miss one or the other really cytogenetic high risk.

So, having said this, I think circulating tumor cells, that might be something we will look into in the future, because circulating tumor cells are readily available, can be assessed without doing a bone marrow biopsy. And what is even more exciting, in addition to the circulating tumor cells or plasma cells, using them is next-generation sequencing. I think at the moment, we are more in a collection phase where we really try to correlate sequencing with our cytogenetics and especially to establish next-generation sequencing in all of our patients. But I think after that collection phase, maybe in the future, collecting peripheral blood and doing sequencing on peripheral blood samples might be the way to go.

In addition, I don't want to forget the imaging. We started with a skeletal survey, and we know that you probably need to lose 30% of the bone before you see a lesion at all. So having imaging, such as diffusion-weighted imaging, whole-body MRI, is also, together with sequencing of the tumor cells, a step into the right direction.

Michael Hughes: Thank you, Dr. Lentzsch.

Bringing this back to the article at hand, how has Kaiser et al. changed the way we discuss myeloma with patients in the exam room?

Dr. Suzanne Lentzsch: I think we have more data on hand. So far, we talked about standard risk and high risk, but I think right now, with a very simple system, we can go into the room and we can tell the patient, "Listen, you don't have any of those cytogenetic abnormalities. I think you have a standard risk. We might give you a simple maintenance treatment with Revlimid." But we might also go into the room and say, "I'm really concerned. You have so-called double-hit multiple myeloma. You have high-risk and at least two of those abnormal cytogenetics which we discussed, and I think you need a more intense maintenance treatment, for instance, double maintenance." I think we know that a high-risk multiple myeloma can be brought into a remission, but the problem that we have is to keep those patients into a remission. So, I think a more intense treatment, for instance, with a double maintenance, or with consolidation after transplant, and a longer and more intense treatment is justified in patients who have that truly high-risk multiple myeloma described here.

Michael Hughes: Dr. Lentzsch, thank you so much for your time and your wisdom.

Dr. Suzanne Lentzsch: My pleasure. Thank you for having me.

Michael Hughes: Listeners, 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.

Pembrolizumab and Bevacizumab for Melanoma Brain Metastases May 08, 2025

Show notes

Host Dr. Davide Soldato and guest Dr. Harriet Kluger discuss the JCO article "Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases." 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 San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Harriet Kluger. Dr. Kluger is a professor of medicine at Yale School of Medicine, Director of the Yale SPORE in Skin Cancer, and an internationally recognized expert in immuno-oncology for melanoma and renal cell carcinoma. She leads early-phase and translational trials that pair novel immunotherapies with predictive biomarkers to personalized care. Today, Dr. Kluger and I will be discussing the article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases." In this study, Dr. Kluger and colleagues evaluated four cycles of pembrolizumab plus the anti-VEGF antibody bevacizumab followed by pembrolizumab maintenance in patients with asymptomatic non-hemorrhagic melanoma brain metastases that had not previously received PD-1 therapy. Thank you for speaking with us, Dr. Kluger. Dr. Harriet Kluger Thank you for inviting me. The pleasure is really all mine. Dr. Davide Soldato So to kick off our podcast, I just wanted to ask if you could outline a little bit the biological and clinical rationale that led you to test this type of combination for patients with untreated brain metastases from metastatic melanoma. Dr. Harriet Kluger Back in approximately 2012, patients who had untreated brain metastases were excluded from all clinical trials. So by untreated, I mean brain metastases that had not received local therapy such as surgery or radiation. The reason for it was primarily because there was this fear that big molecules wouldn't penetrate brain lesions because they can't pass the blood-brain barrier. Turns out that the blood-brain barrier within a tumor is somewhat leaky and drugs sometimes can get in there. When PD-1 inhibitors were first identified as the next blockbuster class of drugs, we decided to conduct a phase 2 clinical trial of pembrolizumab monotherapy in patients with untreated brain metastases. We actually did it also in lung cancer, and we could talk about that later on. Responses were seen. The responses in the brain and the body were similar. They were concordant in melanoma patients. Now, at approximately that time, also another study was done by the Australian group by Dr. Georgina Long, where they did a randomized trial where patients who didn't require immediate steroid therapy received either nivolumab alone or nivolumab with ipilimumab, and the combination arm was substantially superior. Subsequently, also, Bristol Myers Squibb also conducted a large phase 2 multicenter trial of ipilimumab and nivolumab in patients with untreated brain metastases. And there, once again, they saw that the responses in the brain were similar to the responses in the body. Now, somewhere along the line there, we completed our anti-PD-1 monotherapy trial. And when we looked at our data, we still didn't have the data on ipilimumab and nivolumab. And our question was, "Well, how can we do better?" Just as we're always trying to do better. We saw two really big problems. One was that patients had a lot of perilesional edema. And the other one was that we were struggling with radiation necrosis in lesions that were previously Gamma Knifed. The instance of radiation necrosis was in excess of 30%. So the rationale behind this study was that if we added bevacizumab, maybe we could treat those patients who had some edema, not requiring steroids, but potentially get them on study, get that PD-1 inhibitor going, and also prevent subsequent radiation necrosis. And that was the main rationale behind the study. We had also done some preclinical work in mouse models of melanoma brain metastases and in an in vitro blood-brain barrier model where we showed that bevacizumab, or anti-VEGF, really tightens up those leaky basement membranes and therefore would be very likely to decrease the edema. Dr. Davide Soldato Thank you very much for putting in context the combination. So this was a phase 2 trial, and you included patients who had at least one lesion, and you wanted lesions that were behind 5 and 20 millimeters. Patients could be included also if the brain metastasis was higher in dimension than 20 millimeters, but it had to be treated, and it was then excluded from the evaluation of the primary objective of the trial. So regarding, a little bit, these characteristics, do you think that this is very similar to what we see in clinical practice? And what does this mean in terms of applicability of these results in clinical practice? Dr. Harriet Kluger So that's an excellent question. The brain metastasis clinical research field has somewhat been struggling with this issue of inclusion/exclusion criteria. When we started this, we showed pretty clearly that 5 to 10 millimeter lesions, which are below the RECIST criteria for inclusion, are measurable if you use MRIs with slices that are 1 to 2 millimeters. Most institutions in the United States do use these high-resolution MRIs. I don't know how applicable that is on a worldwide scale, but we certainly lowered the threshold for inclusion so that patients who have a smattering of small brain metastases would be eligible. Now, patients with single large brain metastases, the reason that we excluded those from the trial was because we were afraid that if a patient didn't respond to the systemic therapy that we were going to give them, they could really then develop severe neurological symptoms. So, for patient safety, we used 20 millimeters as the upper level for inclusion. Some of the other trials that I mentioned earlier also excluded patients with very large lesions. Now, in practice, one certainly can do Gamma Knife therapy to the large lesions and leave the smaller ones untreated. So I think it actually is very applicable to clinical practice. Dr. Davide Soldato Thank you very much for that insight, because I think that sometimes criteria for clinical trials, they have to be very restrictive. But then we know that in clinical practice, the applicability of these results is probably broader. So, going a little bit further in the results of the study, I just wanted a little bit of comment from you regarding what you saw in terms of intracranial response rate and duration of response among patients who obtained a response from the combination treatment. Dr. Harriet Kluger So we were actually surprised. When we first designed this study, as I said earlier, we weren't trying to beat out ipilimumab and nivolumab. We were really just trying to exclude those patients who wouldn't have otherwise been eligible for ipilimumab and nivolumab because of edema or possibly even previous radiation necrosis. So it was designed to differentiate between a response rate of 34%, and I believe the lower bound was somewhere in the 20s, because that's what we'd seen in the previous pembrolizumab study. What we saw in the first 20 patients that we enrolled was actually a response rate that far exceeded that. And so we enrolled another cohort to verify that result because we were concerned about premature publishing of a result that we might have achieved just by chance. The two cohorts were very similar in terms of the response rates. And certainly this still needs to be verified in a second study with additional institutions. We did include the Moffitt Cancer Center, and the response rate with Moffitt Cancer Center was very similar to the Yale Cancer Center response rate. Now, your other question was about duration of response. So the other thing that we started asking ourselves was whether this high response rate was really because the administration of the anti-VEGF will decrease the gadolinium enhancement and therefore we might actually just be seeing prettier scans but not tumor shrinkage. And the way to differentiate those two is by looking at the duration of the response. Median progression-free survival was 2.2 years. That's pretty long. The upper bound on the 95% confidence interval was not reached. I can't tell you that the duration is as good as the duration would be when you give ipilimumab. Perhaps it is less good. This was a fairly sick population of patients, and it included some who might not have been able to receive ipilimumab and nivolumab. So it provides an alternative. I do believe that we need to do a randomized trial where we compare it to ipilimumab and nivolumab, which is the current standard of care in this patient population. We do need to interpret these results with caution. I also want to point out regarding the progression-free survival that we only gave four doses of anti-VEGF. So one would think that even though anti-VEGF has a long half-life of three or four weeks, two years later, you no longer have anti-VEGF effect, presumably. So it does something when it's administered fairly early on in the course of the treatment. Dr. Davide Soldato So, in terms of clinical applicability, do you see this combination of pembrolizumab and bevacizumab - and of course, as we mentioned, this was a phase 2 trial. The number of patients included was not very high, but still you saw some very promising results when compared with the combination of ipilimumab and nivolumab. So do you see this combination as something that should be given particularly to those patients who might not be able to receive ipilimumab and nivolumab? So, for example, patients who are very symptomatic from the start or require a high dose of steroids, or also to provide a quicker response in terms of patients who have neurological symptoms, or do you think that someday it could be potentially used for all patients? Dr. Harriet Kluger The third part of your question, whether it can be used someday for all patients: I think we need to be very careful when we interpret these results. The study was substantially smaller than the ipilimumab/nivolumab trial that was conducted by Bristol Myers Squibb. Also going to point out that was a different population of patients. Those were all frontline patients. Here we had a mix of patients who'd had previous anti-CTLA-4 and frontline patients. So I don't think that we can replace ipilimumab and nivolumab with these results. But certainly the steroid-sparing aspect of it is something that we really need to take into consideration. A lot of patients have lesions in locations where edema can be dangerous, and some of them have a hard time coming off the steroids. So this is certainly a good approach for those folks. Dr. Davide Soldato And coming back to something that you mentioned in the very introduction, when you said that there were two main problems, which was one, the problem of the edema, and the second one, the problem of the radionecrosis. In your trial, there was a fair percentage of patients who received some type of local treatment before the systemic one. So the combination of pembrolizumab and bevacizumab. And most of the patients received radiosurgery. So I just wanted a brief comment regarding the incidence of radionecrosis in the trial and whether that specific component of the combination with bevacizumab was reduced. And how do you think that this fares in terms of what we see in clinical practice in terms of radionecrosis? Dr. Harriet Kluger I'm not sure that we really reduced the incidence of radiation necrosis. We saw radiation necrosis here. We saw less of it than in the trial of pembrolizumab monotherapy, but these were also different patients, different time. We saw more than we thought that we were going to see. It was 27%, I believe, which is fairly high still. We only gave the four doses of bevacizumab. Maybe to really prevent radiation necrosis, you have to continue to give the bevacizumab. That, too, needs to be tested. The reason that we gave the four doses of bevacizumab was simply because of the cost of the bevacizumab at the time. Dr. Davide Soldato Thank you very much for that comment on radionecrosis. And I really think that potentially this is a strategy, so continuing the bevacizumab, that really makes a lot of sense, especially considering that the tolerability of the regimen was really very, very good, and you didn't see any significant or serious adverse events related to bevacizumab. So just wondering if you could comment a little bit on the toxicities, whether you had anything unexpected. Dr. Harriet Kluger There was one patient who had a microperforation of a diverticulum, which was probably related to the bevacizumab. It was conservatively managed, and the patient did fine and actually remains alive now, many years later. We had one patient who had dehiscence of a previous wound. So there is some. We did not see any substantial hypertension, proteinuria, but we only gave the four doses. So it is possible that if you give it for longer, we would see some side effects. But still, relative to ipilimumab, it's very, very well tolerated. Dr. Davide Soldato Yeah, exactly. I think that the safety profile is really different when we compare the combination of ipilimumab/nivolumab with the pembrolizumab/bevacizumab. And as you said, this was a very small trial and probably we need additional results. But still, these results, in terms of tolerability and safety, I think they are very interesting. So one additional question that I think warrants a little bit of comment on your part is actually related to the presence of patients with BRAF mutation and, in general, to what you think would be the best course of treatment for these patients who present with the upfront brain metastases. So this, it's actually not completely related to the study, but I think that since patients with BRAF mutation were included, I think that this warrants a little bit of discussion on your part. Dr. Harriet Kluger So we really believe that long-term disease control, particularly in brain metastases, doesn't happen when you give BRAF/MEK inhibitors. You sometimes get long-term control if you've got oligometastatic disease in extracranial sites and if they've previously been treated with a lot of immune checkpoint inhibitors, which wasn't the case over here. So a patient who presents early in the course of the disease, regardless of their BRAF status, I do believe that between our studies and all the studies that have been done on immunotherapy earlier in the course of disease, we should withhold BRAF/MEK inhibitors unless they have overwhelming disease and we need immediate disease control, and then we switch them very quickly to immunotherapy. Can I also say something about the toxicity question from the bevacizumab? I have one more comment to make. I think it's important. We were very careful not to include patients who had overt hemorrhage from brain metastases. So melanoma brain metastases relative to other tumor types tend to bleed, and that was an exclusion criteria. We didn't see any bleeding that was attributable to the bevacizumab, but we don't know for sure that, if this is widely used, that that might not be a problem that's observed. So I would advise folks to use extreme caution and perhaps not use it outside of the setting of a clinical trial in patients with overt hemorrhage in the melanoma brain metastases. Dr. Davide Soldato Thank you very much. I think that one aspect that is really interesting in the trial is actually related to the fact that you…

Full show notes at the publisher

JCO Article Insights: ESPAC4 Long-Term Follow-Up in Pancreatic Cancer Apr 28, 2025

Show notes

In this JCO Article Insights episode, host Joseph Mathew summaries Pancreatic Adenocarcinoma: Long-Term Outcomes of Adjuvant Therapy in the ESPAC4 Phase III Trial, by Palmer, et al published December 5, 2024.

Transcript

Joseph Mathew:

Hello and welcome to the Journal of Clinical Oncology Article Insights. I'm your host, Joseph Mathew, and today we will be discussing the article "Long-Term Survival in Resected Pancreatic Ductal Adenocarcinoma with Adjuvant Gemcitabine plus Capecitabine Compared to Modified FOLFIRINOX from the ESPAC-4 and the PRODIGE 24 Trials" by Dr. Palmer et al.

To summarize the relevant evidence, the ESPAC-4 was a European phase 3 multicenter randomized clinical trial published in 2017 comparing adjuvant gemcitabine and capecitabine (GemCap) with gemcitabine monotherapy following macroscopic margin-negative resections for operable pancreatic ductal adenocarcinoma (PDAC). The trial had included non-metastatic patients aged 18 years or older, World Health Organization (WHO) performance scores of 2 or less, creatinine clearance of at least 50 mL/min, and a life expectancy of over three months who had not received any prior anticancer treatment. Patients who had undergone R2 resections were selectively excluded.

Eligible participants were randomized 1:1 within 12 weeks of pancreatectomy to one of the two treatment arms, with chemotherapy initiated within two weeks from the date of randomization. The regimens involved six cycles, each lasting four weeks, for an overall duration of 24 weeks. In the monotherapy arm, gemcitabine dosed at 1 g/m² was given as an intravenous infusion once a week for three weeks, followed by one week off. In the GemCap arm, capecitabine dosed at 1660 mg/m² was added to gemcitabine, given daily for three weeks, followed by one week off. Patients were followed up every three months, with the primary endpoint being overall survival (OS). The study showed that at a median follow-up of 43.2 months, GemCap was associated with a significantly longer OS than gemcitabine alone.

Subsequently, in 2018, the Phase 3 randomized PRODIGE 24 trial was conducted in centers across France and Canada, comparing adjuvant modified FOLFIRINOX (mFOLFIRINOX) with gemcitabine in a similar subset of patients with resected PDAC and reported longer OS with the mFOLFIRINOX regimen. This study, however, had more restrictive eligibility criteria when compared to ESPAC-4, including patients aged under 80 years, WHO performance status of 0 or 1, with no significant cardiovascular disease, and a postoperative serum CA 19-9 of less than 180 U/mL. There was hence a subset of ESPAC-4 patients who did not meet the eligibility criteria for mFOLFIRINOX as set by the PRODIGE 24.

The present study was conducted to estimate the overall 5-year survival rates for patients of ESPAC-4 receiving GemCap and gemcitabine, further stratifying survival in either arm according to the status of the surgical margins (R status) and the resected nodes (N status), and also to investigate whether GemCap retained a survival benefit over gemcitabine in PRODIGE 24-ineligible patients.

A total of 732 patients, evenly distributed between both arms, were followed up for a median period of 104 months. Adjuvant GemCap was found to retain its survival advantage over gemcitabine, with a significantly longer median OS of 31.6 months when compared to 28.4 months with gemcitabine alone.

Further subgroup analysis was performed with reference to the resection margins and the nodal status. As a reminder, in the ESPAC-4 trial, 60% of patients were found to have microscopically positive margins (an R1 resection), and 80% were node-positive. The difference in survival was greater in patients undergoing microscopic margin-negative resections (R0) who experienced a median OS of 49.9 months with GemCap when compared to 32.2 months with gemcitabine. Node-negative patients also had a significantly greater 5-year OS rate with GemCap of 59% versus 53% with gemcitabine monotherapy. However, it is important to note that no significant difference in survival outcomes was observed in margin-positive (R1) or node-positive patients in the two arms.

The investigators also evaluated GemCap in the subgroup of 193 patients (comprising 26.4% of the ESPAC-4 cohort) who were not considered to have met the eligibility criteria for PRODIGE 24. The survival benefit of combination therapy was retained in this group, with patients receiving GemCap experiencing a median survival of 25.9 months compared to 20.7 months with adjuvant gemcitabine.

Although cross-trial comparisons have limited validity, good agreement was noted in adverse grade 3 or greater toxicity associated with the control gemcitabine arms of ESPAC-4 and PRODIGE 24, serving as the basis for a qualitative comparison of toxicities between mFOLFIRINOX and GemCap. Neutropenia was more prevalent in the GemCap arm, affecting 40.8% of patients compared to 28.4% with mFOLFIRINOX. However, granulocyte colony-stimulating factor (G-CSF) was administered to 62.2% of patients in PRODIGE 24. Palmar-plantar erythrodysesthesia (PPE) was also more prevalent with GemCap. Patients on mFOLFIRINOX were more likely to observe grade 3 or greater fatigue, diarrhea, nausea and vomiting, sensory peripheral neuropathy, and paresthesias.

The investigators concluded that GemCap was the standard adjuvant treatment for patients with PDAC undergoing an upfront resection who were not feasible for mFOLFIRINOX. Further exploratory analysis revealed that patients under the age of 70 who had undergone a microscopic margin-negative (R0) resection for node-negative PDAC were likely to derive an OS benefit from the addition of capecitabine to gemcitabine in the adjuvant setting. In contrast, mFOLFIRINOX would be more effective than gemcitabine in patients with positive margins (R1) or involved nodes, as per the PRODIGE 24 trial.

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.

Longitudinal Results from the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment Apr 10, 2025

Show notes

Host Dr. Davide Soldato and guests Dr. Jessica Burris discuss the article "Longitudinal Results from the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Programs" and how persistent smoking following cancer diagnosis causes adverse outcomes while smoking cessation can improve survival. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Davide SoldatoHello 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. Jessica Burris. Dr. Burris is an Associate professor of Psychology at the University of Kentucky and co leader of the Cancer Prevention and Control Research Program at the Markey Cancer Center. Her research focuses on smoking cessation among cancer survivors, health disparities, and behavioral interventions to promote health equity. She also leads the BIRDS Lab, which explores the intersection of smoking, social determinants of health, and cancer survivorship. Today I will be discussing with Dr. Burris on the article titled Longitudinal Results from the Nationwide Just Ask Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Program. So, thank you for Speaking with us, Dr. Burris. Dr. Jessica BurrisThank you for inviting me. Dr. Davide SoldatoSo today we'll be discussing an important study on the implementation of smoking assessment in cancer care and specifically through the Just Ask Initiative. So, we know that tobacco use is a critical factor in cancer treatment outcomes in general, and yet integrating systematic smoking assessment into oncology care has faced various challenges. So, Dr. Burris, to start off our interview, I would like to ask you to briefly introduce the Just Ask Initiative for those of our readers and listeners who may not be familiar with it. So, a little bit about the primary goals and why do you think that routine smoking assessment is such an important aspect of cancer care and why the Just Ask Initiative focuses on this specific issue? Dr. Jessica BurrisSure. So, as you mentioned before, smoking is a really critical factor in terms of cancer care and cancer outcomes. It impacts a lot of things, from complications after surgery up into cancer mortality, but it also impacts patient's quality of life. Their pain may be more severe, they're more tired, their distress levels are higher. So, there's just a lot of different reasons why we need to understand and address smoking in the context of cancer care. But like you said too, there's a lot of barriers as well. But in order to effectively treat nicotine dependence and tobacco use, we really need to know who is currently smoking. And so that was really the driver for Just Ask, wanting to make sure that we are asking every person with cancer at their diagnosis and as they go through treatment, what their smoking history is, if they are currently smoking, which we usually consider to be any smoking or other tobacco use in the past 30 days, so that once we can identify that person, then we know who we need to help. Dr. Davide SoldatoThank you very much. That was very clear. And in terms of methodology, Just Ask was really a quality improvement type of initiative that involved the programs that were contacted and approached to participate in this type of initiative. And the methodology is pretty standard for this type of implementation science, which is the Plan Do Study Act methodology. So just a little bit of background on this type of methodology and why do you think it might be so successful when implementing these types of changes at the structural level and when we are implementing these types of programs. Dr. Jessica BurrisRight. So, the American College of Surgeons requires all the accredited cancer programs, both Commission on Cancer and the NAPBC or the ones that focus on breast cancer, to do at least one quality improvement project annually. And most of the programs do use the evidence-based Plan Do Study Act approach. I think it's a great one. It has a lot of evidence behind it, but it also is very practical or pragmatic. So, you're using data from your local healthcare system or clinic or program to inform what it is that you do. And then you're constantly pulling data out to see how well you're addressing the clinical practice change that you're hoping to achieve. And so, data is going in and coming out and you're using that to inform exactly what it is that you're doing over time. So, it's an iterative approach to practice change and again, one that has proven successful time and time again. And so that's the program that these programs and Just Ask used in order to increase the frequency by which they ask patients about smoking. Dr. Davide SoldatoSo as you were saying, the main objective of the initiative was really to understand if we are asking patients diagnosed with cancer and survivors if they are smoking. And how can we better report this information inside of the medical chart of the patient. So, what was the primary endpoint or the objective that you had for this type of intervention? And can you give us a little bit of results? So, what did you find the implementation of this quality improvement? How did it change the percentages of patients that were asked about smoking habits? And a little bit, what is your opinion on the results that you obtain in the study? Dr. Jessica BurrisSure. So, the goal was simple and that was to have an ask rate that was at least 90%. The way that we defined an ask rate is among all newly diagnosed cancer patients, how many were asked about their smoking history and their current status at that initial visit? And so, we wanted all of the participating programs who opted in to Just Ask in 2022 to achieve that 90% ask rate by the end of this one-year quality improvement project. And again, using the Plan Do Study Act approach, it was a very pragmatic study in some ways. So, what we did was we provided an intervention change package that we made available online. And programs could access that whenever they needed to and pull-down educational resources, patient facing materials, practical tools for changing the EHR or pulling data out of the EHR, any of those number of things. And then we also hosted webinars over the course of the year. And those webinars were great because half the time they were in response to questions that programs were asking as they went through the Just Ask QI project. And the other half of time we were really just reminding programs of the rationale and the reason for making sure that they're asking. And then of course, letting them know that they don't have to stop there, they should be advising patients to quit and assisting them with cessation. Even though that wasn't the goal of Just Ask, the goal again of Just Ask was getting that 90% rate. And so, we had over 750 programs who opted in to Just Ask and did this QI study with us, and it was successful. So, we met the goal, or rather the programs met the goal of that 90% ask rate. And that was maintained over time. And that was just fantastic. So again, we know that the end goal is really to assist patients with quitting, but we can't do that unless we know who to help. And so, you have to ask first. And again, they were able to do that. Dr. Davide SoldatoSo thank you very much. The quality improvement program was absolutely successful. And to go a little bit in the numbers, by the end of the one-year implementation of the program, you report a 98% rate of asking patients who first approached the centers or over time if they were or not smokers. So, you said before that you targeted a 90% ask rate in terms of smoking habits. But when looking at the data, I noticed that you already had in the baseline survey where you asked the programs about what were the practice before the implementation of the Just Ask initiative, already something that was quite close to the 90%. And yet, despite starting from such a good point, which was basically your endpoint, you still observed a major change over the years of the implementation. So, I wanted to just underline a little bit what is the value of this type of programs. And still starting from such a very high standard still, we managed to further improve. And as you were saying, this is pivotal and I think it's fundamental to really understand and see who are the patients that we need to refer and then to help in the smoking cessation. So, I just wanted a little bit of a comment on these very important results, despite already starting from a very good background from the centers. Dr. Jessica BurrisYeah, I'm glad that you brought up the baseline. So, I think one thing that's important about this study is that we looked at our ask rate or the asking as a clinical practice in two different ways. So, the 98% that you referred to that we found at the final survey is based on a response to a question on the frequency of asking. So, it's a Likert type question. And essentially what we did was we combined programs that reported usually asking or almost always asking into one, and that's where we arrived at the 98%. And at baseline it was 92%. What's interesting though is that we also asked them to report the specific number of patients who were seen in their cancer program during the prior six months and the number of patients who were asked about smoking in the prior six months. And with that we could get a proportion. And in every case, the self-report Likert question had a higher outcome than the raw data based on the data that was pulled from the EHR. And so, we saw this increase significantly over time, both in the self-report Likert question, but also in the EHR based data. And so, it was a win in two ways. What I think is really interesting though is that at baseline, even though 92% of programs said that they regularly ask about their patient smoking status, 16% of programs could not provide data that would allow calculation of an ask rate. So, they were reporting that they were able to do so but then could not actually do so. So, I think what that means essentially is that there's a disconnect between what programs are doing regularly or they believe that they're doing regularly and what their data actually shows. And it could be an issue with the quality of the data that's going into the EHR, or it could be an issue with pulling the data out of the EHR. And so one of the things that we saw that I think is a second indicator of success of Just Ask is that the quality of the data that programs were inputting into the EHR related to their patients smoking history and smoking status did improve over time, which meant that by the end it really was the case that the vast majority of programs were asking. And not only that, but they were also documenting it in a way to where it could inform patient care. Does that make sense? Dr. Davide SoldatoAbsolutely. And I think that that explanation really is truly important because I think that it also connects a little bit to how the initiative was able also to change things at the structural level, to be sure that there was the best possible way of asking, but also of having that information readily available inside of the EHR. This also connects a little bit to my next question, which was a little bit about organizational structure and also implementation barriers, which you report also as a self-reported information by the specific programs. So, there was a little bit of implementation barriers that was reported by the programs and this was not a specific endpoint of the Just Ask initiative, but you kind of mentioned it a little bit. The difficulties in pulling data from the EHR in understanding whether the information was collected and how it was collected. This might be one of the implementation barrier when we are looking at initiatives like Just Ask. So, I just wanted a little bit of your opinion if you think that these implementational barriers are more on the organizational side or on the provider side. And how can we use these quality improvement programs to really tackle this type of barriers to improve overall the reach and the importance of our action regarding smoking cessation. Dr. Jessica BurrisThe devils in the details, right? So I think it's a "both and" situation and not either or I think for providers, for individual providers, oncologists, nurses, supportive care providers, the issue of feeling like they're not fully trained in tobacco use assessment and treatment, and also feeling because of a lack of training that they don't feel confident or competent or even comfortable having conversations with their patients about their smoking history or being in the position to where they can really help someone who wants to quit in choosing the best path and way forward to do that that really matters. And so organizational readiness, these programs that participated were pretty high even at baseline in terms of the organizational readiness. They understood that it's a problem and they wanted to do something about it. And they were really eager and chomping at the bit to do so. But that has to trickle down to individual providers. And so, I think one of the implementation strategies that was used was staff training and provider education. And a lot of the participating programs chose that strategy. And I think as staff and providers are trained in how to ask and how to do so in a way that is nonjudgmental and that doesn't lean into things like stigma or blame or making patients feel guilty that perhaps their behavior led to their cancer, but really just understanding tobacco history and understanding nicotine dependence and the best strategies that we have to address those things that helped and that made a difference but it also is things at the system level, like having good EHR data, being able to pull those data out at a regular interval every three months or every four months, or even every six months to make sure that you're tracking smoking and also quitting over time. Both of those things need to happen. And I think those were things that we saw change as a result of Just Ask participation. Dr. Davide SoldatoRelating to this, provider readiness also to counsel patients on how to stop smoking or what is the best strategy. Despite, as you said in the very beginning, this was not the objective of Just Ask because you just wanted to improve the rate of smoking assessment and the quality of reporting of smoking assessment. You still observed higher rates of patients and survivors that were actually referred to some kind of intervention for smoking cessation. So, I was just wondering, why do you think that even though that was not required, you still observe this type of improvement? Like, is it just inherent to the fact that we are improving and we are placing more interest and more attention on the fact that patients should quit smoking, or do you think that it relates to something else completely? Dr. Jessica BurrisI think there's probably multiple things going on. One is once you're fully aware of the fact of the impact of smoking after a cancer diagnosis, you're going to be compelled to do something, I think. And so just the simple fact of knowing now that the patient sitting in front of you has smoked in the past week or two, they may be under a lot of stress because they're coping with cancer and they're coping with the side effects of their treatment. They may even have increased their smoking since their cancer diag…

Full show notes at the publisher

JCO Article Insights: Smoking Assessment Mar 31, 2025

Show notes

In this JCO Article Insights episode, Lauren Shih summaries "Longitudinal Results From the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons–Accredited Cancer Programs" by Jessica L. Burris, et al published November 19, 2024.

Come back for the next episode where JCO After Hours host, Dr. Davide Soldato interviews the author of the JCO article discussed, Dr. Jessica Burris.

TRANSCRIPT

Lauren Shih: Hello and welcome to JCO Article Insights. I'm your host Lauren Shih, and today we will be discussing the article, "Longitudinal Results From the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons–Accredited Cancer Programs" by Dr. Jessica Burris and colleagues published in the March issue of JCO. This study reports the finding of the Just ASK Initiative, an effort aimed at improving universal smoking assessment in cancer programs nationwide.

We know that smoking after a cancer diagnosis is associated with numerous negative outcomes including worse survival, increased treatment related complications, poorer quality of life and higher healthcare costs. Patients who smoke are also at increased risk for cancer recurrence and second primary malignancies. Despite these risks, data show that a significant number of patients with newly diagnosed cancer still smoke and around 15% of cancer survivors continue smoking. Recognizing this discrepancy, national oncology organizations strongly recommend routine smoking assessment and cessation support as part of standard cancer care. However, despite these guidelines, smoking assessment and cessation assistance remain inconsistent across oncology practices.

Surveys show that most National Cancer Institute designated cancer centers have insufficient resources to effectively support smoking cessation efforts. To address this gap, several large scale initiatives have been launched, including efforts by the National Cancer Institute, the Canadian Partnership Against Cancer, and the American College of Surgeons. The largest of these initiatives, through the American College of Surgeons, is the subject of our report today.

In 2022, the American College of Surgeons introduced the Just ASK Quality Improvement Program with the goal of increasing routine smoking assessment. As member institutions, accredited programs are required to complete at least one quality improvement program annually. And in 2022, 40% of programs chose to participate in Just ASK. The primary goal of this quality improvement program was to ask at least 90% of newly diagnosed cancer patients about their smoking status. Offering smoking cessation support was encouraged, but not a mandatory component or primary endpoint for the initiative. To implement Just ASK, participating programs used a well-established Plan-Do-Study-Act methodology which is a structured, iterative approach for improving healthcare processes. Programs used local quality improvement teams and resources for implementation and had access to online training, educational webinars, and technical resources to help integrate smoking assessment into routine care.

Programs completed three surveys: a baseline survey reflecting smoking assessment practices in the year before Just ASK; a midpoint survey after six months of participation; and a final survey after one year in the program. The surveys assess program characteristics, barriers to smoking assessment, readiness to change, and the frequency of smoking related clinical practices such as asking about smoking, documenting smoking status, and advising smoking cessation. Programs reported on implementation strategies they adopted to improve smoking assessment. Finally, programs reported the number of newly diagnosed cancer patients they saw, how many were asked about their smoking status and how many were identified as current smokers during each reporting period. Results from 762 participating cancer center programs were analyzed. The programs represented a diverse mix of practice sites with over 50% identified as community based. Retention in the program was high, with nearly 90% of programs completing the final survey. Most programs reported moderate organizational readiness at baseline along with an average of 4.6 implementation barriers to conducting routine smoking assessment. Barriers included factors such as lack of time, competing clinical priorities, and lack of designated tobacco treatment specialists. At baseline, the ask rate was 87.8% and this increased to 91.9% at the final survey, meeting the previously identified goal for the initiative.

Throughout the initiative, programs reported increases over time in assessing smoking status, in advising patients who smoked and quit, and in documenting these assessments and recommendations in the medical record. Importantly, the smoking rate among patients asked ranged from 18.5% to 19.8% across the three surveys, demonstrating a high rate of current smoking among newly diagnosed cancer patients. The most common implementation strategies adopted by programs to promote change included gaining leadership support, improving documentation on the electronic health record, and training staff and providers. There were no major differences in implementation strategies based on program type. Organizational readiness was positively associated with better smoking assessment practices, and implementation barriers had a negative impact, although not always statistically significant. The number of implementation strategies used by programs showed a positive, significant association with smoking assessment practices at the final survey. Exploratory analyses did not suggest that program type or patient volume had a consistent relationship with the outcomes.

Although the primary goal of Just ASK was smoking assessment and not cessation assistance or intervention, programs did report on cessation related practices. For example, programs reported providing education or self-help materials increased from 26% to 48%, referrals to tobacco treatment specialists increased from 25% to 35%, and referrals to quit lines increased from 27% to 45%. Prescribing or recommending FDA approved cessation medications increased from 17% to 21%.

In conclusion, Just ASK is the largest nationwide initiative to standardize and improve smoking assessment in cancer care. It successfully improves smoking assessment across a diverse range of cancer practices, ensuring that hundreds of thousands of newly diagnosed cancer patients were asked about their smoking status. As nearly 20% of the cohort reported smoking, this represents a critical first step in helping patients access smoking cessation resources. Participating programs demonstrated small but sustained practice changes in smoking assessment, meeting the a priori determined goal of a 90% ask rate. However, as a quality improvement initiative, Just ASK was not designed as a clinical trial, so conclusions regarding the efficacy of the program as an intervention are limited. Selection bias may have also played a role in the findings as program participation was voluntary. Additionally, the initiative lasted just one year and while the initial improvements were steady during that time, the long term impacts of Just ASK on smoking assessment remain uncertain.

Looking ahead, the American College of Surgeons recently completed the Beyond ASK initiative. This initiative is designed to go a step further and focuses on improving smoking cessation assistance and we await the results. The Just ASK initiative demonstrates the routine smoking assessment is feasible to complete as routine cancer care. This assessment is essential as identifying patients that smoke is the first and critical step towards offering smoking cessation support, which in turn can improve health outcomes and reduce cancer treatment costs. While Just ASK was a success in increasing assessment, the challenge now is ensuring that smoking cessation support is readily available for all patients who need it.

Thank you for listening to JCO Article Insights. Please give us a rating or review and subscribe so you never miss a JCO 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.

Botensilimab Plus Balstilimab in Advanced Sarcomas Mar 13, 2025

Show notes

Dr. Shannon Westin and her guest, Dr. Breelyn Wilky, discuss the JCO article, ""Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." TRANSCRIPT Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center. Welcome. Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here. Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is "Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." And this was published in the JCO on January 27, 2025. And please note, our participants do not have any conflicts of interest. So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting? Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases. Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together. Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas? Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old 'red devil', like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation. Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for. Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study? Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas. And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help. But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints. Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that. Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors. The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously. Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect? Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our normal cells, our normal organs, leading to essentially any number of toxicities of basically head to toe, something can get inflamed and you can develop a toxicity from that. So the key take homes with this particular drug with, botensilimab with balstilimab, we saw colitis was sort of the primary immune mediated toxicity and it was about a third of patients, give or take. It happens and it can be aggressive and needs to be managed aggressively. And you know, one of the things that we learned very quickly taking part in this study is how important it is that as soon as patients start to get diarrhea, immunosuppression gets on board. So steroids, early use of TNF alpha blockade, so infliximab for example, if we jumped on it quickly and we recognized it and we got the patients treated, it would resolve fairly quickly and even some patients could remain on treatment. So I think that was sort of the first take home is "Okay if you get colitis, you treat it fast, you treat it early and you can still have patients not only recover, which essentially everybody recovered from this colitis and then being able to continue on treatment and still have their anti-tumor responses." So that's the first point. The second thing that was really interesting is part of the engineering of botensilimab on the back end of the molecule, it's been designed to decrease complement binding and it's thought that that triggers some of these other toxicities that we've seen with prior CTLA-4 inhibitors like pneumonitis or hypophysitis. We actually don't see that with botensilimab. So there's sort of this selective toxicity that may reflect the design of the molecule. But overall the treatment was, we didn't see any new safety signals that were outside of what we would expect in class. And colitis was sort of the dominant thing that we had to be ready for and ready to manage. Shannon Westin: We've been doing it for a while now, so we kind of know what to do and we can act quickly and really try to mitigate and avoid some of the major toxicities. So that's great that that was what was reflected in what you found. And then of course I think: What about the efficacy?" Right. This is what we care about as practitioners, as patients. Does it work and are there any subtypes that seem to benefit the most from this combination? Dr. Breelyn Wilky: Right. So for the sarcoma patients, we treated 64 patients and 52 of those patients were evaluable for efficacy. So a decent size group of patients in sarcomas, where, you know, typically our trials are pretty small, they're very rare, but we had 52 evaluable with at least one post baseline scan. So that was our criteria. And basically we saw across all of the patients, and keep in mind, these are heavily pre-treated patients, as you mentioned, so a median of 3 prior lines of therapy, so most of these patients had had chemotherapies and then about 20% had also had prior immunotherapy as well. So PD-1 treatments or so on. The overall response rate by RECIST was 19.2% for all of the evaluable patients. And then with iRECIST, which is sort of that immune adapted response criteria that allows for early pseudo progression, we actually had another patient who did have that. And so that response rate was 21.2%. Overall, we were really excited to see this in a heavily pre-treated group of patients. But what was really exciting to me was when we looked at the subset of patients that had angiosarcoma, that blood vessel tumor I was talking about earlier with my other patient. So angios come in two flavors. One is this sort of cutaneous type, or meaning involving the skin that has a UV signature, a UV damage signature, very similar to melanoma. So these tumors tend to have a high mutation burden. And oftentimes there is a track record that we've seen responses with immunotherapy in cutaneous angiosarcomas. But the other group that we deal with is called visceral angiosarcomas. And so these are totally different biologically. These are often driven by mutations in MYC or KDR amplification, and they arise in organs, so primary breast angiosarcoma, not associated with radiation, or they can arise in the liver or the spleen or an extremity. So these are very, very different tumors, and the visceral ones almost never historically have responded to checkpoint inhibitors. So we had 18 patients with angio split - 9 with cutaneous, 9 with visceral. And we were just blown away because the response rate for that group was 27.8%. And if you looked at the responses between the hot ones and the cold ones, it was almost equal and a little bit better in the visceral. So we had a 33% response rate in visceral angiosarcoma, which is crazy, historically speaking, and about 20% again in the cutaneous angios. So for a disease where visceral angio gets treated with chemotherapy, might respond initially, but then rapidly progresses - like these people go through multiple lines of therapy - to have a third of patients responding, and then some of those responses were durable. Our median duration of response for the study was 21.7 months, which is just nuts for sarcomas where we just don't see those sorts of long term benefits with the drugs that we have. So I think those are kind of the two main things. There were other subtypes that had clinical benefit and responses as well in d-diff liposarcoma, soft tissue leiomyosarcoma, which are again thought to be fairly cold immune subtypes. So just really exciting to kind of see responses we hadn't expected in a very challenging group of tumors. Shannon Westin: We see all these patients and we have patients that respond so well to immunotherapy with other histotypes. And so it's so excit…

Full show notes at the publisher

JCO Article Insights: Long-Term Outcome of Neoadjuvant Chemotherapy for Rectal Cancer Feb 24, 2025

Show notes

In this JCO Article Insights episode, Peter Li summarizes "Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years," by Dr. Jianwei Zhang et al. published on December 13, 2024.

TRANSCRIPT

Peter Li: Hello and welcome to the JCO Article Insights. I'm your host Peter Li and today we will be discussing the Journal of Clinical Oncology article, "Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years," by Dr. Jianwei Zhang et al.

For a reminder to the audience, the FOWARC study is a Chinese-based study that looked into the treatment of locally advanced rectal cancers with neoadjuvant chemotherapy based regimens with or without radiation. This study was first published back in 2019 where the three-year data showed no difference in three-year disease-free survival over survival between the three study arms. As a reminder of what those arms were, there were one historical control and two interventional arms. The control arm used 5-FU with radiation therapy with five cycles of 5-fluorouracil with radiation during cycles two to four followed by surgery and then seven cycles adjuvantly. Their first interventional arm was the same as the control arm with the addition of oxaliplatin on day 1of each cycle. And lastly, the third arm was FOLFOX only for four to six cycles followed by surgery and then six to eight cycles adjuvantly completing about a total of 12 weeks of chemotherapy.

They recruited about 495 patients with 165 patients randomized to each arm. They were relatively well balanced by age, clinical staging and distance from the anal verge. Median age was about mid-50s with a slight male predominance and patients were primarily stage 3 with 20% to 30% being stage 2. About 30% had clinical T4 disease and about 25% had clinical N2 disease. Median follow up time was 122.5 months or 10 years and their follow up endpoints were disease-free survival, overall survival and local recurrence, and they also performed subgroup analyses based on post surgical pathological staging. Survival was analyzed using Kaplan-Meier method with a significant threshold of p being less than 0.05. About 451 patients actually underwent surgery, which is about 91% of patients. The main reason for not going through surgery was due to refusal but one was due to toxicity and two were due to disease progression in the control arm. Follow up loss rate was about 10% in each group. Now looking at their primary endpoints in their initial study, local recurrence was about 8.8% in the control arm versus 7.9% in the FOLFOX radiation group versus 9.2% in the FOLFOX only group. Distant metastasis was about 30% in each arm and the sites of metastases were primarily in the lung and liver.

Now, following up with 10 years, there were only three new events in the chemoradiation group with local recurrence happening at 10.8% in the control arm versus 8% in the FOLFOX RT group versus 9.6% in the chemo only group. These findings were not statistically significant. In their subgroup analysis by pathological staging, they found that pathological CR or complete response had a lower rate of local recurrence compared to those with increasing pathological staging coming in at 3% versus 4.3% versus 11.6% versus 15.8% in pCR versus Stage 1, 2, 3 respectively. And they found no difference in each stage with each interventional arm. Looking at long term survival their 10-year disease free survival showed 52.5% in the 5-FU radiation group versus 62.6% in the FOLFOX RT group versus 60.5% in the chemotherapy only group with no statistically significant difference between three groups. By pathological staging, they found improved 10-year disease survival in those who achieved pathological complete response versus those who did not with 84.3% in the pCR group versus 78.7% versus 56.8% versus 27.7% in the stage 1 versus 2 versus 3 group. And again they found no statistical significance difference between each arm.

Now looking at the 10-year overall survival rates between the three arms, in the control arm the 10-year overall survival was 65.9% versus 72.3% in the FOLFOX RT group versus 73.4% in the chemo only group. By pathological stage, again, they showed a statistically significant difference in those who achieved pCR versus those who had pathological stage 1 to 3 disease with overall survival being 92.4% in those who achieved pCR versus 84.9% versus 68.6% versus 48.8% in stage 1, 2, 3 respectively. Now in the discussion, authors mentioned that with a median follow up of 10 years, FOLFOX alone had similar disease-free survival, local recurrence and distant metastasis and overall survival compared to those who received neoadjuvant chemoradiation, justifying the omission of radiation without compromising results or outcomes for each patient. There were no differences in subgroup analysis for disease free survival local recurrence or overall survival based on pathological staging. There were only three new events compared to the last follow up, with local recurrence happening only in the chemo radiation groups. Local recurrence rates at 10 years was about 10%. Compared to other clinical trials such as CAO, ARO or AIO-94, the rate of local recurrence was similar to those historical trials.

The authors also compared their findings to the PROSPECT study which looks at the use of total neoadjuvant chemo radiation versus chemotherapy alone, which boasted only about a 2% local recurrence rate. But as a reminder, high risk locally advanced rectal cancers were excluded, mainly those with T4 or N2 disease, which may explain the difference in terms of local recurrence in the PROSPECT versus this study. Another finding is that pathological complete responses are also an important prognostic marker with lower 10-year local recurrence rate, disease-free survival and overall survival with worse outcomes with increased pathological staging. Distant metastasis rates were still at 30%, with the most common site being lung then liver then lymph nodes consistent with other historical studies. Chemotherapy seemed to be better at reducing liver mets than lung metastasis per their findings. In their post hoc analysis of their own study, chemo radiation was also associated with higher incidence of low anterior resection syndrome and persistent ostomy compared to chemotherapy alone, meaning that they had better quality of life with the chemotherapy only approach.

In conclusion, a chemotherapy only approach can be safe and a feasible treatment for locally advanced rectal cancer without compromising outcomes. Omission of radiation may reduce the risk of overtreatment and improve quality of life for some of these patients. However, this does not necessarily exclude the role of radiation as it may still play a role in a response escalation approach for those who do not respond to chemotherapy alone.

This wraps up today's episode. 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.

High Omega-3, Low Omega-6 Diet with Fish Oil and Prostate Cancer Feb 13, 2025

Show notes

Host Dr. Shannon Westin and guests Dr. Bill Aronson discuss the article "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial" and how Omega-6 are predominant in the American diet while the study significantly lowered the intake of Omega- 6 fats.

TRANSCRIPT

Dr. Shannon Westin: Hello everyone and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles.

Welcome, Dr. Aronson.

Dr. William Aronson: Thank you, Shannon, and delighted to be here.

Dr. Shannon Westin: We are so excited to have you discussing your manuscript, "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial," which was published in the Journal of Clinical Oncology on December 13, 2024.

So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help.

Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer.

Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population?

Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems.

Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population.

Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease.

For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available.

Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations?

Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive.

Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial?

Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer.

Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint.

Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks.

Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention?

Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group.

Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners?

Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called 'macrophage colony stimulating factor'. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed.

Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get.

It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial?

Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study.

Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps?

Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what we see, this particular diet and how it's affecting the patient's immune system and how that may favorably affect their course of their prostate cancer.

Dr. Shannon Westin: Well, great. Well, thank you so much for taking the time to chat with us about such an important clinical trial, and I really appreciate all the work you're doing and hope to get to see you soon.

Dr. William Aronson: Well, thanks for having me, Shannon. It's really an exciting finding and I think it's something that clinicians and patients are going to be super interested in.

Dr. Shannon Westin: We love straightforward interventions that actually make a difference, so you guys are to be congratulated for that.

And I just want to thank all of you for listening. Thanks again, and I hope you enjoyed this episode of JCO After Hours. Be sure to check out our other podcast offerings wherever you get your podcasts. Have an awesome day.

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.

Dr. Aronson Disclosures:

Stock and Other Ownership Interests Johnson and Johnson

Speakers' Bureau Company name: Janssen Oncology, Bayer, Blue Earth Diagnostics, AstraZeneca, Pfizer/Astellas

Research Funding: Lantheus Medical Imaging

UCLA Health Article Video

JCO Article Insights: TROPION-Lung01 Dato-DXd in NSCLC Jan 27, 2025

Show notes

In this JCO Article Insights episode, Ece Cali summarizes findings from the JCO article, "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study."

TRANSCRIPT

Ece Cali: Hello and welcome to the JCO Article Insights. I'm your host Ece Cali and today we will be discussing the Journal of Clinical Oncology article the "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study."

Despite significant advances in non-small cell lung cancer treatment over the past decades, second line treatment options for non-small cell lung cancer without actionable genomic alterations have remained largely unchanged since 2000. Many clinical trials failed to demonstrate improved overall survival compared to docetaxel based regimens. TROPION-Lung01 is a global open label randomized phase 3 trial comparing the efficacy and safety of Dato-DXd to docetaxel in patients with previously treated advanced or metastatic non-small cell lung cancer. Dato-DXd is an antibody drug conjugate targeting TROP2 and delivering deruxtecan, a DNA topoisomerase 1 inhibitor, as its payload. The trial is designed with dual primary endpoints of progression free survival, as assessed by blinded independent central review, and overall survival. The initial PFS results were presented at ESMO in 2023 and this article reports more detailed data and overall survival analysis of the trial.

In the TROPION-Lung01, 299 patients were randomly assigned to receive Dato-DXd and 305 patients to receive docetaxel. Patients were stratified by the presence of actionable genomic alterations, histology, treatment with PD-1/PD-L1 immunotherapy as the last line of therapy, and geographical region. The baseline characteristics of the patient population were overall balanced between the treatment arms. I'd like to highlight a couple of key points here. The median age was 63 years in the Dato-DXd and 64 years in the docetaxel arm. Similar to the many clinical trials in the thoracic oncology field, this is younger than the median age of lung cancer diagnosis in the US, which is around 70. African American and Hispanic patients were underrepresented in this trial with 41% of patients identifying themselves as white and 39% as Asian. The D\docetaxel arm had a slightly higher percentage of male patients, 69% versus 61%. The majority of the trial population, 73%, had adenocarcinoma. Patients with actionable genomic alterations were included in this trial if they received one or more targeted therapy and platinum based chemotherapy prior to the enrollment. 17% of the trial population had an actionable genomic alteration in this trial.

When it comes to the efficacy results in the full analysis set, the PFS improvement was statistically significant. The median PFS was reported as 4.4 months for the Dato-DXd, and 3.7 months for the docetaxel arm with the hazard ratio of 0.75 and a P value of 0.004. However, after a median follow up of 23 months, the trial did not meet its primary endpoint of overall survival. The median overall survival was 12.9 months for patients treated with Dato-DXd and 11.8 months for patients treated with docetaxel with the hazard ratio of 0.94 and a P value of 0.53. Objective response was a secondary endpoint and the confirmed objective response rate was 26% with Dato-DXd, and 13% with docetaxel.

Now let's take a closer look at some of the subgroup analyses. Exploratory analyses of key subgroups in TROPION-Lung01 demonstrated differences in efficacy based on histology. In the nonsquamous subgroup, Dato-DXd showed a longer progression free survival of 5.5 months compared to 3.6 months with docetaxel with a hazard ratio of 0.84. However, in the squamous subgroup, Dato-DXd performed worse with a progression free survival of 2.8 months compared to 3.9 months with docetaxel corresponding to a hazard ratio of 1.32. A similar trend was observed in the overall survival analyses, though confidence intervals crossed 1 in both histology subsets, in this case, the differences observed were not statistically significant. In the nonsquamous subset, the median overall survival was 14.6 months with Dato-DXd and 12.3 months with docetaxel with a hazard ratio of 0.84. In the squamous subset, both arms had shorter survival compared to the nonsquamous subset. The median overall survival with Dato-DXd was almost two months shorter, so 7.6 months, compared to 9.6 months with docetaxel corresponding to a hazard ratio of 1.32. While these analyses suggest the potential survival benefit for Dato-DXd in nonsquamous subset, this trial was not powered to test this hypothesis hence these analyses remain exploratory. Another subgroup analysis of note was the group with actionable genomic alterations. Patients with actionable genomic alterations achieved a median PFS of 5.7 months with Dato-DXD and 2.6 months with docetaxel corresponding to a hazard ratio of 0.35. Similarly, the median overall survival was longer in patients with actionable genomic alterations by almost six months, with a median overall survival of 15.6 months with Dato-DXd and 9.8 months with docetaxel corresponding to a hazard ratio of 0.65.

Now, let's talk about safety. Grade 3 or higher treatment related adverse events occurred in 26% of patients with Dato-DXd and 42% with docetaxel. The most common adverse event of any grade seen in the Dato-DXd arm were stomatitis seen in 47% of patients, nausea in 34%, and alopecia in 32%. Treatment related interstitial lung disease occurred in 8.8% of patients on Dato-DXd and 4.1% of patients on docetaxel. Of note, grade 5 drug related ILD was more frequent with Dato-DXd. Seven patients on Dato-DXd and one patient on docetaxel died secondary to drug related ILD in this trial.

In summary, TROPION-Lung01 aims to address an unmet need for patients with previously treated non-small cell lung cancer. For this population, the treatment options remain limited with poor survival outcomes. TROPION-Lung01 is a positive trial by design due to clinically modest improvement in PFS. However, the lack of overall survival improvement is disappointing. Exploratory subgroup analyses suggest Dato-DXd may offer survival advantage in specific subsets such as nonsquamous non-small cell lung cancer and patients with actionable genomic alterations. However, these findings require further validation in a prospective trial since TROPION-Lung01 was not designed to address these questions. The data from this trial alone is not sufficient to argue for a change in clinical practice. However, it informs how the future trials using this drug should be tailored. This highlights the importance of studying potential predictive biomarkers earlier in the drug development and incorporating these biomarkers prospectively into the clinical trial designs.

Due to the lack of overall survival benefit in this trial, the biologic license application for accelerated approval of Dato-DXd for patients with previously treated nonsquamous non-small cell lung cancer was voluntarily withdrawn. New BLA was submitted for Dato-DXd for patients with previously treated advanced EGFR positive non-small cell lung cancer. This BLA is based on data from TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01. Of note, the results of TROPION-Lung05 trial have been just published in JCO.

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.

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