ESMO 2023 GI Cancer Highlights – Codebreak300, CABINET, GASTFOX

Welcome and Overview of ESMO 2023 GI Cancer Highlights Hello everyone I am Rahul Gosain. And I'm Rohit Gosain and we are oncology brothers. Today, we're joined by Doctor Rachna Shroff, who's a practicing medical oncologist and now the Division Chief of Hematology and Oncology at the University of Arizona Cancer Center. In our discussion with Doctor Schraf, we're hoping to focus on 3 clinically relevant studies in GI malignancies that were presented at ESMO 2023 and how these studies will impact our day-to-day practice. Rachna, thank you so much for joining us. Speaker 3 Thank you so much for having me. Speaker 2 Welcome Rachna. Codebreak300 Study: Sotorasib in KRAS G12C Colorectal Cancer Let's dive into our first study code break 300A Phase three study in refractory metastatic colorectal cancer patient population with K Ras G12C mutation. Looking at different doses of sotorasib with pentatumumab versus physicians choice treatment option earlier this year, we also saw some data of adagrasib being active in this setting. Though it was a smaller study. It is important to acknowledge that K Ras C12C is about 3 to 5% of metastatic colorectal cancer patient population coming back to code break 300. So what did the study exactly show? Speaker 3 Yeah, you know this was a a great and I agree a very important study in the sense that it further validates and emphasizes that KRAS G12C is an absolutely targetable alteration and that the combination with an anti GFR in AK Ras mutated population could be clinically significant and meaningful and impactful. So this was basically a study that looked at like you mentioned two different doses of the of Citrazide and and looking specifically in combination with the with the Panatuma. Combination and comparing it to you know what we tend to use in the refractory metastatic colorectal space which we know is a relatively low bar unfortunately. And what was really good and exciting to see is that this combination approach was was clearly impactful in terms of the primary endpoint which was progression free survival and the intention to treat population. And you know there was an improvement in median progression free survival it with both in terms of the lower and higher doses. Of the citrus, but the higher dose with panatumumab median PFS of 5.6 months versus 2.2 months in the investigator choice arm and a strikingly impressive hazard ratio. So you know I think that's where I most people's eyebrows were raised in a really exciting manner. And I think again it's just proof of principle that we can do K Ras targeting therapy with anti GFR and actually have reasonable efficacy the overall survival data also I think. Was definitely good to see in the sense that there was a median OS that was improved with with a relatively amount a short amount of follow up. That being said, it was, you know, the hazard ratios were were crossing 1 and so it's the conference intervals of the hazard ratios were crossing 1. But I think that we need to see exactly how this plays out with a little bit more follow up and a better understanding. You know, I think there's a lot of patients that are getting treatments outside of these outside of, you know, being on the trial that could be impacting the overall survival data. But regardless, I think when you look at where how Code Break was designed with a primary endpoint of PFS, this was absolutely a positive study and I think should be practice changing in terms of how we approach these G12C patients which like you mentioned is a small percent. But a you know a A in a larger incident tumor like colorectal cancer, a meaningful number. Speaker 1 You know as a General Medical oncologist good thing is we can cross cover and appreciate different diseases and lung cancer where it's almost 25 to 30% KRST 12C mutation that's being targeted. So again, something that we know is actionable and can be driving the underlying malignancy, what's not given PFS and OS improvement here, if this drug is available, are you going to be prescribing this or what we covered last year with you for Quetinib, which is also potential option here not yet available. So if you have both of these options, what are you going to be leaning towards? Speaker 3 You know, I think at the end of the day, we don't necessarily have 17 different tools in our toolbox. And so I think these patients really need to get all of these therapies. And it's just a question of the sequencing approach. And I think what we have learned in general in terms of the targeted therapy space, not only in colorectal cancer but just across all solid tumors is. Earlier introduction of targeted therapy seems to perhaps a little be correlated with a more impactful efficacy and so I would probably head to in AG12C mutated patient go to this combination first recognizing that you know you still have frequent nib as well as other therapies that could be sequenced through subsequently and probably with some diminishing returns, but still knowing that there could be potential absolutely. Speaker 2 It'd be interesting Now this is though a good problem to have that how farquitinib does respond after having this medication introduced prior to that. So thank you for covering that. CABINET Study: Cabozantinib for Advanced Neuroendocrine Tumors Now moving right along into neuroendocrine space, here we have another phase three trial, the cabinet study. Taking a look at cabozantineb in advanced pancreatic neuroendocrine tumors and extra pancreatic neuroendocrine tumors that have progressed on other lines of treatment, This is certainly a very big unmet need and we don't truly have good treatment options here. So Rush, now what did the study exactly show here? Speaker 3 Yeah. This was also really an exciting space because like you mentioned, we have really limited therapeutics. And and what I think was great about this was this was refractory neuroendocrine, both pancreatic and extra pancreatic. And so oftentimes when you think through drug development in the neuroendocrine space, we look solely at drugs that are looking at the pancreas, neuro, endocrine. And this one really it was let's cover every single neuro endocrine patient that we can think of, which I think is again really clinically meaningful and relevant. And so this was a study that randomized patients 2 to one to receive cabozantinib which we know is a multi targeting tyrosine kinase inhibitor has a number of different pathways that it targets as versus placebo. And it was a 2 to one randomization very appropriately in my opinion and again a lot of patients who went on the placebo arm with an offered open label cabazantinib at the time of progression and so very appropriately so the primary endpoint in the study was progression free survival and the PFS, I mean you know look if you look at these curves, there's really no question here that this was a very positive study. Again, you know what, what we would give to see hazard ratios of .27 in terms of you know, clinically impactful data. So the median PFSS with with cabazaninib were 3 * 4 times higher sometimes with compared to the placebo arm. And so this was clearly a positive study and is going to be you know paradigm changing in terms of how we approach refractory neuroendocrine. And like I said what's great is is that it's not only in pancreas neuroendocrine but extra pancreatic patients as well. And you know, cabazaninib is not necessarily the easiest drug in terms of tolerance. But there was nothing that was presented at asthma in terms of safety signals that were new, alarming concerning that I think would make it harder to justify using the cabazantinib treatment approach. Speaker 1 You know, I think it's important to state that this study was blinded, but they had to stop the study earlier because of the ongoing benefit. And coming back to the idea of cabazantinib, as a General Medical oncologist, again I'm very used to using this in renal cell or ACC of course and even thyroid cancer, we brought up that not the easiest drug at 60 milligrams. At times it can be a little tough to manage the hypertension and fatigue, but with the first step down at 40 milligrams, usually it's really well tolerated. Speaker 3 Totally agree. I think 40 milligrams tends to be the sweet spot for most patients. But I yeah, I agree. Speaker 1 And you know I think that is the beauty of something like cabazantinib is a lot of us have familiarity with it and how to dose adjusted and how to manage it Absolutely. And again, once this is available, this will indeed be our new standard of care. GASTFOX Study: Chemotherapy for Esophago-Gastric Carcinoma Switching gears to focus on upper GI, we've seen quite a few advances even here with upper GI, we've seen the story evolve with IO and then her two agents. But here in the guest FOX study, we're looking at the right chemotherapy backbone with modified flat versus full Fox. Question on your take on this study and its findings. Speaker 3 Yeah, you know, I want to commend the authors. I I will say as somebody who has LED trials that are. Only chemotherapy and so don't seem as quote UN quote sexy or hot and exciting. These are really the important questions. In terms of clinical approaches to these patients, I mean we are very familiar with using Flot in our perioperative approaches to upper GI and you know we know it's an active regimen. So I really commend the investigators on basically doing a very clean study of looking at patients with unresectable advanced. Gastric and gastroesophageal junction adenose and randomizing them to receive a modified flat approach which is an every two week and you know relatively better tolerated approach I think in terms of flat versus full fox. And you know when you when you look at the at the outcomes, it's it's clear that not only is this kind of an active regimen in the perioperative space, but this is a very meaningful regimen in our advanced patients and you know the overall responses of. Close to 70%, which is just incredible and you know the the survival data with with the OS, again it's not this incredible separation of the curves, but it is, it is an improvement in median OS with a hazard ratio that is is technically a positive study. And so to me what this means is, is that there's clearly a role for the taxanes and dose of Taxol in particular. In the advanced patient population and like I said similar to even the cabazantinib story, we're familiar with Flot, we know how to use Flot, we use it in our period patients. And so I think that this is an important regimen to to now think about especially when you want response and you know a lot of our gastric patients they present very symptomatic and so having a response that's in the high 60% range is incredibly clinically meaningful for this patients and and the ability to. To be able to have them eat and swallow and and do things that are so impactful on quality of life. And so it's just really nice to have data to really support that triplet approach, which again, like I said, we we assumed would be the right thing to do, but now have something to mess up. Speaker 2 Certainly I couldn't agree more. Rushness. Now we are also waiting on clotting 2 driven therapy in this space. Rushna, any patient that you envision using flop versus Full Fox based chemo today in your practice? Maybe someone who has low CPS score where addition of IO has very limited benefit. Speaker 3 Yeah, you know this is it. It's it's a tough problem to have and but a good problem to have, right. You know, now we have all sorts of studies that are looking in that frontline, newly diagnosed advanced gastric and GE junction space and and it's it's hard to kind of put the jigsaw puzzle together because each of them are comparing to to to different types of approaches. I agree with you. You know while the FDA approval supports the use of IO for anybody, I have definitely a bias towards higher CPS score, more likely to use immunotherapy. You know I think as we integrate clad in testing into our our armamentarium which is I think kind of the slowest uptick right is really understanding what is clad in positive and what's in you know since it's more of an IHC approach as opposed to what we are doing with with NGS. You know, you can't argue the data with spotlight and glow and and it's great to have both spotlight and glow again, it's kind of a proof of principle. Fullfox K box, it doesn't matter. But you can add zolfatuximab and and have something that is is meaningful improvement in survival. But again, like you mentioned, response is a really important efficacy endpoint in my opinion in these patients in particular. And so I think to me somebody that perhaps like you mentioned has a lower CPS score and and really needs that response and needs that kind of Sido reduction. This is where I would really think that a flawed approach is something that will be that that's the space in which I think we I would integrate it. Speaker 1 Can I push you a little further on this? We have no data of IO being combined with flat or of course the her two agents, a young healthy patient with really good performance status. Where you are thinking of flat, would you consider adding IO if the CPS score is high? Or would you rather just stick with Fullfox and IO in that settings? Speaker 3 You know, I think with a higher CPS score, I would, I would think about it, you know, and I again. With the flat world, we are starting to see flat IO data in the periop space, and I think that's gonna be informative, right? In terms of how we start to think, for better or for worse, we extrapolate things all the time what works in the metastatic setting we move up to Periop, and what works in Periop we sometimes think works in the metastatic. And so I think in a higher CPS score, I would be harder pushed to think about immunotherapy. And so if I'm going to use a flat backbone, I would especially once I know and feel comfortable that the safety components of flat plus IO is OK. I would probably think about that. Yes. Speaker 1 Thank you. Speaker 2 This is all very exciting and a lot of the mature data to present in future as well, but we are looking forward for more treatment options for our patient population which is impressive where we are at today. Rashna, we have covered a lot of critical data here in the last few minutes. Thank you so much for joining us today and sharing your thoughts to our listeners. Summary of Practice-Changing GI Cancer Data from ESMO 2023 Let's go through a quick summary with Doctor Rashna Shroff. We have covered three important studies, the first one being the code BREAK 300 where we saw PFS and OS benefit with Sotorasib and Pentuma MAP combination in K Ras G12C metastatic colorectal cancer patient population. Speaker 1 We've also covered cabinet study which will potentially provide us with a new standard of care treatment with tabozantinib in pancreatic and extra pancreatic neuron, the crude tumor. Speaker 2 Lastly, we've also discussed modified Flot versus old Fox regimen in metastatic gastric and gastroesophageal junction cancer patient population, but this is a space which is rapidly evolving. Thank you so much for joining us today. Make sure to check out our Lung Gu and breast cancer highlights for MESMO 2023 BR, The Oncology Brothers.