The Oncology Podcast
The Oncology Podcast including The Oncology Journal Club Podcast by Professor Craig Underhill, Dr Kate Clarke and Professor Christopher Jackson; and Supportive Care Matters by Dr. Bogda Koczwara.
Oncology News and Expert Analysis from a unique Australian viewpoint.
Proudly brought to you by The Oncology Network.
The Oncology Network are producers of digital resources that support busy oncology health professionals. For more information visit our website www.oncologynetwork.com.au.
We also invite Healthcare Professionals to subscribe to The Oncology Newsletter and our Oncology Portal for free and exclusive resources at: www.oncologynetwork.com.au
The Oncology Podcast
The OJC Episode 6: ASCO 2024 Special Part 1
Imagine having the latest breakthroughs in oncology from the ASCO 2024 conference delivered with humour, expert insight and personal stories. That's exactly what you'll get in this special episode of the Oncology Journal Club, where Professor Craig Underhill, Dr. Kate Clark, and Professor Christopher Jackson dissect the most impactful research in a uniquely engaging way.
Going beyond the usual presentations, with analysis of practice changing presentations aka 'The Bangers!'
From Professor Jackson's cultural adventures in Invercargill to Dr. Clark's firsthand experiences on the bustling floors of Chicago's conference halls, we bring you an unforgettable review of the key highlights, including the Destiny Breast 06 abstract.
No other ASCO Commentary is going to combine Spotify playlists and visions of senior oncologists in mankinis with high-level expert analysis. The OJC team are famous for reviewing oncology research with unique humour and entertaining insights.
So join us for Part 1 of the ASCO Special from The Oncology Journal Club Podcast!
For papers, bios and other links visit the Show Notes on our website.
For the latest oncology news visit www.oncologynews.com.au.
We invite healthcare professionals to join The Oncology Network for free - you'll also receive our free weekly publication The Oncology Newsletter.
The Oncology Podcast - An Australian Oncology Perspective
Welcome to the Oncology Journal Club ASCO special episode part one. Here we take a famously different approach to oncology research. If you're looking for an enlightening and entertaining take on ASCO 2024, the OJC team has you covered with their unique blend of expert analysis and humor. Our hosts go beyond the usual presentations to highlight how the research will impact clinical practice. I'm your producer, rachel Babin from the Oncology Podcast. Joining me are our amazing hosts, professor Craig Underhill, dr Kate Clark and Professor Christopher Jackson. For additional insights and links to all the papers, visit the show notes on oncologynetworkcomau and don't forget to check out part two of our ASCO special. If you or your organisation are interested in podcast sponsorship, advertising or production opportunities, please reach out to us at info at oncologynetworkcomau. This episode was proudly produced by the podcast team at the Oncology Network.
Speaker 2:G'day. Kia ora, Kia ora. Welcome everybody to this OJC podcast special Post-ASCO Thoughts. So many of you will be attending or planning to attend some Post-ASCO webinars or face-to-face meetings in various cities throughout Australia and New Zealand. This is something a little bit different. We're going to be interpretive, dancing some Kaplan-Meier curves and describing them orally, which will be interesting, but this will be our take on some of the potential practice-changing interesting data from ASCO. So welcome, Professor Jackson. Kia ora, Coming live from Invercargill tonight, I understand coming live from Invercargill tonight I understand.
Speaker 3:Yeah, I've got the great privilege of visiting Aminai in Invercargill to do a hui on kids care, which is a really important issue in this population down south, talking about both ethnic inequalities and cancer outcomes, and also issues around rural access to care as well. So great to be down here in Invercargill looking forward to the hui tomorrow and beaming in for Esco.
Speaker 2:Explain hui. That probably means something different in Australia.
Speaker 3:Yeah well, hui is quite hard to describe. It's part of our cultural vernacular. It's a meeting on a marae which has a very strong cultural component to it. It's a formal welcome, usually what's called a pōwhry, where you're welcomed onto the marae, which is a Māori meeting house, and you have the meeting, and then you have a lot of food, eating, talking, a lot of good rhetoric, sharing of ideas, a lot of connection, and then finishing with karakiri or prayer and then closing. So it's going to go all day and it's going to be great.
Speaker 2:Yeah, good on you. It's a bit of a privilege to be asked to do something like that. Fantastic, it's a huge privilege, and Invercargill's right down the bottom of New Zealand, is that right?
Speaker 3:Well, we would call it the most southern point rather than down the bottom. Yes, thank you. As a colorectal oncologist, to being at the bottom of New Zealand is probably quite appropriate.
Speaker 2:Welcome to Dr Kate Clark. Kate, you went to a hui with 50,000 of your closest mates in Chicago. How was it?
Speaker 4:It was great First time since COVID for me and just amazing. I was just telling the boys I got to finally meet Dr Mark Lewis and we've done a Mark Lewis meets previously on OJC, so please have another look at it. An amazing oncologist, just an all-round nice guy and, yeah, 50,000 people in the room. I'd forgotten what the buzz felt like. It was just uplifting, really uplifting.
Speaker 2:Yeah, okay, we'll put the link into that OJC Meets episode with Mark Lewis. I'm just going to pull you up there. Use the term post-COVID.
Speaker 3:Yeah.
Speaker 2:So I don't know what it's like in New Zealand at the moment, but we're right in the middle of it. There's huge impacts still on the health system, so post-lockdown is probably the more politically correct expression, I think.
Speaker 4:Yeah, no, you're probably right. I think I'm, like many, feeling more than a little burnt out by the whole concept and you know that isn't a very responsible attitude. I'm with that, but that's my emotional response to the whole thing. So, no, I would agree with you. We are still mid-COVID. It's still a problem. Get your updated boosters ASAP, please.
Speaker 2:Yeah, that's right, chris.
Speaker 3:And just checking in on that, kate too, did you also get to the Second City Comedy Club in Chicago this time?
Speaker 4:I even took some colleagues who'd never been to stand-up before and we had a ball. Yep had stand up before and we had a ball. Yep, had a ball fantastic and go to spotify frank turner and the sleeping souls went to a gig on the first night, which is interesting with that amount of jet lag.
Speaker 2:Brilliant, brilliant gig, brilliant gig we went to u2 at chicago fields one year. That was pretty plenty amazing. But yeah, let's put a link to Spotify to this hot new band. Don't you love the OJC? You're not going to get that at the Post-ESCO meeting in some restaurant in Sydney or Melbourne. All right, kate, do you want to kick off? Tell us what you thought was some of the potential exciting or practice-changing abstracts of the meeting? There was a lot in the ASCO Daily News and featured in the media about breast cancer. So what took your eye there?
Speaker 4:I struggle because I do treat breast cancer and I enjoy looking after people with breast cancer. But it feels so much further down the research track that maybe the excitement is a little bit fringy rather than the big movements that are happening in the cancers that are catching up. But I did get up at half past seven in the morning in Chicago to go to LBA 1000, which was Destiny Breast 06. So this is, I think, fascinating for those of us getting to learn to use trastuzumab, daraxetan and other antibody conjugates that are targeted-esque. So this was patients with HER2 low or ultra low. So to be defined as HER2 low you had to have HER2 IHC 1 plus, were you allowed 2 plus. You definitely weren't allowed to be FISH amplified or just the ultra low, just had a blush, so some staining on their HER2-IHC, so a little blush and they gave them trastuzumab Teraxetan at second or later line. In those patients who were also ER positive, who also had what we would now consider standard of care, so endocrine therapy and a CDK4-6. The comparator arms were capecitabine, nabpaclitaxel and paclitaxel, so appropriate comparators. And the difference in progression-free survival was 13 months versus eight months, so a significant five months different. Obviously, os is going to take a bit longer to read out month's different. Obviously, os is going to take a bit longer to read out.
Speaker 4:So really, really interesting, because this is supposedly a antibody conjugate that is aimed at HER2, but you don't need a lot of HER2 for it to gain benefits. So is that because it's leaky? Is that because we've got the story up about HER2 expression up the yin-yang? I think there's an awful lot of research still to be done. We've still got problems with interstitial lung disease in this drug, so this is still something that needs very careful, very expensive monitoring. And, just as an aside, there was a chinese group that have invented a anti-her2 antibody conjugate that they thought would be better as it's more stable, so less leaky. That actually had higher rates of ILD and introduced new ophthalmologic toxicities. So we just I think we're still in the infancy of understanding how these things work. These things work. We know that we're not 100% sure how and the toxicity management was tricky. So that was my one breast cancer banger.
Speaker 2:So tell me, Kate, about HER2 ultra-low. So if you add up HER2 ultra-low with the blush that you mentioned and then the 1+, 2+, 3+, how much is the proportion of breast cancer Does that cover off on?
Speaker 4:Yeah, so it pretty much. Only there's very few people who are excluded. I think it was 20% in total. So if you include your genuine triple negative breast cancers and your genuine ER negative breast cancers and your genuine ER positive HER2, absolutely nothing. It's only about 80% of all breast cancers. So it is now a no-brainer to have trastuzumab duroxetan, at least as a thought for most people with breast cancer At the moment still in later lines of therapy. But that's a huge population of people.
Speaker 2:Yeah, there you go, Interesting Chris.
Speaker 3:So, kate, is it hitting the target?
Speaker 2:Kate's doing a shoulder shrug.
Speaker 4:Big shoulder shrug. Nobody made any effort to explain what we're actually looking at. So I think there is some thought that what we're seeing is HER2 changes all the time and all you need is a little bit of this to direct the drug to where it's supposed to be going. Or are we looking at something that's particularly? You know, I haven't seen any data in the HER2 zero population and that will be, I think, really interesting. So does it even matter? You know, I think that will be really interesting indeed. I remember back in the day when Chris and I are very similar ages, when I was. I remember back in the day when Chris and I are very similar ages, when I was, trastuzumab was a brand new drug and we knew it worked. But it took a long time to figure out how it worked, and I feel like we're in that place with these drugs at the moment. The assumption is they're a target in a chemotherapy and you're targeting it, but I'm not sure that's true.
Speaker 3:I think there's other stuff going on there we don't understand. Yeah, I mean, that was very much the same for cetuximab, wasn't it? You know EGFR expression being a poor prognostic marker, and then degree of EGFR expression didn't actually correlate with cetuximab activity, and you know groups didn't benefit. And then, of course, the RAS story. I guess you know HER2 is expressed quite broadly on many normal tissues and to a certain extent in normal tissues. So the off-target hitting of a drug, antibody conjugate, I guess, is a concern. That's where the ILD comes in. Are there other toxicity signals?
Speaker 4:Kate. Well, no, that's what I think was really interesting is that there doesn't appear to be an excess cardiac toxicity, or maybe we're just getting really good at looking at that and looking after that. The Chinese one that had the ophthalmologic toxicities I hadn't heard about that, about trastuzumab duroxetan, so that is interesting too. What's different about their drug? Is it the epotype of HER2 they're aiming at? Is it their cytotoxic payload? Yeah, again, the jury is out. So, I think, lots and lots of questions. Of course, the biggest toxicity of trastuzumab duroxetan at the moment is the price, and it is. Even with cost shares and access programs, it is still at the obscene end of.
Speaker 3:How obscene Kate what number.
Speaker 4:Oh, I can't even remember because I've just had I've literally just started my first lady this week. It is in the order of tens of thousands of dollars, a dose every three weeks.
Speaker 2:Yeah, okay, I was hoping to get through an episode where we didn't talk about drug costs, because it's all a bit depressing. Financial toxicity yeah, one of the things about going to ASCO it's this American feast, isn't it, where everything's bigger and better and abstracts that would be plenaries at other meetings are tucked away in a poster or in a small room. But let's just put a caveat on tonight's episode that we're just presenting the data and of course, a lot of them. Kate just mentioned the endpoints of this study with regression-free survival. Some of those I'm going to talk about had that as a primary endpoint, which of course we would disagree with. But we'll put costs aside and just talk about the results so we can get through in time. Are you happy with that?
Speaker 3:No, craig. No, I'm not, because drugs are only any good if the patients can access them.
Speaker 2:Fair enough. All right, Asterix. It Good on you, Kate. What else took your eye then? If there was nothing else much in breast cancer that you were excited about? What made you excited?
Speaker 4:The lower GI abstract session was a banger. It was more exciting than the plenary and it was exciting for those of us who work in MDTs because actually of my three next abstracts only one is about medical oncology. The other two are about surgery and interventional radiology.
Speaker 3:So what, what.
Speaker 4:Exactly. You know, cancer is a team sport and I think it's really important that we enlist our team members. So but let's see, we're literally in the order they come up on my tabs on the computer. Andrea Sersek presented an update durable, complete responses to PD-1 blockade alone and mismatch repair, deficient locally advanced rectal cancer, and that is LBA3512. And now, with 41 patients completing treatment, every single one has achieved a clinical complete response, median follow-up of 28.9 months. Not a single person has required any local therapy or had systemic relapse. Now, interestingly, this is DMMR rectal, which is left-sided, so where the BRAF DMMRs don't tend to hang out. She only has one in her cohort who's BRAF mutant. So they did identically. But it's just curious whether that's an artifact of the population being rectal cancer very left-sided or whether that will bear out something in the future. But absolutely fantastic. You know, those waterfall plots and swimmer's plots are not changing. How much longer we have to go for the naysayers to be quiet will be interesting. Three years, five years.
Speaker 2:Yeah, wow, so that's pretty exciting. This is further follow-up of the previously presented. This is further follow-up of the previously presented. This is the trial done at Memorial Sloan Kettering. Is that correct, kate? So this is a longer follow-up of the same cohort.
Speaker 4:Yeah, and of the so-called, there is an international phase two which is I think we've got about 160 patients on it, but that is yet to read out. But that again will be interesting because it's across different disease, different hospital settings in different countries. The other interesting that came out of London but I'm terribly sorry I can't remember whether it was UCLH or whether it was the big place in Surrey. I think it was UCLH nine weeks of pembrolizumab in DMMR patients and they got 67% pathological complete response with just the nine weeks. So I think the six months of disalimib is that necessary. There's a lot of translational correlative studies being done to look when response happens, what's the best guidance of response, et cetera, et cetera. So I think we will be watching this with interest. But if I had DMMR rectal cancer, I think I would be wanting a discussion with an oncologist about immunotherapy and I think I would be trying to avoid surgery if at all possible if I could have very significant surveillance.
Speaker 3:Yeah. So, kate, I may be one of those naysayers. I mean, I think in some ways this population is primarily lynch rather than what we see in clinical experience, certainly in our part of the world. So I think that's really relevant. And I also think the other critical thing to remember is that DMMR, colon and rectal have an extraordinarily good outcome anyway, stage two and stage three. So in my mind this is about morbidity reduction, not about mortality, because the majority of these people, 80% plus, don't relapse anyway. So it's about organ preservation and I think organ preservation is a really important outcome In rectal cancer, in colon cancer, where your mortality is around about 0.5% to 1% anyway for admission and your morbidity for immunotherapy is 5% plus for disabling disease, in a disease which can be killed with surgery anyway.
Speaker 3:We have to be careful about not jumping on the technology bandwagon and being thoughtful about how we weigh those up. The same, you know, we had the that was a neoprism study with pembrolizumab you mentioned, and we had the NICHE-2 study, which was ipinevo in DMMR, colon cancer, also showing extraordinary response rates In terms of a downstaging therapy. I think that's really important for minimizing surgical morbidity and also in people who are not fit for operations, but as a straight out substitute for an operation. I think we have to weigh that quite carefully.
Speaker 4:Yeah, just to. I said rectal for a start, so I think rectal is different. I am a what am I? Premenopausal woman. I don't want my pelvis irradiated, right? So that's a straight up. Thanks very much. I would rather hold on to my nether regions as they are, so I think that's a more complex conversation. I find it fascinating what to do with the niche data in those patients who don't require downstaging. I agree with you, if they look primarily unresectable, they look tricky to resect. Cool downstage sounds like a good plan, but all of the lynches you're going to take their whole colons out at some point anyway. So it does kind of seem odd. Again, I find that fascinating. So I was very excited to see that we don't seem to have, at least at 28 months, a late relapse or a distant relapse problem. So I think intellectually this is fascinating.
Speaker 3:I agree with that, and I also think that you're absolutely right, kate, that TNT is highly morbid and that it is worthy of reducing morbidity. But I think we have to be very clear as to what we're doing, which is about a modality switch from surgery to drug therapy.
Speaker 4:Look the other thing that I found absolutely fascinating because I know that well. I know in our MDT we often talk about using RFA in those patients who are medically inoperable. So this is collision trial. I'll put the horse back in front of the cart. Collision trial surgery versus thermal ablation for small size colorectal liver metastases, and it is abstract 3501. So what this group did was they randomized patients who had less than or equal to 10 colorectal liver metastases and nothing outside of the liver to either.
Speaker 4:I've got to get this straight because it was a little bit tricky either thermal ablation or surgical resection. Now, in real life, what actually happened was some of them got a combination thereof, but they were analysed in their intention to treat groups and surgical mortality was 2.1%. Nobody had a grade five event due to thermal ablation and it was very clear that it is non-inferior to choose RFA over surgery, because it's a non-inferiority trial. That obviously can't claim superiority but numerically at least was probably due to the patients that you lose at time of surgery. So I think that's really exciting because rather than having a whole de-roofing or a big shark bite scar, you may have a weak scar if access is an issue, but otherwise you can have it percutaneously. The vast majority of these patients did have percutaneous RFA and it's an overnight stay in hospital, home, brilliant, so I think that was really exciting.
Speaker 3:Yeah, kate, I think the open versus transcutaneous RFA is a pretty big difference, isn't it? You know the open RFA has often been superior to the percutaneous ones, and seeing the percutaneous ones deliver is important for clinical practice and, like you say, it's a quicker recovery too, isn't it? Have you found that people are hesitant to use?
Speaker 4:thermal ablation in your clinical practice. Look, I think it has been considered a second option, like for patients who maybe who were older, who had anesthetic risk. I like this data because it suggests to us that we can use the cheaper, more efficient, more patient-focused and not lose any advantage, and that's fantastic. The only perhaps advantage you're losing is you're not gaining tissue, which you know, for oncologists and translational research. You know we love a bit of, you know, no meat, no treat and all of that. But I think the last person that I was involved with who had RFA was 84, and he is now disease-free and well out to 86, you know, and that's really exciting. We went to see him on the round the next morning and he's like Kate, I don't know why I'm still here. Can I go home please? So very exciting, and it's always nice to see something that requires less morbidity to get the same outcomes. And then the final thing I want to talk about and I know that many people around the world will be talking about this abstract for a long time is abstract number 3500, transmet. So this is chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases. This is an incredibly brave trial. So a French, canadian and Italian group, I think, if I got that straight, and they randomized patients between best possible chemotherapy or chemotherapy and liver transplant. How that practically worked was patients were selected by their local MDTs who had liver only metastasis and had had a period of disease control on chemotherapy and it didn't have to be very long. And then they were referred on 140 odd. 150 odd were referred to the group and they ultimately randomized 40 odd in each. So the reason why people didn't get randomized is if the local group thought that was stable disease but the central group thought that it was actually progressive disease. On chemotherapy they were excluded. There were some people who were excluded due to small pulmonary nodules the local team hadn't thought relevant and there were some patients who the central team said I can resect that. So they were defined as resectable. When the local team thought they were unresectable, the patients were in the majority though it was not mandated in the protocol left-sided or as RAF wild type patients.
Speaker 4:The chemotherapy was paused, they went on the transplant list and they were to be transplanted within two months and that happened for the vast majority of patients and the intention to treat analysis.
Speaker 4:The five-year overall survival was 57% in the transplant arm versus 13% in the chemotherapy alone arm, and in the per protocol analysis which is a bit sneaky but I think is something that you could discuss with a patient who's made it past transplant the overall survival rate was 73% versus 9% in those that had only received chemotherapy. More interestingly, the median progression-free cycle after transplant was only 17 months. More than half of patients had a second site of radical therapy, mostly to the lung, and again I think that speaks to what we're learning about lung mets and colon cancer being a slightly different beast than lung mets elsewhere. So this is where I've always been a naysayer. The patients have always asked can you just transplant me my liver please? And I've always said no, that's rubbish, and it was an absolute contraindication a decade ago, but now it looks like for a small select group of people should be an option if we can find enough livers.
Speaker 2:Yeah. So, Kate, I was going to raise that last issue because we've always, I think, the teaching was that there'd been some pilots of it and people didn't do well because of the immunosuppression and in fact they might do worse with the transplant than having chemotherapy. So this really turns that on its head.
Speaker 4:Yeah, totally upset my biases. I think they were very circumspect.
Speaker 3:Look, I found that really fascinating. I think with the transplant what I found so fascinating was the three to five-year PFS was only 20% in the transplanted patients versus 0% in the, obviously in the people who got chemotherapy. So actually you're only curing a very small number. It's a large thing. It's about cytoreduction in that group and, kate, my experience has been exactly the same as yours, which is people have always said to me, can you transplant me? And I always said no, because no data, et cetera, and also the fears about immunosuppression, which really weren't borne out in this. But the improvement in overall survival, man, that's staggering. And I completely agree with you that the issue is going to be around about the availability of organs to transplant to get that addition and disease control.
Speaker 4:The interesting thing that the presenter spoke about was that, although they had an agreement with their liver transplant groups so they did get priority, they only used 2% of the available livers and so their transplants only took up 2% of the available transplants. That happened during the trial within the jurisdictions the trial was running. So it feels like us, who don't do a lot of transplants, that maybe we'd be using a lot of livers but maybe we wouldn't be compared with what's going on.
Speaker 3:Well, I think it's a fascinating and changing space because, of course, the reduction in hepatitis, with the vaccination, of course, is making a difference, and also my sister, who's Norwegian, or should I say, married in Norwegian. They have compulsory donor status in their country and you have to actively opt out of that, whereas ours is an opt-in system and Norway has been one of the countries which has led in this area because they've had a compulsory system and there's a lot to be said from that in terms of organ donation. My opinion, once you're gone, you're gone and certainly having that kind of a system whereby your eyes and your kidneys and your liver could be used to save someone else's life would be a great thing to help someone else after you're gone.
Speaker 2:Yeah, Interesting discussion. So I see earlier comments about cost and it's an interesting first world problem, isn't it, when we have published WHO essential oncology drug list which most countries can't access, and here we are talking about liver transplants. But it will be interesting to see further follow-up and probably bigger studies to try and replicate the results. We've been burnt in the past with transplants in solid tumors, notably the breast cancer work that came out of South Africa. So I think it'll be a matter of probably waiting a bit longer before we jump on that bandwagon. But we'll see, Chris, what else happened?
Speaker 3:Oh, Craig, do you think they're going to do that? Do you think they're going to repeat that study? I think the data from South Africa doing breast cancer was about BMT and people who had no residual disease. This is about taking out the organ which has been affected and has got metastatic disease in more than 20 tumours. I don't think the study is ever going to be repeated. I think now that's been done, no one's going to agree to be randomised.
Speaker 2:Do you think so? So no, my point being about a small study showing significant difference in a high intensity treatment. Yeah, I would want to see a bit more data. I would think we're talking about 40 patients randomised into each arm, so that's a small study, right?
Speaker 4:Yeah, but we're not talking about a 15% difference with a p-value of 0.04. We're talking about a p-value of 0.0000003, I think it was, it was something ridiculous and a hazard ratio of 0.2. You know, this is a stonking difference and it's not subtle and it's consistent and he could explain it. So you know. Longer follow-up of these patients will be interesting, but most of the patients in the control arm are dead, so they can't get any better. That's what I'm saying. They can't miraculously do better later.
Speaker 3:I think one of the other challenges of the scientific research that you'll face is the scientific perfection. And then there's actually what you can achieve no-transcript, but actually ultimately a jurisdiction has to agree that it's an ethical study and that you can actually proceed with that study in your jurisdiction, and patients have to agree to be randomized to that. And until you know, whilst transplantation is restricted, all right, chris, what else happened in GI? I think one of the problems I had with that last study was reconciling it with the ORCHESTRA study, which was a study of multi-organ metastatic colorectal cancer who could have up to 80% of their tumors to bolt and most of them got 100. This was people who had metastatic disease in three sites or liver only, with paralympic lymph node, adrenal or peritoneal disease. So these are people who had three sites of disease or five liver lesions plus one of those other high-risk sites, and they had to be 80% debulkable and a third had less than five lesions.
Speaker 3:The fascinating thing about the ORCSTRA study was that there was no significant difference between the intervention arm, which was the debulking arm, and the chemotherapy-only arm, which is suggesting that three-organ metastatic colorectal cancer or liver plus high-risk site is incurable and should be treated with systemic disease. Those with liver and lung had a median overall survival with chemotherapy 28 months and with surgery plus chemotherapy plus debulking had 30 months. So no difference. Peritoneal disease actually did better with chemotherapy 26.9 versus 24.3. And those who were good responders to chemotherapy were still at 29 months versus 32 with major debulking. So adding major debulking with high morbidity and multivisceral disease was getting maybe one or possibly two months additional and part of that is because people who undergo those radical procedures don't get back to chemo.
Speaker 3:And in actual fact we should be saying three-organ disease doesn't help people when you get to cytoreductive therapy. So you put that in the context of the liver transplantation and what it's suggesting is that if she's only got one or two organs with colorectal cancer, that's worth an aggressive approach. Three or more or liver plus one other high-risk site that probably remains incurable. So I found that really useful to help start to delineate some boundaries. For a while we've had exagerative surgeons who've argued over pelvic exageration with metastatic disease. Sites vary as to whether they will exentrate with another organ of disease. People who've done puristonectomies will vary as to whether they will also take on people with oligometastatic liver or lung disease also. But I think this is saying if you've got three plus this study is really saying the benefits of further debulking with interventional approaches probably just isn't there.
Speaker 2:Okay, thank you, orchestra, and then anything else for us, chris.
Speaker 3:Checkmate 8HW is another study in DMMR colorectal cancer. Now we know from Keynote 177 that people with DMMR colorectal cancer benefit from single-agent PD-1 inhibitor-like pembrolizumab. They do better. 60% of people are cured. We know that with first-line data, so that is now the standard of care. Checkmate 8HW was ipinevo times four, followed by nevo versus dealer's choice chemotherapy. It also had a nevo-only arm which I guess is comparable to 177, but that's not yet been reported.
Speaker 3:Dmmr colorectal cancer Patient characteristics are quite critical in this. A quarter had BRAF mutated status, 21% had NRAS or KRAS mutant status and they were the ones who did really badly in Keynote 177. But a quarter had unknown status. So that's a big black hole in terms of what those patients were and quite high for our community. Only 11% had Lynch, but a lot were unknown, of course, and so this I think represents more the patients who I see in my clinics, who are mostly DMMR but BRAF mutants by and large, with only a small spattering of Lynch out there. What they found was with ipinevo versus chemotherapy the 12-month PFS was massive 80% with ipinevo and at 24 months 72%, which means if you've got disease control at 12 months you are 90% likely to still be under disease control at two years, which is just huge. And with chemotherapy it's 20% likely to be under control at 12 months. So look, I'm a complete PFS skeptic and I really love seeing the OS data.
Speaker 2:Yeah, I'm amazed that you're presenting this in a positive light, Chris. What's going on?
Speaker 3:Look, but the gap in PFS is massive in that group. Of course he attempted to do cross-trial comparison between 177, which is the PEMBRO study, and Checkmate, which is the NEVO IPI. And you look at it numerically, of course IPI Nevo is higher than Pembro but of course there are difference in patient characteristics. There's a third arm which is Nevo only and we need to see how IPI Nevo compares to Nevo because that's, you know, patient selection, the same trials. We need to see what IPI is adding because of course it adds toxicity, but this is a pretty stonking PFS gain in that study. The hazard ratios make my eyes water In BRAF mutants, the hazard ratio of 0.37, for example, which is certainly A plus in the ESMO Med of clinical benefit scale.
Speaker 2:All right, and I'm surprised neither of you mentioned Esopec, so one of you going to talk to us about that before we wrap up GI.
Speaker 3:Yeah, esopec of course, and esophageal cancer of course. Cross has been the topic of the GEOA for a number of years in the GI oncology community and is discussed every week in the upper GI MDM Of course. Cross was a randomized study in adeno and squamous cell carcinomas of the esophagus which looked at five weeks of carbotexil really low-dose carbo-AUC2, but every week of course. So comparable exposure to three-weekly AUC6, with peclotexil at a dose of 15 mSq are lower than what you would do if you had metastatic disease and that was radio sensitization doses, five weeks compared to surgery alone. And it did improve overall survival.
Speaker 3:Our FLOT was a study predominantly of gastric cancer, so GOJ and gastric, and we did not have adequate data in esophageal cancer to say whether the FLOT regime actually worked. And this is in the background also where we had OEO2, two cycles of cisplatin 5-FU, improved overall survival compared to surgery alone. And then we had real, so OEO5, which was four cycles of EOX versus two cycles of CF, which was negative. So intensification of chemo and esophageal cancer previously had been negative. So I didn't necessarily think this was going to be a slam dunk. People said it was after neo-Aegis but actually it wasn't at all a slam dunk and what the study shows headline is that FLOT is better than CROSS, and that's the headline. So I think for most people it's going to displace that.
Speaker 3:There's quite a few complexities to the study, though, that are worth diving into. So, for starters, two-thirds to 70% of people who had CROSS actually completed it. Now that is really really low, and CROSS is a low-intensity treatment for esophageal cancer. We CROSS is a low-intensity treatment for esophageal cancer. We know that people with esophageal cancer have nutritional issues. We know they often have comorbidities. We know they've often lost a lot of weight. So they are often a comorbid population and high-intensity therapy in esophageal cancer is actually sometimes difficult to deliver. But CROSS, in my experience, has actually been quite a doddle. It's easy to deliver but in actual fact it was hard.
Speaker 2:Chris, when they say not completed, it's one thing to finish the radiotherapy, but because of neutropenia you've dropped out the paclitaxel in the last week, so that's a not completed. Are you saying 30% of the patients really didn't get their dose of radiotherapy, or do we have the details on that?
Speaker 3:No, I don't think we've got the detail of it yet, craig. And remember, esophageal cross is 41 gray of radiotherapy. So it is absolutely and utterly about downsizing the tumor slightly without increasing the leak rate. That's the purpose of the therapy. So it's a local, regional therapy to allow you to get out. When we gave high-dose chemo RADs preoperatively, like the STAAL trial, for example, with esophageal cancer using cisplatin 5-SU with doses of 50 plus gray, people leaked and they died. So intensification of preoperative therapy is not always a good idea because people suffer in the postoperative phase. So we've seen other studies whereby in the first year postoperatively people with intensive neurodegenerative therapies tend to die. But I think for people who are fit for either CROSS or FLOT, it's now clear that FLOT is better. For people who are comorbid or who can't tolerate multi-agent chemotherapy, then CROSS is still going to remain an option. But you know, cross was a local, regional treatment. Flot is a systemic treatment and most people with esophageal cancer die of systemic disease. So you know, the king is dead. Long live the king.
Speaker 2:So in the pre-immunotherapy availability days in Australia post-chemo radiotherapy people with residual disease we give immunotherapy. But I've often thought the chemo that you give with the paclitaxel and carbo low dose is not enough and that's why you know we're seeing these systemic relapses. So I'm not surprised by these results. But one of the problems we'll now have in Australia is if people are getting FLOT and then have their surgery, they won't qualify for the immunotherapy postoperatively. So there's still a whole lot of work.
Speaker 4:But we know that doesn't help, craig, that trial has been done. So Astige looked at post-flot node-positive or R1 resection so the ones you're frightened about and they randomized them into ipi-nevo versus completion of the flot, and the completion of the flot arm did better. Now there is, of course, a missing arm, which is nothing at all. So are what we're doing? Is the FLOT assisting or is the ipinevo killing people? We don't know. But what we do know is that there isn't a role for IO in those patients with the data that we have currently. So the people are better off to complete the FLOT Now. Again, that went against my biases, which would have been that if you haven't done particularly well on FLOT, why give more? But the data that we have at the moment is that's what we should be doing.
Speaker 3:What study was that, Kate? I don't think I've read that.
Speaker 4:VESTIGE V-E-S-T-I-G-E. It was presented at ESMO GI last year. Albatron was.
Speaker 2:Yeah, yeah. So I'm not surprised by the results, chris, because I think more systemic treatments better, but I still think there's going to be more trials to do Kate.
Speaker 4:I am fascinated because the difference between FLOT and CROSS and SOPEC is about 10%. It's about the same difference that you see in MAGIC versus FLOT. So the addition of the taxane seems to be what's pushed the chemotherapy into the superior bit. So you give all of the good drugs up front. Unless we start giving flotary, we can't give much more chemotherapy to these poor people up front. Yeah, craig and Chris are both pulling the best faces. Yeah, I've just invented flotary. I will never give it to anyone. I've just invented flotary. I will never give it to anyone, but I'm sure somebody has tried. You know we can't get much more chemo. So I wasn't surprised myself. But I had previously held hope that maybe what we see in rectal cancer, which is that if you have excellent local control you have excellent systemic control maybe that's what we were seeing. But then that's been proven wrong. So I did a lot of eating humble pie this ASCO. But that's the wonderful thing about the job we do is that you're wrong all the time and you can get proven wrong.
Speaker 3:That's right and God we trust. Everyone else needs data. I think there's a lot of future directions here. Right, we could look at a rectal type approach with FLOT followed by CROSS, for example, followed by surgery. So there's other trials to do there Addition of IO, stratified according to your PD-L1 status and, of course, kate, while you point out, the VESTIGE study, which I need to read, demonstrated that IO is inferior to FLOT.
Speaker 3:We, of course, don't know about the combination, and the cardinal rule of medical oncology is if some is good, more is better. So let's chuck all the agents together, particularly if there's non-overlapping toxicities. I think the reality, though, is that many patients are not fit for FLOT, particularly those who have a lot of weight loss, particularly those who have a lot of comorbidity, and so we have to be careful here. I find chemotherapy gives people good responses in their swallow quite early on, and the other thing is that people in the global oncology community have been delighted by the study, because, actually, radiotherapy globally isn't actually that accessible, and so they can deliver radiotherapy locally, and they've been really pleased that it's validated the role of chemotherapy being able to be given in your local community.
Speaker 2:And if we want to learn from other cancers, we know that perioperative is probably the way to go. So I think there's a whole generation of studies incorporating FLOT, plus pre-op immunotherapy and post-op as well. So great discussion. My take home from all this discussion about the GI today has been really about MDTs right. So we've had, you know, discussion about debulking. We might have discussions about transplants in selected patients. There's a whole area of discussion still in the esophageal cancer patients. Are they fit for flight? Is that what we're going to do? I think we now have options where you're going to individualize it in an individual patient according to the team's approach and your local circumstances. So very interesting ASCO probably more questions than answers, but exciting to see all of that new data. So I think we're going to wrap up this episode and we're going to pick it up again real soon with the second post-ASCO look, concentrating on some lung which was really pretty exciting data and some data in melanoma and other tumors.
Speaker 2:If you're sick of listening to stuff about ASCO, I'd refer you to episode five of the OJC, which came out a couple of weeks ago and has had some really excellent feedback, including from Associate Professor Jeremy Shapiro in Melbourne, who reached out and said he was really enjoying the podcast, called into question my mantra that three drugs were better than two in prostate cancer, but he reminded me that in the low-risk patients it should really be two.
Speaker 2:But he reminded me that in the low-risk patients it should really be two. I think, if you listen again, that's what came across in the paper we presented, which was a summary of the data at the moment in advanced prostate cancer and the role of the new novel antigen receptor inhibitors. But thank you, jeremy, for the feedback. It's great to hear that people are enjoying the podcast. So if you want a bit of a chuckle and also some educational material, listen to episode five. So thank you both. I know you've both got some commitments tonight and it's getting late in New Zealand, so we'll just leave it at that. Thanks very much and we'll see you again next week.
Speaker 3:Craig, can I just check Jeremy Shapiro is that the guy who wore the Borat Mankini rode a unicycle and did some juggling at AGITG one year?
Speaker 2:No, please don't, that triggers me.
Speaker 3:If you mention that image, I think Jeremy, we need some more Juggling Mankini YouTube videos soon.
Speaker 2:No, kate, thank you so much. I know you've got a big family celebration tonight, so thanks for finding time to record this and enjoy your evening.
Speaker 4:Thank you, craig. So the idea of Jeremy Shapiro half naked just reminds me that I have witnessed Chris wearing nothing but a guitar. Oh sure.
Speaker 3:That never happened.
Speaker 2:Oh, dear. Well, do you mind leaving the thank you, Rachel, behind the desk there?
Speaker 3:Thank you.
Speaker 2:Rachel, she's got a thumbs up and we'll see you again next week. Bye everybody, ciao.
Speaker 1:Thank you for tuning in to the Oncology Journal Club podcast, proudly brought to you by the Oncology Podcast. Part of the Oncology Network For healthcare professionals. Seeking regular news, updates and insightful discussions, we invite you to join our community at oncologynetworkcomau. Your free registration includes a complimentary subscription to our weekly publication, the Oncologynetworkcomau. Your free registration includes a complimentary subscription to our weekly publication, the Oncology Newsletter, a valuable resource to stay updated on the latest advancements in the field. We value your input and welcome your feedback and paper recommendations via our social media channels, email and website. Your insights help shape the conversation and drive the direction of future episodes. This is Rachel Babbin signing off for the Oncology Journal Club podcast.