Journal of Clinical Oncology (JCO) Podcast

• Pembrolizumab and Bevacizumab for Melanoma Brain Metastases

  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 collected a series of biomarkers, both circulating ones, but also some that were collected actually from the tissue. So just wondering if you could explain a little bit which type of biomarkers you evaluated and whether you saw any significant results that could suggest higher or lower efficacy of the combination. Dr. Harriet Kluger Thank you for that. So yes, the biomarker studies are fairly exploratory, and I want to emphasize that we don't have anything that's remotely useful in clinical practice at this juncture. But we did see an association between vessel density in the tumors and improved response to this regimen. So possibly those lesions that are more vascular are more fed by or driven by VEGF, and that could be the reason that there was improved response. We also saw that when there was less of an increase in circulating angiopoietin-2 levels, patients were more likely to respond. Whether or not that pans out in larger cohorts of patients remains to be determined. Dr. Davide Soldato Still, do you envision validation of these biomarkers in a potentially additional trial that will evaluate, again, the combination? Because I think that the signals were quite interesting, and they really make sense from a biological point of view, considering the mechanism of action of bevacizumab. So I think that, yeah, you're right, they are exploratory. But still, I think that there is very strong biological rationale. So really I wanted to congratulate you on including that specific part and on reporting it. And so the question is, really, do you envision validation of these biomarkers in larger cohorts? Dr. Harriet Kluger I would hope to see that, just as I'd like to see validation of the clinical results as well. The circulating biomarkers are very easy to do. It's a simple ELISA test. And the vessel density on the tumor is essentially CD34 staining and units per area of tumor. Also very simple to do. So I'd love to see that happen. Dr. Davide Soldato Do you think that considering the quality of the MRI that we are using right now, it would be possible to completely bypass even the evaluation on the tissue? Like, are we going in a direction where we can, at a certain point, say the amount of vessels that we see in these metastases is higher versus lower just based on MRI results? Dr. Harriet Kluger You gave me an outstanding idea for a follow-up study. I don't know whether you can measure the intensity of gadolinium as a surrogate, but certainly something worth asking our neuroradiology colleagues. Excellent idea. Thank you. Dr. Davide Soldato You're welcome. So just moving a step further, we spoke a lot about the validation of these results and the combination. And just wanted your idea on what do you think it would be more interesting to do: if designing a clinical trial that really compares pembrolizumab/bevacizumab with ipilimumab and nivolumab or going directly for the triplet. So we know that there has been some type of exploration of triplet combination in metastatic melanoma. So just your clinical impression: What would you do as an investigator? Dr. Harriet Kluger So it's under some discussion, actually. It's very difficult to compare drugs from different companies in an investigator-initiated trial. Perhaps our European colleagues can do that trial for us. In the United States, it's much harder, but it can be done through the cooperative groups, and we are actually having some discussions about that. I don't have the answer for you. It would be lovely to have a trial that compared the three drugs to ipi/nivo and to pembrolizumab/bevacizumab. So a three-arm trial. But remember, these are frontline melanoma patients. There aren't that many of them anymore like there used to be. So accrual will be hard, and we have to be practical. Dr. Davide Soldato Yeah, you're right. And in the discussion of the manuscript, you actually mentioned some other trials that are ongoing, especially one that is investigating the combination of pembro and lenvatinib, another one that is investigating the combination of nivolumab and relatlimab. So just wondering, do you think that the molecule in terms of VEGF inhibition, so bevacizumab versus lenvatinib, can really make a difference or is going to be just a mechanism of action? Of course, we don't have the results from this trial but just wondering if you could give us a general comment or your opinion on the topic. Dr. Harriet Kluger So that's a really great question. The trial of pembrolizumab and lenvatinib was our answer to the fact that bevacizumab is not manufactured by the same company as pembrolizumab, and we’re trying to give a practical answer to our next study that might enable us to take this approach further. But it does turn out from our preclinical studies that bevacizumab and VEGF receptor inhibition aren't actually the same thing in terms of the effects on the blood-brain barrier or the perilesional tumor microenvironment in the brain. And these studies were done in mice and in in vitro models. Very different effects. The lenvatinib has stronger effect on the tumors themselves, the tumor cells themselves, than the bevacizumab, which has no effect whatsoever. But the lenvatinib doesn't appear to tighten up that blood-brain barrier. Dr. Davide Soldato Thank you. I think that's very interesting, and I think it's going to be interesting to see also results of these trials to actually improve and give more options to our patients in terms of different mechanism of action, different side effects. Because in the end, one thing that we discussed is that some combination may be useful in some specific clinical situation while others cannot be applicable, like, for example, an all immunotherapy-based combination. Just one final comment, because I think that we focused a lot on the intracranial response and progression-free survival. You briefly mentioned this but just wanted to reinforce the concept. Did you see any differences in terms of intracranial versus extracranial response for those patients who also had extracranial disease with the combination of pembro and bevacizumab? Dr. Harriet Kluger So the responses were almost always concordant. There were a couple of cases that might have had a body response and not an intracranial response and vice-versa, but the vast majority had concordant response or progression. We do believe that it's a biological phenomenon. The type of tumor that tends to go to the brain is going to be the type of tumor that will respond to whatever the regimen is that we're giving. In the previous trial also, we saw concordance of responses in the body and the brain. Dr. Davide Soldato Thank you very much. Just to highlight that really the combination is worth pursuing considering that there was not so much discordant responses, and the results, even in a phase 2 trial, were very, very promising. So thank you again, Dr. Kluger, for joining us today and giving us a little bit of insight into this very interesting trial. Dr. Harriet Kluger Thank you for having me. Dr. Davide Soldato So we appreciate you sharing more on your JCO article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases," which gave us the opportunity to discuss current treatment landscape in metastatic melanoma and future direction in research for melanoma brain metastasis. If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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  23:59
• JCO Article Insights: ESPAC4 Long-Term Follow-Up in Pancreatic Cancer

  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.   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.

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  6:47
• Longitudinal Results from the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment

  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 diagnosis. And now you have this information. I think people who are providing cancer care, they want to improve the health and the life of the person sitting in front of them. And if they understand that smoking is a detriment or a hurdle to their doing so, then they're also more inclined to try and help that person quit smoking. And so, I think the asking and the documenting likely led to an increase in assistance and referrals to tobacco treatment specialists or to a state quit line, which was also common, simply because that's part of providing quality care. I think also there's been a greater emphasis nationally, in part led by the National Cancer Institute and a cancer moonshot initiative that it led, they're really focused on getting more treatment to more patients with smoking and increasing the reach and the effectiveness of the treatments that we provide. And so, I think there has been a shift in oncology care broadly to put more attention on smoking and smoking cessation as part of standard cancer care. And so, I think this kind of shift in the field also informed things as well as, again, thinking about the patient and the individual who's in the room and wanting to do something about the problem that you've just identified. Dr. Davide SoldatoAnd one thing that I believe is truly exceptional about the Just Ask initiative is really also the diversity of the type of programs that you involved. Like, you went from community centers to more academic centers. And really, I did not have the impression reading the manuscript that there was any difference in the way this type of quality improvement initiative can really benefit all these programs and all these centers. So, I was just wanting to have your opinion or comment on how do you think this type of initiative could be transferable across the country and across different settings and different types of cancer care? Dr. Jessica BurrisYeah, I'm really glad that you brought that up, because I think most of the clinical trials that are done in this area are done at academic medical centers, which are admittedly kind of resource rich places to receive cancer care. And so, what works in academic medical center may not work in a small rural practice in the middle of Kansas, for example, or in Mississippi. And it may not work in other community-based practices, even if they're larger and set in an urban setting. And so, one of the things that frankly I loved about Just Ask is that it was very heterogeneous in terms of the sites and the participating groups. And so not only was it national and by far the largest initiative in this area, again with over 750 different programs, but the programs were diverse. So, we had large community-based programs, integrated networks, smaller community programs. And then the academic centers were actually the smallest. Only like 10 or 12 out of the 750 plus were academic. And so, it was very different than what is the norm in this research area and in this area generally in terms of clinical practice. And we were able to show that the type of program that participated had no bearing on their success. And so, when we think about initiatives that work and interventions that work, we also really have to think about what is scalable and what could be disseminated across different practices. And this is one of those things that can. It worked and it worked across different swaths of group, which was great. Dr. Davide SoldatoAbsolutely. And just one last comment about the intervention, and it's also a point that you raised in the manuscript. This initiative, like many others also at the national levels that have been reported previously, they rarely had really the participation or the perspective of the patients embodied inside of them. So, I was wondering, how do you see the field moving forward. Like you envision something that would implement sort of a co-creation with patients or cancer survivors in order to really create something that is more appealing and takes more into consideration what is the patient perspectives when we are approaching something like smoking cessation, which as you were mentioning before, it can have a lot of stigma or already some negative feelings by the patients and feelings of guilt regarding the fact that they smoked and that might have caused that cancer. So just a little bit of your opinion as to how you see the implementation science in smoking cessation moving forward while integrating also the patient perspectives. Dr. Jessica BurrisYeah, that's a great question. So, this is something that I've thought about a lot in my lab and at Market Cancer center, which I'll use as an example. But oftentimes what we see is that even when tobacco treatment is offered as part of standard cancer care, even when we try to remove barriers like the financial cost of treatment at Markey, we embed it within our psych oncology program. And so, all of those services are offered for free. The rate at which patients say, yes, they want to engage in treatment is much, much lower than what we would want. And so that means two things. One, we need to offer help repeatedly to patients and understand that their willingness to quit and their willingness to accept treatment likely would change over time. And so, we need to keep coming back to people. It's not a one and done situation. But then also we need to understand what the barriers are from a patient's perspective. So why are they saying no? That they're either not ready or that they don't want treatment. They want to, quote, unquote, go it alone. And oftentimes what we hear is that patients want to be able to do this by themselves. They want to feel like, I quit smoking and I did it all by myself. And this is this huge thing that I've overcome. Not too different from the perspective that a lot of patients have about fighting cancer. They want to fight this addiction, this dependence that they've had oftentimes for multiple decades. And so, I think one thing that might be beneficial is to think about having peer led tobacco treatment. So have a patient who was able to quit successfully and have them provide counseling alongside a trained provider so that patients see someone like them who's went through it in the context of cancer care and who was able to overcome and to fight and win against tobacco, essentially. I think the other thing is trying to make sure that when we're asking about smoking and when we're offering treatment that we are not accidentally harming patients by bringing up feelings of stigma or guilt or shame. And I think one way to make sure we don't do that is to really lean on clinicians who are trained in addressing social determinants of health and other supportive care. So, our social workers, I think would be great. They're oftentimes embedded within oncology care. They are surely able to be trained as tobacco treatment specialists. They're already working with patients; they're addressing other barriers to care. They're sensitive in how they ask questions oftentimes. And so, they're really an ideal partner for this work. And we have found in a lot of settings that social workers are great in terms of being tobacco treatment specialists, including what we saw in Just Ask. Dr. Davide SoldatoThank you very much. That was really very, very interesting. And so, last question, moving forward, we improved the rate of asking patients. We are able to document this addiction more clearly in the EHR. So how do you see the field moving forward? In the manuscript, you speak a little bit about the Beyond Ask initiative. So just a little bit of a background about what is this initiative, what you are planning to do, and what do you think would be the best way to really act on this information that we are starting to collect in a better way and more frequently. Dr. Jessica BurrisYeah. So Beyond Ask really took everything that we did in Just Ask and amplified it. So instead of focusing on asking, we really said to make a difference and to improve cancer outcomes, ultimately patients need to be able to quit smoking. It's not enough that we know who is smoking, but that we help that individual or those groups of people quit. And so Beyond Ask had the goal to increase cessation assistance. So, either prescribing medication to help with smoking cessation, referring to a quit line, or another evidence-based program, or personally providing cessation counseling on site at that cancer program and to try and improve again within assistance. It was another one-year study, but we increased the frequency of surveys. I think we ended up with five total surveys. So, we were capturing two to three months at a time instead of a six-month period. And the data that we were capturing was very similar to what we did in Just Ask. And I can say we're still doing the data analysis, but it was another major success. So, with Beyond Ask, we had about 350 participating programs, many of whom not all, but many did participate in Just Ask. So, I think Just Ask kind of energized people around addressing the issue of smoking in their patient population. And again, they were really chomping at the bit to do more. And so, we offered Beyond Ask just after Just Ask. So Just Ask was 2022. Beyond ask was 2023. It ended in the spring of 2024. And again, another success. Dr. Davide SoldatoThank you very much. So, we are eager to see the results of this study. So that leads us to the end of this interview. So, thank you again, Dr. Burris for joining us today and speaking about your work. Dr. Jessica BurrisThank you. Dr. Davide SoldatoSo we appreciate you sharing more on the JCO article titled Longitudinal Results from the Nationwide Just Ask Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Program. If you enjoy our show, please leave us a rating and a review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcast. 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.  

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  26:50
• JCO Article Insights: Smoking Assessment

   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.  

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  8:35
• Botensilimab Plus Balstilimab in Advanced Sarcomas

  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 exciting to see an option for these really hard to treat tumors that our patients struggle with. So this is so, so very exciting. I wanted to make mention, you know, I was really impressed with the amount of translational work you were able to do in this early phase study. So do you want to review just maybe a few of the key findings that you guys discovered? Dr. Breelyn Wilky: It's always great. I'm a translational researcher at heart and we do a lot of immune correlative work. And I think the reason I got so excited about this field to begin with was trying to learn why it works for some patients and why it doesn't work for other patients. So I'm a huge believer in learning from every patient that we can. So it's such a testament to the company, Agenus, who sponsored this trial to invest their time and resources into correlative studies at this phase. It's huge. So we learned a couple of things. IL-6 or interleukin 6 is a cytokine that basically has, in other tumor types, been associated with worse outcomes. And what we were interested in this group is we saw the same thing. And again, sarcomas have very, very little correlative biology that's done. We're really in infancy and understanding the microenvironment and how that milieu balances out in our tumors. So we were really excited to see again that lower peripheral interleukin 6 associated with improved overall survival. So again, kind of sorting out a group of patients that might be immunologically favorable when it comes to this type of therapy. The other thing that's important to know about sarcoma is so the other tumor types are lucky and have PD-L1 expression and the tumor is a biomarker, but we never have PD-L1 expression. We can find it in sarcomas and it can be loosely correlated with a chance of benefit with immunotherapy. But I've had patients respond that were PD-L1 negative, and I've had patients that were loaded with PD-L1 that didn't seem to make a difference. And that's not just in this study. So we saw in this trial a trend towards improved overall survival with PD-L1 expression that wasn't significant, but there was like this trend. And it's really interesting because, again, this is largely a CTLA-4 directed therapy. And so what we wondered is if PD-L1 expression is an index of sort of this underlying potential immunogenicity. And actually PD-1 works very late in the whole immune process. That's really at the very end where you've got the T cell that's facing the tumor cell and it's just activating that T cell that's already grown up and already educated and ready to go. Whereas CTLA-4 is really educating in early immune responses and expanding the T cells that have potential to kill. So I'm interested to look into this in more depth in the future to see if this is actually the biomarker for CTLA-4 directed therapy that we've been looking for, because we really don't have a great sense about that. And then the last piece just to note is that in this trial, like most others, very, very few sarcomas had high mutational burden. Everybody was very low, which reflects the population. And it's just really more encouragement than an immune cold tumor with very crappy neoantigens can still respond to immunotherapy if we get them the right agents. Shannon Westin: Yeah, I mean, I'm taking notes because we have such a struggle with this across the gynecologic tumors. I'm like, “Okay, maybe this is finally it.” So hopefully your work will go on to really inspire us across a number of solid tumors that have been traditionally cold. So, so very exciting. And I would just say for my last question, obviously, congratulations on this successful study. What do you think are the next steps for this combination in sarcomas? Dr. Breelyn Wilky: So, again, just to your point, this trial enrolled a bunch of different subtypes, and sarcomas are not the only immune cold tumor that this combo has looked really promising for, microsatellite stable colorectal cancer, ovarian cancer that was platinum refractory, non-small cell lungs. So I think the future is really bright for immune cold tumors kind of across the board. So, yes, lots of hope for not just sarcomas but in terms of our patients, I just have to be so grateful to Agenus for their interest in a rare disease. Sometimes it's hard to get that interest for a very challenging group of patients that are all heterogeneous, they are not all the same and our big clinical trials are a few hundred patients. It's just a very different environment. But they have been so supportive and involved in making sure that sarcomas are represented in their priorities. So there are ongoing discussions about what the optimal way to explore this further in sarcomas is going to be and I cannot wait to have the official plans in place. But my hope is this will not be the last that we see of these drugs for our patients. Shannon Westin: Well, I support that and my vote is on your side. So, thank you so much again, Dr. Wilky. This time just flew by. This was such a great discussion and I mean, I think it's, again, a testament to your exciting data. And thank you to all of our listeners. This has been JCO After Hours’ discussion of “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas,” published in the JCO on January 27, 2025. So be sure to check out the full manuscript. And we hope that you enjoyed this podcast. And if you want to hear more about research published in the JCO, check this out on our ASCO JCO website or 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. 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. Dr. Wilky Disclosures  Consulting or Advisory Role: SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx Research Funding: Exelixis Travel, Accommodations, Expenses: Agenus    

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