GI ASCO 2024 Highlights with Dr. Pamela Kunz – CheckMate 8HW, EMERALD-1, NETTER-2

Welcome to GI ASCO 2024 Highlights Hello everyone I am Rahul Ghosain. Speaker 2 And I'm Rohit Ghosain. Speaker 1 And we are the oncology brothers, while another GI ASCO in the books, there's so much happening all around us in oncology with each of these meetings. In less than 8 weeks, we've covered data from breast cancer from San Antonio Breast Cancer Symposium then from ASH 2023. Today we are here covering GI ASCO 2024 and then next week we're off to Gu ASCO. There's so much to learn and appreciate here. For GI ASCO 2024, we're joined by none other than Doctor Pamela Koons, A prominent leader in the field of GI medical oncology from Yoel Cancer Center. In our discussion with Doctor Koons, we hope to focus on the role of immunotherapy and MSI high colon cancer, then focus on HCC. We will also talk about CTDNA. And yes, of course if we have her, we'll touch on neuro endocrine tumor with better too and how these studies will impact our day-to-day practice. Pam, thank you so much for joining us. Speaker 3 Thank you for having me. Speaker 2 Pam, welcome. CheckMate 8HW: Dual Immunotherapy for MSI-H Colorectal Cancer So the first study that we're diving here is Checkmate 8H W This study had three arms, particularly focusing on Ms. high high colon cancer patients. We do know that pembrolizumab has been approved as a blanket approval in this space. The particular primary endpoint here was PFS and secondary endpoints being oral survival, safety profile and oral response rate. It had three arms where patients who were randomized to 2:00 to 2:00 to 1:00 where the first arm was nivolumab by itself and then the second arm being NEVO, IPI followed by NEVO maintenance and the third the investigator choice chemotherapy. Your thoughts here in terms of the results and particularly the application of this in our clinic setting, especially when we have pembrolizumab approved in the setting? Speaker 3 Yes, No, I think that this is sort of an exciting and potentially practice changing study out. Reminder our listeners that this is a sort of interim preliminary analysis in the sense that it really is only showing us the results of one of the primary endpoints. So comparing Omnivo iffy versus the investigator choice chemotherapy clearly showing a benefit as we can see with the separation of these two curves. And as you already said, we have an indication for single agent checkpoint inhibitors in the setting what where this adds to the literature and to potentially our practice is dual checkpoint inhibitor. So this is I think will be an option for our patients of using Ippy nivo in this setting. Where I'm really interested is to see the data of that other primary endpoint where we're comparing Ippy nivo versus nivo. I think we always should question whether more is better and both in terms of efficacy and in terms of the side effects, how you know, I'll, I'll also remind our listeners that really only about 5% of patients with metastatic colorectal cancer are you know MSI high or deficient MMR. So this is really a minority of patients that we'll see in practice. But I think that this is really important. This represents an option, but I think we need to see the data for this other primary analysis. Pete. Speaker 1 And thank you for covering that. Though a minority MSI hybrid checkpoint inhibitors has been a success story. A few things that Roy, I want to emphasize here that it be those used in the study was 1 milligram per kilogram. The most of the recent studies outside Melanoma have been using this dose. And then second, there is a subset of a patient population that have MSI high but also have B RAF V 600 E mutation. Even with this Co mutation, immunotherapy is still an active option. And then we're talking about adding two immunotherapies together versus pembro and neva alone when we're doing that, this is coming at a cost of a higher toxicity. So those are the things that we really have to keep in mind. EMERALD-1: TACE with Durvalumab for Hepatocellular Carcinoma So in 2020, but TZO Bev was approved for unresectable locally advanced or metastatic HCC. But when it comes to the disease that is still confined to deliver, we do rely on liver directed treatments such as SBRT or Y-90. This brings us to Emerald One where we are combining local treatment and systemic treatment tased with dervalumab and bevacizumab with primary endpoint being PFS. Pam, your thoughts on the study design and its findings? Speaker 3 So I think you gave a great intro. I think that you know certainly the use of liver directed therapies for liver confined HCC is really critical. However, we've seen this explosion of systemic therapies for the use of HCC over the last few years that have really been practice changing. I think that as you said this is a three arm study looking at durvalumab plus TAS followed by durvalamab, durvalamab plus taste followed by durva Bev and then placebo plus taste. And so I think that an arm that's potentially missing is a systemic therapy only arm because I think that the question is really you know how are we changing the paradigm here. I think certainly the punchline is that Durva Bev and taste is really has in in comparison to taste itself as a prolonged median progression free survival. I think this will certainly represent an option. I'm not sure if how practice changing this is in talking with, you know this was sort of a a conversation amongst a lot of us at at GI ASCO again we'll represent an option. There are a number of ongoing studies that are looking at both the combination of systemic therapy and taste or even this question of systemic therapy versus taste. Taste won't go away as an option for patients in this space. But I think my real question is you know whether we need to do the combination or whether it's an either or. But I'd welcome your guys thoughts on this too. Speaker 2 No, I agree. Especially when we rely on localized control with TASE SPRTY 90 where SPRT and Y-90 are certainly superior. The question becomes is that whenever we involve bevacizumab in any of these regimens and rely on PFS, that becomes very questionable because from being a VEGF it definitely helps to make the scans look better. But the important thing is, does it translate to survival data. And important thing here is that this was unresectable disease. And to your point, definitely want to stress that the arm that is missing in an unresectable or non curative setting is can we use systemic therapy completely And that would truly be the comparison here. Speaker 3 Yes, I I totally agree and I think your point about the selection of primary endpoint is a really important one also and whether PFS can really translate effectively as a surrogate to OS in this population. So I think you know there are again a number of ongoing studies that will have systemic therapy versus taste. So stay tuned for that. But I think you know this represents a possibility for the right patient and certainly adds to the body of literature. Speaker 1 I'm actually going to push a little more to Rohit, what you mentioned. I think taste is a good option, but a lot of us use SBRT or Y-90. To me, I'm still not convinced unless I see overall survival benefit. I anticipate using SBRTY 90 and then sequentially coming to our systemic options. It's all going to come down to multi ID approach. Yes I can say this because I am in the community but I'm affiliated with the university settings and I have access to that Multi ID settings in rural community settings where you might not then sure you want to do everything upfront but as of now I think relying on Y-90 or SBRT over taste might be my preference. NETTER-2: PRRT in First-Line Neuroendocrine Tumors Our other important study, we saw exciting data from Neuroendocrine tumor world in ESMO 2023 with exciting data from cabozantinib now PRRT in earlier lines which we were expecting was going to happen but glad it is happening. Now. Oxratide which has been approved as a first treatment for well differentiated neuroendocrine tumor for decades, significant PFS benefit PRRT versus oxratide in Natter 2. This is convincing your thoughts here. Speaker 3 Thank you. I'm so glad my favorite tumor type that you included so well. I guess I'm not really allowed to have favorites, but but happy to try to translate this. So yes, I think to your point, this is the first study actually first solid tumor study looking at radioligand therapy in the first line setting for any solid tumor. I'll remind our our listeners that Pluvicto or Latitian PSMA is available for treating metastatic prostate cancer. Latitian Dotatate is now available really second line and beyond or grade one and two gastroenteropancreatic Nets. So this study was really looking at it in the first line setting. I'll also just in terms of calling out the eligibility, looking at it in a slightly higher grade tumor population, so Ki 6710 to 55%. This was a positive study. I will also call out since we spent a bit of time talking about endpoints. PFS is actually the preferred primary endpoint for neuroendocrine tumors compared to many other solid tumors. Given the indolent nature of the disease, it would be a impractical to do an OS endpoint in this disease, but patients also go on to get many subsequent therapies which sort of muddies the OS endpoint. So, so clear so positive study on the basis of the PFS. The other interesting thing is that the response rate was about 40% which is also we really need more therapies that yield tumor shrinkage. What we have not seen is these data broken down by primary site. This included pancreas, small intestine and some unknown primaries. So I think those data will be interesting to see. Now the real question is how does this like change our practice? I think that this will be you know available as a first line treatment. I'm not sure that every patient needs to get this as a first line treatment and I think that there are definitely still patients for whom somatostatin analogue either octreotide or Lanreatide makes sense. Those patients would be patients with lower volume disease, asymptomatic, perhaps the really low Ki 67, perhaps patients with higher KS 67 bulky disease, those who need objective tumor shrinkage, you might consider this. So I think it's a really important study and I mean and I the disclaimer is I certainly participated in this, but I think the take away is that there's still a number of first sign options. This may not be the right first sign option and then I'd love to hear your guys input. I think this is also not widely available in the community. So it's really thinking about how we partner with community oncologists and how we sort of think through that element. Speaker 1 Yeah. Ben, thank you so much. First to cover this and bringing that in light that this is not readily available in all community settings and we keep bringing this up because most of our patients today are getting treated in community settings. This is our chance to partner up with the centers to make this available even in first line if it's the right patient or in the later lines. Because there is the significant PFS benefit that we're hoping will translate in OS at least in my practice even when I was in the rural settings, often with neuroendocrine tumor. As we get them started on treatment, we'll have them reach out to a tertiary coronary center that can at least provide this and these patients can be on their radar. Speaker 2 But again in rural setting where I'm working though we are tied up with a bigger centers UPMC but again some patients are unwilling to travel out to these settings. So the choice becomes is relying on systemic option itself. So that's always a conversation, but again, hopefully we can convince the population, especially when the data is so convincing. Speaker 1 And that's where hopefully cabozantinib can also help. We'll see. CTDNA: Prognostic and Predictive Biomarker in Oncology OK, now on to another hot topic before we close. Circulating tumor DN A/C TDNA has been not only for GI malignancy but literally for every cancer. Pam from the annual ASCO 2022 where we first saw the glimpse of CTDNA dictating how we can use this in our clinical practice for early stage colon cancer. Now to bespoke update of Galaxy dynamic trial, can you please share what are you doing with all this information today for your patients outside clinical trial? Speaker 3 So I think this there are a few key takeaways. I think one, this is a rapidly evolving space and so I think there are a number of different assays that are available. I'll remind our listeners that there are really two forms of circulating tumor DNA. There is the tumor informed which is really based on kind of tumor somatic profiling then building a circulating tumor DNA profile off that. And then there is tumor agnostic which is plasma based entirely. And I think that key takeaways from these two studies, Galaxy and Bespoke in addition to some others for that circulating tumor DNA is one of our best prognostic biomarkers. Certainly the presence of circulating tumor DNA demonstrates worse survival than if you did not have circulating tumor DNA. So that's the prognostic element. I think that we are starting to see emerging DNA that it emerging data that it is also predictive indicating that treating with so for example treating with adjuvant therapy in the stage two and or three settings that we are starting to see that there is a predictive element of circulating tumor DNA. But I think a key take away that I heard from sort of the presenters and these studies and discussants and colleagues is that we're not quite ready to de escalate therapy on the presence of sort of a negative circulating tumor DNA. However, if you have a positive circulating tumor DNA, there is, I think people are feeling more comfortable using that to escalate therapy, perhaps adding adjuvant. So I will call out really excellent presentation for those who would like a summary on this. Doctor Aparna Parikh did a like beautiful summary as a discussant on some of these and I learned a lot from that and I think that it was a really nice take away just on some of the basics as well. Speaker 2 Thanks so much for a. Speaker 3 Comment Happy to hear? Yeah, happy to hear what you how you guys are using it too. Speaker 2 Right. We certainly utilize exactly the similar way that you stated, but the only question that we run into sometimes is that when the patient is not on actually any treatment now we are doing the circulating tumor DNA. The first one in the post resection is negative on serial follow-ups. First of all, are you serially following them versus? If you do and this turns positive, And in those settings when the scans are negative? That's always a difficult situation. Speaker 3 That is I think really challenging and I think that using this as a surveillance tool, I think we just we don't, I think a lot of people are doing it. I think we don't know and I will full admission. I don't see a lot of these patients in my practice right now because I'm focusing on neuroendocrine tumors. So you guys may have more real world practice in this than I do, but I think that we need more data and there are so many clinical trials in this space looking at surveillance. I think some of the data and I think maybe I'll mention a couple points that were brought up in these presentations is that the use of surveillance does actually help increase our sensitivity of this test. And so we're learning more how to use this and what that means. I'd like to call out and I think this was from the bespoke study by Doctor Cassie. One thing I really liked in his study was the patient questionnaires and how patients really thought about the use of circulating tumor DNA. I think that what he demonstrated is that patients actually appreciated having more information and that this was not a negative in terms of quality of life or in terms of serving as a stressor. That was really I surprising to me actually. But I think if you think about it, just arming ourselves with more information is better. We all know that the uncertainty of a cancer diagnosis is incredibly stressful. So I think that this is an important element to incorporate into these other clinical trials, but back to you. Speaker 1 Guys, absolutely. As if now at least I have not used this serially, I'll use it to dictate in low risk if the patient's going to get adjuvant chemotherapy or not. And then I've relied more so on the scans and the tumor markers. But I do think this is a tool that we need to keep in our back pocket and just wait for more data so that we can deploy this in the right way for most of our patients. Speaker 2 And I think Rahul, the data for serially of course is not completely there. But what one can use from serially standpoint is if it is positive and you're not planning to do some scans for next six months, at least one can be more diligent and doing those scans sooner. I don't think it's truly changing the treatment right there, but at least someone to be mindful of because I just you don't want to miss that early progression. Speaker 1 Yeah, because and bespoke by Doctor Cassie, there were about 40% detection of Oligo metastatic disease and perhaps that is how that played out. So I think that's very important. Summary of Practice-Changing GI ASCO 2024 Studies Pam, thank you so much. I was just going to bring that up. Key point. Speaker 2 No, thank you, Pam. Thank you so much for taking the time to cover all these exciting and perhaps practice changing studies and some of it rather practice informing from GIS Co 2024 with us today To our listeners, let's go through a quick summary with Doctor Pamela Koontz. We have covered key studies including the role of immunotherapy in colon cancer followed by Tase and immunotherapy in hepatocellular cancer and PRRT in upfront settings for neuroendocrine tumor and the role of circulating tumor DNA from CHIIASCO 2024. Speaker 1 Is TASE over SBRT or Y-90 the right local modality for HCC? Are we ready to embrace PRRT as our standard of care for all our neuroendoquin tumor in first line settings? These are some of the things we got a chance to discuss with Doctor Coons today. Speaker 2 Lastly, we also discussed the data from Bespoke and Galaxy on circulating tumor DNA. Continue to follow along for more conference highlights. We are the oncology brothers.