Episode 125: FOXTROT & Discussing peri-operative treatment in Colon Cancer with Professor Jenny Seligmann

Simply Oncology Podcast Recording Perioperative SACT CRC-20260925_110507-Meeting Recording

Welcome to the Simply Oncology Podcast. This next episode, we are going to the perioperative treatment of colon cancer. Now, John, we did a previous episode. We did it with Noreen Starling. Well, we've done Noreen Starling with a metastatic colorectal landscape. We have Richard Adams with rectal, but now we are going. further up into the colon with the wonderful, like a colonoscopy with the wonderful Professor Jenny Seligman from Leeds. Jenny, welcome. And Jenny, have you ever been described as further up the colon? Haha. Jenny Seligmann 1:53 Yes, actually. I would tell you who by. But yes, I have been described as further up the column, but that's fine. I've been called worse. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 1:59 Yeah. Yeah. The. And Jenny, would you like to, there might be some listeners out there that just want to think, well, why should I listen to Jenny Seligman? Do you want to just lay out some of your creds on colon cancer and what you've been involved in? Because you've been involved in some of the major trials here in the UK. Jenny Seligmann 2:20 Yeah, so I have been involved in colon cancer research probably for about 15 years. So I initially did my PhD based upon translational research and biomarker research in the betastatic setting, working on some UK trials. And then I worked on a big trial platform called Focus 4, in the metastatic setting. But more recently, I've been involved in the Foxtrot trial, which I know we're going to come to today, and then launching the follow on studies from the Foxtrot trial and then the translational work from the Foxtrot trial. And also another trial, Ariel, which is running in the UK as well with Richard Adams, who you've previously spoken to. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 2:49 Mhm. Jenny Seligmann 3:03 But in terms of credibility, it's I'm lucky. I mean, yeah, I'm very involved in ESMO as well. And again, just to put it out there, UK people should get more involved in ESMO. There's lots of opportunities. So in things like the guidelines and things like that. So that's been ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 3:07 That's enough credibility. That's a lot of credibility. That's enough. That's enough. Jenny Seligmann 3:23 Really helpful in my career. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 3:26 Fantastic, Jenny, welcome. We are in good hands. I feel safe. Yep. Now, Jenny, as Noreen and Richard were disappointed in us before, I'm sure you'll be disappointed in us in this episode when you realise how poorly we understand colon cancer. So we're going to start from the beginning. From memory, an operable colon cancer meant you went to see a surgeon, they cut a bit of bowel out, sometimes they stitched it back together, sometimes you had a stoma, and then you probably had some adjuvant chemotherapy. I suspect things might have moved on a bit. Is that what we're still doing? Is it different? Jenny Seligmann 4:06 Well, I think that's a very good question. So across the world, that is the majority of the management. So this hasn't changed in 25 years. So there was no advances since the addition of oxaliplatin to 5-FU in like 2005 when the mosaic trial reported. So in some ways, your knowledge is not so outdated. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 4:16 Mhm. Mhm. Mhm. Jenny Seligmann 4:30 However, this is where Foxtrot was moving to shift the dial because what has failed in colon cancer is trying to add things to adjuvant chemotherapy. So anti-EGFRs failed, bevacizumab failed, and we've just been left with doublet chemotherapy. So the Foxtrot ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 4:40 Mhm. Mhm. So good old-fashioned oxaloplatin and 5FU, the bedrock of GI chemotherapy. Yeah. Jenny Seligmann 4:55 The bedrock, but it's actually not brilliant because number one, we've got two major problems in localised colon cancer. Number one, we're treating too many people and that's where the research of ctDNA comes in. So can we find the people we can de-escalate? ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 5:05 Mm-hmm. Jenny Seligmann 5:13 but also we've got a large proportion of people who we're giving oxalaplatin to and it's not working. So they're coming back, we're giving them the same chemotherapy, we're not personalising anything. So there was two ways to improve colon cancer, three ways actually. Number one, thinking about giving some of the chemo before surgery like we do in gastric cancer, like we do in bladder cancer, well across many cancers. So can you give neoadjuvant treatment? Number 2, can you personalise? So can you give immunotherapy? Can you target BRAF? And then #3, can you use ctDNA? And so all of these are kind of ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 5:41 Mhm. Yeah. Jenny Seligmann 5:52 all part of what we're trying to do in the UK. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 5:55 No, no, I'm going to go in. I'm speaking. Okay, you mentioned BRAF, and I was going to get into this. When we talked to Richard and Noreen, there was all sorts of chit-chat about targets. MMR deficiency, BRAF, Raz, was Raz in there? Yeah, Raz was in there. Jenny Seligmann 6:10 Ohh. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 6:14 But is that in the is that in the game? Jenny Seligmann 6:17 So this is where you should be really excited about colon cancer. Colon cancer, I can see your excitement levels rising, but from where they were at the start. So colon cancer, in my opinion, is the new lung cancer. It's the new melanoma. So all, you know, us, ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 6:21 Well, I am excited. I'm permanently excited. What is this? Jenny Seligmann 6:37 GI cancer doctors have been looking at all of these exciting drugs and all of these cancer types and actually a lot of them are coming into colon cancer. So number one, BRAF, absolutely. We now have a first line trial suggesting that we can double overall survival by targeting BRAF. with chemo in the first line. So that's called the breakwater trial. So that's great. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 7:03 Yeah. And what agent is that using? Jenny Seligmann 7:06 So that's encarafenib and cetuximab. So you have to use a BRAF along with an anti-EGFR agent. We won't go into that. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 7:07 Yeah, yeah. Any specific? Oh, I've just already asked the question. Is there any? Jenny Seligmann 7:16 Do you really want me to go into the scientific rationale? I'm very happy to, but I might send you to sleep. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 7:20 Is there like a one-line answer? Bamboozle him, Jenny. He's got no idea. My brain is like there's a little hamster on a wheel here, so you got to speak to the hamster. Jenny Seligmann 7:24 So, if if you target... Fine, okay, so if you imagine you've got your BRAF receptor, so that's downstream of your EGFR, and that's firing off signals. So what happens to that is that stops negative feedback to the EGFR, so you can block BRAF, but then you end up having your EGFR firing upstream. And so that's why they found that the BRAF agents didn't work by themselves, because they did some cool dynamic cell line stuff. And then they found that then if they target the EGFR at the same time with cetuximab or panatumumab, then double blockade, actually, you needed both, unlike melanoma. to block the pathway. So that's how we've ended up with encaratinib and cetuximab. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 8:14 I think that was worth having that little explanation. Jenny Seligmann 8:19 It was really cool, really cool paper to be fair. But then we've got MSI. So MSI has completely changed the landscape in colorectal cancer. We are now curing people with metastatic colorectal cancer with immunotherapy. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 8:35 Drop the C bomb. She's dropped the C bomb. Jenny Seligmann 8:38 I have, no, and I have, I have, and we're seeing really long-term survivors in these patients that were only alive for two years. Not all patients, so I think that's the important thing to say. So only about half of patients seem to be long-term benefitors, but actually when we come to the perioperative treatment, immunotherapy is ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 8:48 Mhm, mhm. Jenny Seligmann 8:57 is a huge player there. But we've also got RAS inhibitors coming through to be tested. We've got HER2 being tested coming through. We've got KRAS 12C. We are refining our anti-EGFR population. We're looking at immunotherapy strategies for the MSS, not even just the MSI population. So there's loads coming. In what was a really, really quiet time over a 10-year period, there's lots coming now. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 9:27 I think we've put the cart before the horse, because we're talking about all of these exciting things happening in the future, but there's loads of stuff happening now. So I want to bring us right back through to... Yeah, you've jumped the gun. That's question six or seven, John. Now, we'll come back to those. Okay, okay. Let's talk about what's happening now. So Jenny Seligmann 9:38 Mm. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 9:47 You, we talked about how adjuvant treatment is, was the standard of care. I know that there's still, I don't know, have we have we ever put to bed the duration of adjuvant treatment and whether you should have? Or is that not the Scott? Oh my Lord. Is that the Scott? Oh my Lord. I just remember, yeah, boring. It's up to the listeners to decide if they're bored, okay? Jenny Seligmann 10:01 Yeah. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 10:07 Our presenter and our guest cannot say it's boring. OK. Jenny Seligmann 10:13 So, so, so... ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 10:14 OK, it is boring. OK, fine. Jenny Seligmann 10:18 Despite A meta-analysis with 20,000 patients, we're still at the point where there's still some contention between three versus six months. OxCap, 3 months, that's fine. But your T4N2s, like your really high risk patients, most people would still take them out to six months, but only use oxaliplatin for three months. So ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 10:32 Mhm. Mhm. Okay. Jenny Seligmann 10:38 I wouldn't say even despite this huge meta-analysis, I wouldn't say there's a completely uniform policy. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 10:44 Okay. It's always nice to have something to argue about. Okay, so we're still not sure about that, but we've got a bit of a bit of a feel. So Foxtrot, tell us about Foxtrot. How has that changed things? Or how should it be changing things? Jenny Seligmann 10:55 Sure. Okay, so Foxtrot was a really simple concept. So essentially looking at what was going on in other tumour types, the whole premise of the trial was to move six weeks of the planned chemotherapy you were going to give anyway, so part of the six week duration before the operation. So it was nearly 1000 patients were recruited in the UK and Denmark and Sweden and the primary outcome was met. So there were fewer disease recurrences at two, then three years, giving the treatment before surgery. So kind of makes sense. It's completely in line with what we've seen in gastric cancer. So what you could see is you could see reduction of so pathological response. You could see downstaging in terms of the tumour in the nodes, all of the things you would expect. Safety wise, there was no particular safety concerns in giving the chemotherapy. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 11:50 Yeah. Jenny Seligmann 11:57 And in terms of the operation, because of course, I think you have to remember with perioperative trials rather than adjuvant trials, this isn't a trial for oncologists, this is a trial for an MDT. So you have to have your surgeons engaged, you have to have your radiologists engaged, you have to have your surgeons, your pathologists engaged. And actually in terms of ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 12:00 Mhm. Mm. Jenny Seligmann 12:18 operative morbidity, if anything, there was a reduction in serious complications perioperatively and that was one of the biggest concerns. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 12:27 And that's because presumably you're downstaging the tumors, so the extent of the surgery or the complexity of the surgery reduces, you know, comparatively, I assume. Jenny Seligmann 12:37 Yeah, so our surgeon, so of course that none of this was like a secondary endpoint. It wasn't statistically significant because it was never going to be. But what our surgeon honestly thinks is that's part of it. But also another part of it is that we as physicians, oncologists are seeing the patients are like, oh, look at your blood sugar. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 12:49 Mmh. Jenny Seligmann 12:56 And there is an element of prehab that probably goes into it. I also think there's a dampening of things like the neutral lymphocyte ratio and like the systemic inflammatory response. So I think it's probably multifactorial in terms of, you know, the impact. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 12:59 Uh-huh, mhm. Mmh. AND. And perioperative trials in all cancer types are so hot right now. We're seeing it in lung cancer, we're seeing it in adenia, in melanoma, we're seeing it in bladder, we're seeing it in cervix. It's super hot, this topic. The advantage of the down staging, the path CR rate, but what were the primary endpoints of the trial, like the actual golden endpoints that you You hit. Jenny Seligmann 13:38 Yeah, so that was, well, it was two year relapse free survival. There was some contention about whether it should have been three-year DFS, but that's the nitty gritty. But that was met and that was statistically significant. And then it was a 5% difference in recurrences. And then if you look at three-year disease free survival, ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 13:44 Mhm. No. Mhm. And what was the difference? Okay. Jenny Seligmann 14:01 and then that held true in that. Another really interesting thing about Foxtrot was during the period of the trial, the understanding of the role of mismatch repair status became really well understood. So again, we now know and Foxtrot helped to really delineate that these pathways should be completely different. So our DMMR patients, ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 14:03 Mhm. Oh. Mhm, mhm. Jenny Seligmann 14:23 had no benefit whatsoever from giving six weeks of chemotherapy, which is what we would know and expect nowadays. Whereas the PMMR patients actually, you know, the difference was more marked if you then gave it to the biomarker group. And then this is then led on to all these sexy trials. So we can talk about where the ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 14:27 Mm-hmm. Jenny Seligmann 14:43 that this is going and in particular the neoadjuvant the neoadjuvant IO space. I suppose one point is well why what can what are the disadvantages of this and I think this is an important point is that is we're in a space in colon cancer where we're half trying to escalate. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 14:53 Mmhm. AND. Jenny Seligmann 15:02 to improve outcomes, but then we're half trying to de-escalate to reduce the amount of chemotherapy. So we kind of find ourselves between two forces. So the problem with the neoadjuvant setting in any tumour is can you identify patients? Because of course, all your adjuvant trials are based upon the resection specimen. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 15:03 Mhm. Mhm. Mm. Jenny Seligmann 15:23 Whereas in neoadjuvant, you've got your imaging. And that has been, I suppose, the difficulty in implementation. Not so much in the UK, the UK are great, our radiologists are great. But across the world, a lot of colon cancer cases are not discussed at the MDT until after. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 15:26 Mhm. Jenny Seligmann 15:41 or surgery. So there's a real implementation shift that's needed to deliver this. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 15:42 Okay. And presumably this was again, we're looking at the higher risk one. So is it the node positive at diagnosis that were included in Foxtrot? What was the what was the stage inclusion there? Stage 3? Jenny Seligmann 15:55 Ohh. So, well, that's the problem is there's some bits that CTs are great at. So CTs are quite good at identifying T3, T4 versus T1, T2. Node positive or negative is a bit more difficult. And this is particularly the case for the inflammatory like ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 16:05 Mhm. Mm. Jenny Seligmann 16:18 DMMR tumors. So it's most of a problem for the immunotherapy trials. But for Foxtrot, it was T3 or T4 any node. Of course, some MDTs only put in T4N positive. Some other MDTs were happy to put in T3N zeros. But it was, and I suppose ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 16:26 Yeah. Okay. Mhm. Jenny Seligmann 16:37 some of the criticism of Foxtrot is that you could be over treating patients who wouldn't normally get adjuvant treatment. So it's this balance that's been that's been trying to be found. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 16:42 Mm. Combination, yeah. And so we've done Foxtrot. We've learned that perioperative chemotherapy improves that relapse-free survival at two years and seems to hold true to three years of disease-free survival. Where does that, what does that platform move us on to? Because we never, we never rest, do we? Jenny Seligmann 17:13 Oh, of course not. No. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 17:14 So, and one question: have you started implementing Foxtrot treatment in your centre? Jenny Seligmann 17:20 Ohh, yes, of course, so, so two ways to... ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 17:21 Good, good, because that would have been really awkward if he said no. As I said it, I was thinking, I hope Jenny says yes, because... Jenny Seligmann 17:25 No, what? What? Let me tell you about what we've done. This is my life. So number one is guidelines. So can you change the guidelines? So number one, we've changed the NCCN guidelines. They want to particularly focus on the T4s. That's fine with me. You know, I'd rather people were treating their T4s than ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 17:31 Yeah. Yeah. Mhm. Jenny Seligmann 17:47 sticking on not wanting to treat T3s. So that's great. The ESMO guidelines are about to be updated for the first time in six years. So as I understand, there's going to be a nod towards neoadjuvant treatment. So that makes a big difference. The surgical societies have given a nod. The radiological societies are now coming up with guidelines for assessing. So we've made a huge shift. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 17:48 Mm. Mhm. Jenny Seligmann 18:13 We always understand that practise changes early adopters, mid adopters and late adopters. We saw it for rectal cancer. And so I think we're at the mid adopters phase. So in the UK, I think patients that present with a T4 will almost certainly usually be offered neoadjuvant chemotherapy unless ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 18:18 Mhm, mhm. Yeah. Yeah. Mhm. Jenny Seligmann 18:32 they're obstructed or there's a good reason. So I think across the UK, increasingly in France, increasingly in Europe, increasingly across Europe, this is a strategy. China, it's pretty adopted. The states are getting there. South America are getting there. But yeah, in terms of initial implementation, fine. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 18:33 I. Yeah. Jenny Seligmann 18:52 So I don't rest though. And the thought is, well, what can we do better? So we saw we've got no personalization. We need to do better. We've got personalization in the metastatic setting. The biggest other parallel strand of research ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 18:57 Mhm. Mhm. It. One last question. If you had a patient and you knew their MMR status and they were MMR deficient, would you give them the chemotherapy? Having said previously that you saw in the trial that they derived minimal benefit. Jenny Seligmann 19:23 No, and I think a huge impact of Foxtrot has been moving the testing from the post-op setting to look for Lynch to moving it to the pre-op setting. So you absolutely wouldn't do that. And then this will become obvious why you wouldn't do that when I tell you about the next tranche of research. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 19:31 Mm. Mhm. Mm-hmm. Jenny Seligmann 19:44 Yeah, yeah, yeah, you've done a great segue, so... And the, the, the, yeah. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 19:59 Anyway, enough of that. Yeah. I don't need to be mocked. You mocked yourself. Anyway, or something. Jenny Seligmann 20:08 This is a great dynamic. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 20:09 Yeah. I want to hear what Jenny says, not what you say, Mike. Thanks. Thank you very much. Jenny Seligmann 20:15 Right, so let's talk about deficient mismatch repair. So, as non-colon doctors, do you do you do you feel comfortable with what deficient mismatch repair tumours look like? ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 20:26 Well, we encounter them elsewhere. You do endometrial cancer. I do a lot of that. So I would feel like I'm pretty all over it, but I'm not going to go head to head on it. Jenny Seligmann 20:30 Right. Yeah. So in brief, in localised colon cancer, it's about 15 to 20 percent. So it's actually quite a lot more than you would see in endometrial. And of course, these are the types of tumours with lots of different mutations. And so they're very visible to the immune system, unlike proficient mismatch repair tumors, which in colon cancer are very known to be ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 20:48 Mm. Jenny Seligmann 21:01 you know, not very sensitive at all to immunotherapy. So these are your sensitive patients and it's 15% in the locally advanced compared to 5% in the metastatic and certainly includes more older patients as well. There was a landmark trial, it was presented in ESMO in 2003 that got in the presidential ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 21:16 Mhm. Jenny Seligmann 21:22 session by Maroon Shalabi from the NKI, and this was called the Niche trial, and that gave two cycles of nevo Ipi, and so two doses of nevo, one dose of Ipi, and then patients went straight to surgery, and there was a pathological complete response rate. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 21:23 Hmm. Jenny Seligmann 21:42 of 67%. There are no relapses at all. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 21:46 Like, imagine presenting that data. Like, I think if I like, this is why I would never be asked to do it, I would just go out of mic drop, I'd point to the slide and walk off and say, done. Jenny Seligmann 21:48 Oh, it was amazing. She didn't need to. The Shalabi plot came up and everyone stood up and clapped because please remember, we are not melanoma. We are not lung cancer. You know, we are not seeing stuff like this. You know, relapse free survival at three years, 0% is absolutely unheard of. So ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 22:01 Yeah. Yeah, just mic drop. Yeah, yeah, yeah. Yeah. The. Can we make it? Can we make a plea if anyone's at Esmo and they've got great data that they do a mic drop and just walk off if they have super data? Jenny, you're involved in. Yeah, could you do? I could push that. Would you would you try it? Jenny Seligmann 22:26 Well, we'll come on to our next series of trials and all of my opportunities to do that. It's the kind of thing that I feel like I could nearly get away with doing. Miriam could probably do it more than I could. She's a friend and she could almost, you know, in her Dutch way, she could probably get away with doing that with her gravitas. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 22:28 Fine. Yes. Yeah. AHMED. Yeah. Jenny Seligmann 22:45 But yeah, so this is massive. The problem is, is that that's not a randomised phase three trial. So we've run the neoprism trial. So Kaikin Shu run that from UCL, showing very similar data in terms of pathological complete response and waiting for survival. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 22:59 Mhm. Jenny Seligmann 23:07 But none of that is enough to push the needle in terms of the regulators. So in terms of the regulators, what they want is a phase three trial, which compares neoadjuvant immunotherapy to standard of care, very much like Foxtrot did with chemotherapy. So the Azure 2 trial, so that's a commercial trial that's already completed recruitment. So hopefully then ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 23:13 Yeah. Mmh. Jenny Seligmann 23:29 that will then become an option. But certainly in Scotland, they found a way to get nevo whippy in the neoadjuvant setting. But at the moment, if I'm at the MDT, ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 23:35 Mhm. Jenny Seligmann 23:41 For AT, I need a patient to be unresectable to give them immunotherapy. Otherwise, they go straight to surgery and then have adjuvant chemotherapy, which, as you can imagine, having seen this data in 2003 really feels quite frustrating. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 23:46 Mhm, mhm. 13 years down the line here. And the Azure 2 trial, what agents are they using? What immunotherapy combo is that? Jenny Seligmann 24:03 So, that's dostarlimab. So, that's 12 months perioperative dostarlimab, and that's then being compared to straight to surgery versus chemotherapy. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 24:05 Yeah. Yeah. So that's a single agent compared to the dual CTLA for PDL. So are we expecting, because, you know, in the other sites, dual seems to drive more toxicity, but potentially better responses. Are we expecting similar responses to the dual or? Jenny Seligmann 24:27 Yeah. Oh, so in some ways, so the data that we've seen so far is that you get very similar levels of pathological complete response, but you need to give it for longer with the single agent and the doublet. So they've gone with single agent for 12 months and you could ask yourself, well, what's the contribution of the adjuvant, if the blah, blah, blah. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 24:38 Mhm. Okay. Well, this is always this is always the question in every perioperative trial we get these great path CRs and then you're asked to give another 12 months or eight months of immunotherapy or post-op treatment and you're like, but we've got a path CR. And we don't know that answer because we haven't done the trial work. Jenny Seligmann 24:54 Um... Yeah. Yeah. I know. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 25:12 been if you get a path TR you stop. Jenny Seligmann 25:15 And you're never, and I'd be very surprised if that trial is ever done, to be completely honest. I don't think it's in the people who run these trials' best interest. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 25:18 Mm. So it would be commercially done. It wouldn't be done in a commercial study, that's for sure. Now, we've broken your flow. So if I had a zero or two, where does that take us next? Jenny Seligmann 25:24 No. No. So hopefully that takes us to a point where we can offer this as standard of care to these deficient mismatch repair patients. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 25:43 So we're MMRP, we're foxtrotting, we're MMRD, we're Azure twoing, but we're going to split the, but we're going to split or some or something to that effect. And then in within the MMRP, we're going to split that up, no doubt, into something else. Jenny Seligmann 25:46 Right, so... Absolutely. So, yes, of course, no. Of course I am. I don't stand still. So we had four years ago we had the Foxtrot platform funded. So we are at Foxtrot. We've just had approval for Foxtrot 7. So yeah. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 26:09 Mhm. Seven? Whoa! I thought we were, I thought we'd stopped at 4. What happened? What's 5, 6? Goodness gracious. Jenny Seligmann 26:19 No, no, no, no. Well, so let me talk since we just talked about Azure 2. So Foxtrot 5 is looking at giving Dostarlamab in older patients because we don't really have any evidence base in older patients. So GSK funded us to do that and the UK delivered. So we were amazing. Our sites were amazing. We delivered. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 26:34 Mhm. Jenny Seligmann 26:43 recruited the trial nine months ahead of target. And we should be reporting next year. It's close to recruitment. But what we're also doing in Foxtrot 5 is then moving on to Foxtrot 6, because the obvious question is, ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 26:51 Mhm. Jenny Seligmann 27:01 If you've cured all these people, do you really need to do an operation on them? So in rectal cancer, organ preservation is standard of care, but in colon cancer is not. But people are kind of doing it ad hoc. So as the Foxtrot groups, we've, so Campbell Roxborough, who's a surgeon up in Glasgow, is leading this arm. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 27:07 Yep, yes, those Tanamab, wasn't it? Yep. Great name. That is a great name. That's a very Scottish name, isn't it? Jenny Seligmann 27:22 It's a very Scottish name. It's a very Scottish name, yeah. So he's leading that. So that's giving six months of dostarlamab. And for those patients that we think have a complete clinical response, they continue another six months and they're on an organ preservation protocol, which is quite similar to the rectal cancer one. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 27:42 Yeah. Jenny Seligmann 27:42 but this is the first time it's been tried in colon cancer. But our UK investigators are amazing and they're up for the challenge. Of course, you then have to argue that colon cancer surgery is not as morbid as rectal. And then you have to follow up. You have to do a full colonoscopy rather than just doing a ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 27:56 That is right, yeah. Mm. Jenny Seligmann 28:05 and sigmoidoscopy. So there are pros and cons, but people are doing this in an ad hoc way. So we want to see in a prospective way, can we do this? So that's five and six. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 28:07 Mm-hmm. Mhm. What about 7? You said we're up to seven. Jenny Seligmann 28:19 Well, 7's still a bit controversial. ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST) 28:20 And I'm going to follow this on, Jenny, with what's your favourite Foxtrot.