How to Treat Colorectal Cancer – Treatment Algorithm with Dr. Smitha Krishnamurthi

Hello, and welcome back to the oncology brothers podcast. I'm Rahul Gossane here with my brother and co-host, Rohit Gossane. Today, we're kicking off a three-part series on colorectal cancer, starting off with treatment algorithm today. In our second episode, we'll take a deeper dive in one of the biggest advances in this space with breakwater study for B-Raff-Ree 600 E positive disease. And then to close off, we'll touch on side-effect management for our available options here. Okay, so today, with focus on the current standard of care, we're excited to have Dr. Smitha Krishnamuthi, a GI medical oncologist from Cleveland Clinic. Smitha, thank you so much for joining us. Oh, thank you so much, Rahul and Rohit. It's an honor to be here. Thanks so much again, Smitha, for taking the time to walk us through your treatment landscape, and we'll dive into this further because we have quite a bit to cover, starting out with data around CTDNA, neoageven, and adjuvant role of IO, particularly in MSI high disease, and then diving into metastatic space. Where we'll talk about single agent versus dual checkpoint inhibitor, and then breakwater study, which is NKRAF-NIP, CIFT-TUXAMAB, and chemotherapy of front for B-Raff-Ree 600 E. And we'll see how citedness plays a role with RAS status in deciding our treatment regimen, sticking with our localized disease first. For stage one, following resection, we tend to follow these patients with surveillance, colonoscopies, and imaging. Outside of that, stage two, post-resection, one has been utilizing CTDNA, which has been playing rather a bigger role, which we initially thought was a prognostic marker. But after what we've seen with dynamic study, five-year update, we're using this as a predictive tool as well, where if CTDNA is positive, then administering adjuvant chemotherapy is beneficial. If CTDNA is negative, one can forego chemotherapy. Outside of clinical trials, how are you using CTDNA, whether that's for localized disease, or even in metastatic space? Outside of clinical trials, I feel like for the low-risk stage two, proficient mismetropair, this is where it's most helpful, because they are, could rarely be positive, but if they are positive, as you know, it's such a high risk of recurrence. It's such a strong prognostic marker. It far outperforms any of the other indicators we look at like, you know, tumor-biting and lymphobasca invasion, etc. So I do discuss it there. If somebody is positive, I tend to use a double-it-chema therapy. Like I actually would introduce oxalic platin with five-a-feu or capesida-being to try to maximally clear the CTDNA to try to prevent recurrence for high risk. So like at the T-4A patients, you know, I feel like that even the data from dynamic indicates that the CTDNA is not perfect, and they do have a high risk. And so even if they're CTDNA negative, I do offer chemotherapy for high risk stage two. And then I'm typically using the three months of K-box, because it's like short and done and you know, we've done our best there. Smith and I know we'll talk about stage three, stage four. Outside stage two, are you using CTDNA when it comes to surveillance? What about that oligomeric static disease? If it's recacted, are you using CTDNA to make any clinical decisions? Yeah, I tend to use CTDNA when a patient has a normal CEA at baseline. You know, they're all studies showing that even for those patients, when they recur, 50% of the time the CEA becomes abnormal, but that's not great. We know CTDNA is far superior to CEA, and because there are these patients who could have oligomeric static disease, cured with surgery, I do discuss it with all my patients who have a normal CEA at baseline. And again, we all agree with that. Sorry, Rahul, before we move on, you talked about stage two, though, that's a rare entity where we still will have MSI high disease, but CTDNA is positive, though the role of Adjuvant chemo is limited. What are you doing if the CTDNA is positive for MSI high stage two? MSI high stage two A, I'm generally not checking CTDNA. We think they have such an excellent prognosis, highly cured with surgery alone, but now of course with atomic, we have NCCN is now, who has a line in there that one can consider adjuvantatezo chemotherapy for patients with T4B tumors. I think T4A also has a high risk, so I would see if the insurance would cover it in that setting. So for those patients, CTDNA positive T4, like a high risk MSI high, certainly would offer them the atomic regimen. Actually, let's talk about atomic regimen here in a second, but before that, we all acknowledge CTDNA is not black and white. If you think so, keep in mind here, CTDNA post surgery is a poor prognostic marker. And we also have data that escalating systemic treatment based on CTDNA was not very fruitful. Outside, in community settings, we've been extrapolating data from colon cancer a lot across multiple disease sites when it comes to CTDNA. So colon cancer is actually taking the lead. Okay, moving along for that stage three base of idea trial for low risk stage three, oxali platen for three months is good enough, but coming back to this MSI high disease. If you have data from niche two study, one cycle of ipinivo and then one more cycle of nivo alone followed by surgery and then atomic study. This is what you were referring to full fox with a tizalus map for 12 cycles and ongoing a tizalus map to complete additional six months. For that MSI high, resectable stage three disease, what is your practice niche two or atomic? This is such a great question because it's really a space where we could use a random mice trial because as you mentioned, the niche two trial results were so impressive with just such a short course of immunotherapy. It was very well tolerated. They only had four percent of patients having grade three, four events with that short course of immunotherapy and reporting 100% three year DFS. You know, in the real world, I think it's not going to be 100%, but I think it's going to be quite good. The issue though with nivoadjivan therapy is the staging because we don't have great CT staging, especially in the US, we're not used to it. I think they're far more used to it in the UK and Europe. So there's likely were patients in niche who would have had low risk stage two disease, possibly even stage one disease. So we have to keep that in mind when we look at those fantastic results, whereas atomic, everybody had pathologic stage three colon cancer. So definitely a high risk group there and that has become the standard of care now. I think it has a lisman full fux in the US for patients with a susceptible disease, but three year DFS was 86%. Maybe we could get it to 100% with nivoadjivan. So I feel like this is still an open question. I think, you know, so certainly our practice here and it's also suggested in CCN. If you have a bulky tumor or something that is T4B, it's clearly invading another structure. And CCN also says we have bulky lymph nodes to consider nivoadjivan therapy. And I think that I would definitely use nivoadjivan immunotherapy for somebody who clearly has an advanced MSI high colon cancer, but the question is if it's not advanced, what to do. I think if you don't even see it on the CT for, you know, go right to surgery, but then if it's visible on the CT, you know, what to do. We do have data from recently Jenny Seligman from the Fox track group and Miriam Salabi from nation pulled their data showing that among patients who have CT stage T3, T4 disease treated with just chemo, the three year DFS is about 80%. So it's suggest if you're good at identifying T3, T4 on CT, you could use that to, you know, route just to the other patient there. But it's definitely still a research question. Thank you so much for stressing that very important point. That is with niche 2. This was rather CT imaging finding how we are deriving to the appropriate staging while in atomic it was a pathological finding. Just some of the important discussion points here is that niche 2 has been a phase 2 study with ipinevo upfront while what we are seeing as you stated is met 100% DFS at three years, which is remarkable. And that's 95 percent patients with major pathological response, 75% complete pathological response. And for atomic study, which is rather a phase 3, DFS here is 86% as you stated with the comparator arm, which was 77% with just adjuvant chemo there. Well, at least in my practice, if it is bulky, in data, then I'm relying on a nevoipy combination. All right, moving along into metastatic space, where biomarker NGS testing plays quite a bit of role in deciding our treatment regimen. Smitha, for MSI high metastatic disease, data for single agent pembrolosumab versus ipinevo, again, one can argue all along. But what is your go-to regimen here? I think the checkmate 8HW study was very important comparing the four doses of low low dose ipinema-map, four doses with nivolumab versus nivolumab versus chemo. They had a separate arm for first-line patients with chemo. And clearly, the PFS is superior with the doublet ipinevo. At two years, we're looking at like about 74%, and it was about 55% with nivolumab alone. And they even looked at PFS after the second line therapy, and it maintains that superiority. So it really does look like there's an advantage to starting with if you need the concern has been the toxicity. You're going to have more toxicity with adding the anti-CTLA4. But when you really look at what were the increased toxicities, you know, they're primarily endocrinopathy, like hypothyroidism, adrenalin sufficiency, which we have considered to be manageable, especially in the metastatic setting. You know, it seems like a good trade-off to, you know, take leaveothiroxin for the rest of one's life to have this extended efficacy with the immune therapy. I do think it be Nevo is the standard for most patients, unless there's a reason why you think that the patient wouldn't tolerate it. Absolutely. And again, the study that you pointed out here is checkmate 8HW when we're talking about hippy low-dose, that's one make per gig, an avolumab combination. This is every three weeks for four cycles, and then it's Nevo alone. A few things to point out that improved PFS has a ratio is 0.21. This is exciting. And then the other thing to appreciate that hippy-nevo combination also had better overall response rate. So again, hippy-nevo, if in front of you, that patient can tolerate often ends up being the right choice. An avolumab or permeralismab by itself is not wrong. Okay, moving along, another important NGS mutation that now we can target ends up being BRAF-R600E. Here now the standard of care is full-fox or full-fury with NKORRATHNIB and CITUXAMAB based off breakwater. Here the overall survival improved from 15 months to 30 months. Let that sink in. Doubling of overall survival. This is amazing. And we're covering this particular study in a lot more detail for our second episode, so make sure to check that out. Besides MSI and BRAF-R600E, SIDENESS and RAST-DATIS also plays a role. We'll still continue to debate the role of anti-UGFR versus VEGF-INDIBITERS, SMETHA in your practice. Who gets front-line anti-UGFR? And how do you pick between CITUXAMAB and PANETIMAMAB? Oh, that's interesting. I want to make the point though that I think especially with breakwater, we have to have the NGS testing upfront. Yes, yes. We have to know mismatch repair, of course, right away. We need to know that, to know if this patient is getting immunotherapy. And then we need this NGS to determine if they should be getting the breakwater regimen. So, you know, really feel that we should be using CTDNA to accomplish that. Like, relatively quickly, you get your results back typically in less than two weeks. We've been sending liquid and tissue, but that liquid by-f-d gives us the results quickly. And so, with that being done, the NGS testing has no B-Raph mutation and RAS while type, left-sided, hurt-to-not amplified. Certainly, can get very high response rates with doublet and anti-UGFR. Parodym did show with full Fox PANETIMAMAB versus full FoxBAB, an improvement in survival about four months. And, you know, that hasn't really taken off in the US to become first-line uniformly. Here, I think, because they showed like about 60% of patients did get anti-UGFR therapy, second and third line, those who start off with the BAB, but not everyone. And we do have that Canadian trial, very old studies, a Tuxa MAB versus Best Support of Care, five months improvement in median survival, if you know your RAS while type. So, it does seem like you could get that survival benefit, perhaps, at any point in the treatment timeframe, maybe doesn't have to be right up front. And it is a big deal for patients because of the RAS, as you know, FoxBAB, it's nice, you don't lose your hair and there's no outward RAS, but we do have to discuss it with our patients. And I think for somebody who has a high tumor burden, where they really could benefit from a better response rate, I certainly would recommend the anti-UGFR. If we're trying to convert unresectable to receptable, it will definitely use it. For patients who are not going on to anti-UGFR, or let's say for somebody who has a RAS mutation, or we just can't use it, then if they're fit enough, I do recommend like FullFirinox or FullFuxiary with BAB, you know, because of the tribe data showing that five months improvement in survival compared to doublet therapy. It's tough treatments, not for everyone, but it's also not forever. So you can get your maximum tumor shrinkage generally in like three to four months and then go on to maintenance. So I do use that a lot. We're just digging in a bit more with the RASH story Smith. I will, we will get a chance to dig in a bit deeper in our toxicity check podcast there. But with regards to the RASH, after utilizing Doxie Cyclein initially, 100 milligrams twice a day for about a month and then switching to about once a day, if the patients are still having a RASH, what is your clinical pearl around that? Okay, so in addition to the moisturizing and using like the dandruff shampoo, you know, on scalp and body, I think it's important to use the steroid cream. So typically using like 1% hydrochlorosone on the face and stronger steroid cream for like chest and back soaking, you know, even soaking in like a vinegar water solution as a disinfectant can help. And I should really jump here about two things. One, when we're adding N-corroffineptic to succumbab for that B-Raff V600 E, that's another thing for us to keep in mind that RASH. But thankfully, we did not see whole lot more RASH when we're combining these two agents. The other thing that you touched on was hurt to amplified. It is so important for us going back to that NGS and biomarker testing, because if this is hurt to positive disease, we have strong data that anti-UJFR is not the right medication affront, because likely this disease is going to be resistant. So testing for that RASH, testing for her to biomarkers B-Raff affront is so critical. Yes, totally agree. Rahul, you started out by where there are very limited studies of doubling of oral survival. Yes, it is exhuighten time, especially when we are seeing a lot of the doubling of oral survival, even come in multiple myeloma from what we saw from ticklidstemab, as well as antibody drug conjugates whether that's TDXD or N4 to Mavidotin and bladder cancer. So exciting times and date. All right, it's with us sticking through colon cancer there for the RASH mutant disease, which is if it is right-sided, the choice is full fox or full fury with Bavicismab. On progression, continuing on with the 5FU and switching oxaliplatin or Irino-T-Kenn, whichever one has not utilized it, and then what next of the disease was to progress the choices, a regular affinib, or TAS-102 plus Bavicismab or frequent NEP. How are you sequencing and what's your approach here? I would point out I am somebody who, when the full fox Bav isn't working, I go to Irino-T-Kenn Bav. I've actually not seen any data that continuing the 5FU is helpful. It's very common to go from full fox to full fury. Oxaliplatin needs 5FU to work. Irino-T-Kenn does not. And so it's kind of nice for patients. Unfortunately, they're diseases progressed. We have to make the change, but at least you don't have to have that infusion pump. I tend to sequence like that. But when the IV chemo isn't working, we don't really know what is the best option. We don't have any head-to-head comparisons or prospective control trial. But I tend to use TAS-102 with Bavicismab. Patients are in the mode of coming in for IV treatment. There may be already on Bavicismab. It's easy to continue. I know in sunlight, not all the patients had prior Bav. But it was about 70%. And there was an improvement in median survival with the Bav. So I do use that as my third line if there's not a trial. And then I've been using Fluentinib. Again, no head-to-head comparison, Fluentinib versus Regar-Affinib. They seem to be very similar in toxicity and efficacy. The pivotal Fluentinib study allowed patients to have prior TAS-102 and Regar-Affinib. So I think most of us are using the Fluentinib. I do stepwise dosing with Fluentinib. I found that stepwise dosing for Regar-Affinib was a game changer. I mean, patients used to hate that drug. And then I was surprised when patients would have disease progression on Regar-Affinib. They'd be sad to come off of it because it was so easy. So with Fluentinib, I have seen sometimes the blood pressure shoots up right away. Or even just like a loss of appetite weakness. I can think of some patients. So I have been using, unless somebody's like, you can see the very fit, I've been using, starting at three milligrams for the first week, then go up to four and then five, based on tolerance. And again, the step up dosing here for Regar-Affinib that we were referring to ends up being redo study led by the Kaisab. For test 102, there's also data of every other week by Dr. Kathy Eng. Smitha in your practice every other week, test 102. Or do you stick with the approved label? I'm glad you brought that up. Yeah, I forgot to mention. Definitely, that's another game changer. That data from Dr. Engen-Colley's, Chris Kahn, Vanderbilt, five days on, and then weekend, and the next week off, five days on again. So basically 10 days every month, they're on treatment, and their data is impressive compared to historical controls performing as well, and so much less toxic than trying to get through those two weeks. When I used to give the days one through five and eight through 12 every four weeks, the myelus oppression, the fatigue, it was really difficult. And again, here less toxic and we're not compromising efficacy based on this retrospective analysis. I know we keep alluding to this third episode that will focus on toxic city management, but as we're talking about some of the side effects here. we have to appreciate that 5FU and Cape Sytabine now has an updated FDA label, which requires DBYD mutation testing upfront for all our patients. So far, we've touched that anti-UGFRs can cause rash, end-coratheneb, yes, that rash, but a little more anemia, and then here with our refractory options with oral TKI's, keeping an eye out for hypertension, fatigue, and rash should be on our radar. Smitha, before we close, anything more to add here for your final thoughts around treating colon cancer in 2026? I would just add that I feel like the jury is not out on CTDNA for early stage disease and escalating or deescalating, because, you know, for stage three disease, I was a phase two study, had a variety of options, physicists could choose what their baseline regimen would be and what they would escalate to or deescalate to. And so I feel like the current study that's open in the US, the NRGGI O8, or circulate, will definitively answer the question for stage three and T4N0, PMMR, colon cancer, what is the benefit of CTDNA? Absolutely, Smitha, before we let you go, I know Rahul said one last thought there, but quick question here. With regards to CTDNA, how hot this topic is? If one has undergone surgery and one has oligometastatic disease, post-surgery, one did receive six months of adjuvant therapy, that is with full fox. Now, CTDNA is positive, but imaging is negative. How are you going about your management? Are you going to continue on with further chemotherapy, imaging modality, monitoring, or CTDNA surveillance? Yeah, so that is a great question, because in that setting, I tend to be, and I think most people are, we're getting imaging quite frequently, right? So somebody had a liver metastasis resected. I'm getting the liver MRI every three months. I tend to add chest and pelvis imaging like every other time, so every six months. So we're looking quite closely, and so I actually have not been checking CTDNA routinely. I think this is another great research question, you know, to see if somebody is positive. What can we do? Because I do feel for these patients of all oligometastatic disease, the most important treatment is recognizing the oligomet and resecting it or blading it or radiating it. I think we will accomplish more than with chemo. So somebody's positive, I don't know that just starting them on chemo is the way to go. Is it really going to be a cure if they already like progressed on adjuvant chemo? And then, you know, ultimately when the met comes, we want to be able to catch it. And, you know, act. I've had experience where the CTDNA can be positive, more than like, you know, the anticipated six months before the scans show disease. And it can be hanging over somebody's head for like even like 18 months. So I think in this setting where we are imaging frequently, I don't update it frequently. I'm going to jump on the same bandwagon here, even when we're getting imaging at times it might prompt me to do a different type of imaging. Instead of CT, I'm leaning into MRI or even pushing as far as saying, hey, let's get a PET CT and make sure there's no occult lesion here. So I think it can help there. Thank you. Have to do all that with a positive test. Absolutely. Yeah. Yeah. But again, we don't have clear data saying if I was to treat that CTDNA positive disease, if we are changing any overall outcomes. Exactly. Two things for our memory. CTDNA is bringing a lot more questions right this minute rather than answers, but we're eagerly looking forward to more data there. We've covered a lot here. Samantha, thank you so much for taking the time to walk us through the current treatment landscape for colorectal cancer. For our listeners, let's do a quick recap from today's discussion. In today's treatment algorithm discussion around colorectal cancer with Dr. Smitha Krishnamurthy, we touched on CTDNA guidance management, which has now become the standard of care for stage two colon cancer for many patients. We then touched on neoagevin and adjuvant immunotherapy based off niche two and atomic trials. We also have ipinevo as a combination for MSI high metastatic disease, picking that right patient for dual checkpoint inhibitor, or single agent immunotherapy is a conversation we continue to have in our clinics. Robert, your thoughts around metastatic disease? Right, Rahul, we clenched toward the breakwater data, reiterating that N-corrafinib with the Tuxumab and chemotherapy, whether that's full fox or full fury, is rather the standard of care for B-Raff V-600E disease. We will take a deeper dive into this particular trial breakwater and findings in our next episode. Today, we also talked about making that decision based on sightedness and rast status. Then, to close, we touched on the refractory treatment options that are regraphinib, TAS-102 plus Bavisusumab, or for quintinib. Thank you for tuning in. Be sure to check out our other treatment algorithm episodes, FDA approval, discussions, and conference highlights. We are the oncology brothers.