Standard of Care Treatment for Colon Cancer: A Discussion with Dr. Aparna Parikh

Intro Hello everyone. Welcome back to Oncology Brothers. I am Rahul Ghosein and along with my older brother Rohit, he is older. We're going to dive into yet another important topic today, the management of colon cancer, if you're someone who's striving to keep. Speaker 2 Up to date. Speaker 1 In this disease site. This one's for you. Today, we're honored to have Doctor Aparna. Speaker 2 Parikh, A medical. Speaker 1 Oncologist also my birthday twin who focuses on colon cancer from Mass General Hospital Doctor Parikh is also part of the NCCN guideline committee for colorectal cancer. With Doctor Parikh, we hope to cover her treatment algorithm for colon cancer. Aparna, thank you so much for joining us of. Speaker 3 Course. Thanks so much for having me, Aparna. We have quite a bit to cover here. So we'll start off with our localized disease which is stage one and stage two. Stage 1 and Stage 2 Colon Cancer First in stage 1, these patients are diagnosed with incidental finding or on screening colonoscopy. They definitely need surveillance. But medical oncologists have very limited role here or rather no role and in stage 2, which gets tricky especially after this revolution of circulating tumor DNA. Can you start us here on your treatment paradigm, particularly for stage two? Yeah. So I think stage stage 2 is you know it's sort of definitely an interesting area and suffice it to say I think a word of caution as we sort of dive into this area. I think some of the areas that we're going to be talking about circulating tumor DNA still a rapidly evolving landscape, much prospective clinical triad data, trial data is still needed. That being said, I think I'll make the argument today that I think there are some settings in the stage two scenario where I do think it's appropriate to use the test and how I use the test. Again, having conversations with patients that this is still very much in its infancy at least as a predicted biomarker, not necessarily prognostic. So you know this stage two patient, let's start just talking through the MSS patients, we can come back to MSI later. But the MSS patients that are stage 2 low risk patients, we still again for risk stratification we look at sort of the tried and tested clinical pathological features that have been around for quite some time, you know T4 lymph node status, how many lymph nodes are harvested 12/12 or less considered to be inadequate perforation, obstruction, all of those things. And so if a patient doesn't have any of those features, we know that those patients do very well and in that setting feel very confident just offering surveillance. That being said, I think this is a scenario where I do start to have conversations around circulating tumor DNA because there are a small number of patients that have low risk stage two disease that do go on to recur. The caveat being is that in a low risk patient population when your baseline prevalence is low, you do have to worry about some false positives, right? And the way I discussed this with patients is that even the tools that we use such as the clinical pathological features, we know that there's false positives there too, right? We're treating some that don't need treatment and the we are not treating others that would And at least to date circulating tumor DNA, the PP VS as well as kind of the hazard ratios have you know routinely emerged as kind of a stronger predictive or prognostic biomarker. So having that conversation with patients saying yeah, we you know you could get a false positive but we generally know that CTDNA detection is bad and we've all seen the Kappa Meyer curves of the positive patients where can a nearly all the patients who are ultimately positive will go on to recur and we're starting to see now evidence that you can actually reverse that recurrence with chemotherapy. So a low risk CTDNA, you know CTDNA positive patient I would actually offer chemotherapy too and that chemotherapy I would actually offer doublet chemotherapy too. I'm just given the prognostic value of that. That being said and we'll talk a little bit about this, even with Stage 3, I think in the positive patients that are lower stage 3. Similarly when we think about 3 months versus 6 months of K box versus full box. I don't think we have a lot of time today to go into the idea design and some of the flaws with a non inferiority design. Non-Inferracy Design But I I'm probably the minority but I'm generally a person who you know errors on the I I don't personally love Cape. I find that I mean you probably actually in the community setting do better than we do sometimes with with Cape. So I tend to be someone who will err on the side of you know stage 3 higher risks or even low risk patients who are younger for example who don't want to potentially compromise any cure will err on the side of six months but having a very low threshold to drop the ox alley. So kind of staying very vigilant on top of the neuropathy and at the earliest signs of someone getting neuropathy, you have to, you know, you have to be a cycle or two ahead of it right before you leave them, you know, kind of really, really hurting down the line. Speaker 1 Aparna, thank you. There's so much to unpack. Just quit on stage G just to dial the clock back a little. Going back to CTDNA, you've mentioned that if it's positive, yes, we're all moving forward with chemotherapy, be it negative or positive. CTDNA and adjuvant chemotherapy Are you following these patients serially or are you using this test for one time to decide your adjuvant treatment? Speaker 3 I am. I am not recommending it serially for everyone. Will Ioffer it? Yes. And will I have discussions? Yes. We, you know, do have a clinical trial. So in that setting of course. But I think that you know, the challenge as you know as well as I do is you know, we're scanning these patients depending on stage, you know, twice a year ish, you know two, you know, especially the three patients, you know, two maybe a little bit less, but if so, when you're scanning anyway, do we know a, we don't have any treatment yet that we can give if a patient is positive, We know that negative doesn't necessarily mean there's no cancer there. There's still some limitations with sensitivity. We also know that if you were to be someone that recurs in a place that is potentially curative like the lungs, CTDNA does a lousy job of detecting lung metastases and you know an oligo, a lung nodule that you're following over time that ends up being convincing for an oligo metastatic site of recurrence. If you were just relying on the the CTDNA testing, you wouldn't miss that too. So I do think it's a it's something to talk about with patients and I certainly want people to feel empowered in that shared decision making and you know, definitely have a lot of patients ask and we'll certainly do it. But you have other patients that kind of get this like you know, I don't know if I want to know and then it feels like a little bit of a ticking time bomb and then what are you going to do? You just scan a little bit earlier and does scanning a little bit earlier actually do anything for outcomes and I don't think we know that. Speaker 1 I have to jump on, on the same bandwagon. That's been my practice. And the other thing is we mentioned T4. This is also where CTDNA data is. Again, we're not diving into that all that deep, but it's not the best. Speaker 3 Yeah. And T4 disease I'm going to treat anyway, right. So at T4 patient, if you kind of look even previously from the DYNAMIC study, T4 patients don't do as well, they almost do as badly as you know a positive patient. So you're going to give them chemotherapy anyway. So in AT4 negative patient, I'm still not yet like de escalating care. Now diving into our stage 3 space, what is your management entails especially now talking briefly about IDEA trial here, I know that whether would we utilize if it is low risk, any thoughts on utilizing Cape side of being approached for three months versus sticking with Fullfox itself. Stage 3 management You know my practice is very heavily skewed towards younger patients. I run the young onset program here and you know with the idea in a non inferiority study design you have to accept to call something non inferior, you have to accept some loss of efficacy, right. And that loss of efficacy may be small but in a younger patient that few percentage loss of efficacy it's sort of like OXALI in stage two, right. In a younger patient you might have a little bit of a different discussion around how much you're going to push the OXALI than an older patient. And so though three months of K box is totally appropriate and would be guideline like concordant, I you know have had discussions with some of you know some of these and there's something something about these like T1 tumors that are node positive, right. There's some data too that if you're AT1 tumor and you became node positive like that's not great either. So there, there's these certain conversations that I have with patients around like what does that actually mean? You know if you have any issues with Cape we could do this and again like yes it's a port but you know you can titrate it easily you can stop the ox alley early. So I I'm a little bit again I acknowledge that I might be a little you know I think I know of a few other people who kind of practice this way and it may be a little bit my bias but I tend to be again a little bit more on the full fox and then drop drop early side of things rather than than Cape and then kind of kicking myself later. People are having a hard time. I think at the end of the day it's still patient centered approach and especially when you're talking about young patients the chance of cure is what we are targeting here and even slight toxicity increase with longer term here and still giving them better chances of cure is certainly something advisable. So thanks for going over your thought process here, talking about the metastatic space. First-line therapy for MSS If you don't mind going over your first line treatment regimen here, what are you exactly using and is your decision based on sightedness or molecular information here? Both, yeah, both. So I think let's you know, let's come back to immunotherapy maybe and just stick on the MSS patients. So I think this algorithm is you know generally right, again biased towards younger patients. I think there is still independent of B Rav V600D patients. There is still some small kind of survival benefit with kind of triplet therapy plus or minus Bev. And so even sometimes for the left sided RASP well type patient rather than just reverting straight to doublet plus or minus anti GFR, I will often use triplet therapy first. You know obviously in someone who has a higher burden disease you want cider reduction. But and again one of those things you peel back and you can go to go to maintenance holidays over time. And but in terms of someone if you're like OK, I don't necessarily think they're a burden of disease even if they're young Warrens like triplets seems like a little bit of an overkill if they're Ras wild type and left sided. I still think you have to have a discussion around anti GFR in the first line, especially again biased towards younger patients. I think you need anti GFR of course. But you know even from the PARADIGM study many of the patients didn't get anti GFR in later lines of therapy and so does withholding it in first line when you get it later actually is that a detriment? I'm not sure we have that data. And so but I don't I'm not necessarily dogmatted around first line. You have to have Fantasia far if you're left sided, I think you absolutely have to have it in your treatment paradigm but not necessarily in the first line maybe get and can preserve that quality of life a bit more especially for the younger patients. But I think for the Rasmutant, RASMUTANT patient you definitely double ABAB, you know right sided patient obviously same that's a double ABAB that's right sided and Ras Wild type as well Alfredo. Speaker 1 Thank you so much for going over that. Going back to the Ras wild type younger patient, when we're talking about anti EGFR let's say. Anti-EGFR therapy in younger patients A small subset. Speaker 1 But if this patient is hurt to amplified, are you still considering anti GFR at all in their paradigm or knowing that they don't respond well, you're going to let that go and just rely on your anti her two therapy eventually? Speaker 3 Let that go and rely on anti her two directed therapy. Yeah yeah I think pretty, pretty strong data. That's a mechanism of resistance. Again, if you get to 4th, 5th, you know this, you know, maybe you try it and just see what happens then. But certainly do not give it in earlier lines of therapy. Yeah. So Ras. Yeah, exactly. So first line Ras. Ras wild type patient who's known her to. I would not give anti GFR. Speaker 1 Thank you for touching on that. I know we've briefly skipped over MSI high patients here and an early stage your treatment paradigm. Early stage treatment for MSI-high patients We saw some data from Ipnevo as well from GI ASCO and this disease site looks exciting. We have pembrolizumab approved here. What are you doing in these settings? A patient that has MSI high. This is the same patient population where you can also see B RAF mutations as well. Speaker 3 Yeah. So I think the MSI still Trump's B RAF, right. So even though there's that overlap, I think we still go to Ms. to immunotherapy first. You know, I think we all are looking forward to seeing the Nievo alone arm from the GIS Co presentation. I think, I mean, certainly it's hard to ignore those kind of two year differences with those Kaplan Meyer curves from that study. I think 1 interesting thing to just point out from that study that is also important was there's from from from the Keynote study and then the Checkmate study. In Checkmate also there's differences in the central testing that was happening in terms of MSI high status and kind of we know that even even at our kind of academic institutions sometimes like it can be confusing in terms of whether the tumor is truly MSI high or not. And so I think we have to take that into account with the differences. So generally speaking you know my prior to seeing that data my you know was just first line pembro and then you know there are those rare patients that are just bulky, bulky, MSI high disease. And then I would take pause of you know actually using CTDNA for monitoring those patients because I didn't want to lose the opportunity to you know again full box you can give even if a bili is 15. So you can get cytoreduction quite quickly with just doublet and don't need to worry about your your LFTS there you know. But I think that 30% pembrolizumab non responder rate in the bulky, bulky patients, I still started with them, you know therapy. But there were patients where I gave immuno chemo too, 'cause I was like I don't want to lose this window there or just start IO and then monitor with with you know cell free DNA and kind of make sure you're you're getting a response there or switch to chemo. But now I think in those bulky patients, I haven't like I I haven't had one since GIS go that I felt compelled to do ippinivo for. But sort of thinking about when that might come, I I do feel like that I might actually try that ippinivo rather than you know, ippy chemo or just switching to chemo for the bulkier patients, absolutely. It'll be intriguing and depending on how the trial plays out to see the Nivolumab single arm exactly, I think still waiting for that that arm to see where that flies. Now Perna, this particular patient, you started the patient on five, a few regimen depending on the molecular signature here. What are you considering for second and third line options? If MSI high started on immunotherapy now, the patient progressed now 10 to 12 months out on progression of this disease. What are you considering for second and third line option, especially after for Quintinib being available as well with TAS 102 Rigrafnib? Yeah, so assuming they're like a year out and it wasn't you know they were on doublet alone and not a setting for example where you keep back on maintenance and you're kind of going back, you know then obviously switching your chemotherapy backbone. So you've done that, you've done your anti AGFR if you're Ras wild type. But even and I think highlighting the fact that I do the Ras wild type in second line even if they're right sided, I will still give Antihjovar therapy. I think that's important. And I think we're starting to realize with some biomarker analysis of even paradigm that it's no it's it's probably not just it's we knew it's not just sightedness like but we're starting to understand maybe what some of those there may be have some you know resistant subclones that were there. So I do use Antihjovar therapy in even in second line for a right sided patient. So we've done all of that. I, you know, I've been using Lonsurf and Bev even from the phase two data a few years ago, I think maybe now 20/17/2018 when the Lonsurf Bev data came out. And so that's generally my kind of refractory treatment of choice. I just don't, I'm not a big rego fan. Even with the redose regimen starting at 80, I just didn't like it. I never saw any, you know, true benefit certainly never saw any responses. I found even at 80 just people felt lousy on it. You know and I think you know for Critim did get third line you know it labeled definitely I have given for Critim now and a few people that like don't want to like why don't you do the infusion just do the pill. I'm not going to give lawn surf to people that are. We get people that come down from Maine for example and you know you can kind of do quicker talk checks with them and send them on their way. So that's how I've used, I've only used it a handful of patients. I do find it easier than rego. So it is still a kind of. To Ki bitch type of side effects, but I I have found it. I have found it easier than rego. Speaker 1 So Taz 102 is something I have used BI Weekly, I've only used for Quintonib once and I started off 5 milligrams, had to quickly decrease the dose and start off slowly. So it was a learning curve. I've stopped part of the clinical trials. So for my community side of things, it was a quick learning curve and we've seen this over and over with TKS be a Reg Raff Neb or in my community practice lenvatineb or anything. So just starting off slow ends up being a whole lot better and that's going to be my practice moving forward. Speaker 3 Thank you so much again for joining us. We've covered quite a bit here and we truly appreciate you going over this treatment algorithm. With this for our listeners. Let us go over a quick recap. Speaker 2 DTDNA has been a hot topic in almost every solid malignancy, but the colon cancer trials have been leading the path. Here in this discussion with Doctor Aparna Parikh from Mass General, we touched upon how to use CTDNA in our current practice when it comes to colon cancer. Speaker 3 With Doctor Parikh, we also had a chance to understand how to sequence our current available treatment options in colon cancer from immunotherapy to friquitinib. We had a chance to touch on lot of the recent data and looking for advancements in future. We appreciate you tuning in. Make sure to check out our hepatocellular carcinoma and upper GI discussions as well. We are the oncology brothers.