The Oncology Podcast

S3E1 The Oncology Journal Club Podcast: ASCO GI Highlights 2025

• The Oncology Network • Season 3 • Episode 1

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Welcome to The Oncology Journal Club Podcast Series 3! Proudly produced by The Oncology Network

Three respected oncologists dive deep into the most significant research presented at ASCO GI 2025, bringing you practice-changing insights amidst a backdrop of political uncertainty affecting medical research.

Professor Chris Karapetis joins hosts Professor Craig Underhill and Professor Christopher Jackson to unpack ground-breaking colorectal cancer studies that are reshaping treatment paradigms. The conversation explores how targeted therapies are dramatically improving survival rates, with the DEEPER study demonstrating cetuximab's superiority over bevacizumab for left-sided RAS wild-type disease, achieving an impressive 50-month median survival when combined with chemotherapy.

The experts dissect the BREAKWATER trial, which shows promising benefits of combining encorafenib and cetuximab with chemotherapy for notoriously aggressive BRAF-mutant colorectal cancer. This combination achieved a 61% response rate versus 40% with standard care, with responses lasting significantly longer – representing a potential new standard of care for this difficult-to-treat subgroup.

Perhaps most surprisingly, our panel discusses how an inexpensive, familiar medication – aspirin – could reduce colorectal cancer recurrence by 40% in patients with PIK3CA mutations according to the ALASCCA study. This finding highlights how molecular profiling is becoming essential across treatment stages, not just for expensive targeted therapies but also for optimising use of accessible interventions.

The discussion extends to exciting developments in pancreatic cancer with a novel pan-RAS inhibitor showing meaningful activity, and advancements in immunotherapy for MSI-high colorectal cancer, confirming combination therapy's superiority. For gastrointestinal oncologists navigating an increasingly complex treatment landscape, this episode offers crucial insights to optimise patient outcomes through precise, personalised approaches.

Subscribe to The Oncology Newsletter for regular updates on the latest cancer research and join our community at oncologynetwork.com.au.

The Oncology Podcast - An Australian Oncology Perspective

Speaker 1:

Welcome to the Oncology Journal Club podcast, a dynamic and engaging learning resource for medical professionals. I'm your producer, rachel Babin from the Oncology podcast. Joining you today are your hosts, professor Craig Underhill and Professor Christopher Jackson, along with our special guest, professor Chris Karapetis. In this episode we'll be diving into the key highlights from the recent ASCO GI meeting, breaking down the latest research and insights. For links to the papers discussed and bios of our hosts, head to the show notes at oncologynetworkcomau. The Oncology Journal Club is proudly produced by the Oncology Network's podcast team. Thanks for tuning in. Let's get started.

Speaker 3:

Welcome everybody to this ASCO GI OJC special. It's a great pleasure to introduce Professor Chris Karapetis, or Christos as some of us call him, who's a professor of oncology at Flinders University, flinders Medical Centre in Adelaide. I knew Chris way back to when he was at Guy's Hospital. Not long after I was also a research fellow there and Chris came back to Adelaide and set up the research unit and so he just had his 25th year anniversary there and I understand you got a surprise party, which was nice.

Speaker 4:

Yeah, yeah. No, it was nice. You sort of reflect when you're at a place for a long time at how things have changed, and they've certainly changed a lot since I started here. So there is something really nice about seeing all that development and seeing all the people that have kind of come along with you and people that have developed over the years and their careers have flourished, and just to think that you've kind of helped out in a way.

Speaker 4:

Yeah, no, it's good. It was very kind of reassuring, affirming, and kind of made me feel old but good.

Speaker 3:

Fantastic Good on you and it's not such a great pleasure to introduce Professor Chris Jackson, New Zealand. If anyone needs to turn on their closed captions, please do so now. Welcome, Chris.

Speaker 2:

Kia ora Craig, Thanks, the warmest introduction you've given me in a while. I think you must have been foreshadowing that I was going to say geez, 25 years in one place and you're older than Craig. You're really old.

Speaker 3:

How are you not? I think he's a couple of years younger than me.

Speaker 2:

No, no, no, no, ck, you're already young. It's you that's really old.

Speaker 4:

Just to be clear, I was a very young oncologist when I returned from England. Yeah, so it's a bit older.

Speaker 2:

You said it craged us older.

Speaker 3:

All right, let's get into it. So, chris, what was the general vibe of the meeting? Because, of course, it all was happening in the midst of Trump inauguration and NCI announcements and stuff like that.

Speaker 4:

Yeah, yeah. So ASCO GI happened in San Francisco. It's a meeting that's been going on for a while. Originally I think there were a few different cancer societies that sponsored it, but it was always kind of known as ASCO GI the proper term for it is the Gastrointestinal Cancer Symposium and now ASCO are the sole sponsors of the meeting. There were 4,000 people that attended. 3,000 attended in person, 1,000 had online-only registration. So it's big but not huge. And from Australia there were only four people that went along and from New Zealand only one. So the five of us bonded really well through the meeting. So, yeah, very low numbers, I think from this part of the world. The majority of attendees are actually from the US, I think something like 2,500 US delegates, and then there's the rest of the world. But yeah, it was kind of low numbers from this part of the world.

Speaker 4:

I was there representing the HITG in various things a rectal cancer task force meeting sponsored by the NCI. I prepared a presentation and we sort of talked about the latest research in the area of rectal cancer. So I arrived on the Tuesday, the day after the new administration, the Trump administration, come in in the US, and on the Wednesday all NCI-sponsored meetings were cancelled. So my meeting, my task force, was cancelled. There were a number of people who had made the trip across to San Francisco from various parts of the US to be there for those meetings. Well, they were told to go home and they were told that the American federal government is reprioritizing, establishing a new agenda.

Speaker 4:

So things are certainly changing and I think everybody was quite surprised that it and research and through organizational structures and strategies, one particular organizational structure, and that is the federal government of the US, is changing all of that and doing it very, very quickly and that's going to have a flow-on effect. That's going to affect research, I think, in a major way. Asco, I'm pleased to say, the feeling I got in talking to various people is that they are definitely holding firm around their policy and strategy, which is deeply rooted in equity. One of the previous presidents of ASCO would often refer to equity every patient, every day, everywhere, across research, education and quality. I think that's still ringing true through that organization. It was still a good meeting, but that task force meeting didn't happen, unfortunately.

Speaker 3:

Was there any discussion about the DIA stuff?

Speaker 4:

Yeah, look, there was a really good lecture on day one. It was the keynote lecture of the meeting. The lecturer was Pamela Coons, who works at the Yale School of Medicine. She's a recognized expert in neuroendocrine tumors of the GI tract in particular. And she gave the keynote, which was titled Shattering Barriers with Inclusive Science, and she really focused on diversity, equity, inclusion and B. There's a D-E-I-B the B is belonging and she gave an excellent presentation on the importance of all of these aspects, of not just research but of policy and of care.

Speaker 4:

She gave a presentation at the ASCO annual meeting, results of a big face retrial that she had led. But then what followed on from that, she said, was a very difficult period for her in managing discrimination that was based mainly on gender, and she gave a number of examples of how it affected her and how it affected her career. And at the end of her presentation there were a number of questions from really concerned researchers saying what's going to happen to me now? What's going to happen to my research? What's going to happen to my grants? And these are researchers, some of whom are really focused on these issues as part of their research projects.

Speaker 4:

What happens to their research? No one's quite sure what's going to happen. We know that there are major changes, but it was just amazing how quickly the situation has changed. I'm really hopeful that ASCO will stay kind of true and firm in continuing to support the DEI themes through everything that they do. They've done a lot of work in this area over the last 20 or 30 years. It's just crazy to think that they can undo it. I consider it to be so kind of embedded in their ethos. Yeah, I agree.

Speaker 2:

Yeah, and I think also a lot of it is not just in their backyard, but it's also in our own backyard too. I mean, new Zealand abolished Te Akawhai Ora, which was the Māori Health Authority, last year, following on from an election which moved to a more right-wing slash, populist-style government. So these political changes do have a big impact on people, and they're not just things that happen overseas, they're things that happen in our own backyard as well. You know. That said, here we are three white blokes in a podcast, a chat about diversity, inclusion, et cetera. But you know, I think one of the key things is DEI isn't about diversity, equity and inclusion. What it's about is not excluding people, and since when did not excluding people become a controversial thing? So you know, frankly, it's a bit daft.

Speaker 3:

ASCO you mentioned. I mean it's an international organization in effect, so hopefully they won't just sort of acquiesce to this.

Speaker 4:

Yeah, and I hope so. I hope so too. And I mean there are a number of international colleagues that I met with who were kind of grumbling about the changes and some were actually saying that they will probably change their mind about attending the ASCO annual scientific meeting on the back of these changes. But I agree with you, I do see ASCO as very much an international organization. If you look at membership at the ASM, if you look at attendance, it's very international.

Speaker 2:

So hopefully they'll stick true to their Lancet, of course, has also just declared themselves as the watchdog on the US administration and how they're going to impact on change. That's in the Lancet editorial from last month. And of course, New England Journal of Medicine ran a series of reckoning of its own history of unconscious bias and racism as well. So I hope all of those journals and all of those organisations stay true to the principles they've preached over the last couple of years and double down and show actually, as professions and professionals, we have standards and we must stand up for those at every possible opportunity.

Speaker 3:

Yeah, and for you know as a regional cancer clinician. I mean, you know the equity issues is sort of at the heart of everything we do. So let's hope people don't just collaborate with this, because I think that's part of it. Cancelling those sessions seems to be People are more worried about what they'd do if they proceeded. What are they really going to do if you still had a discussion about rectal cancer? It seems a bit odd. Anyway, let's get into the science discussion. Try and lift the mood. There looked to be some really interesting stuff, christos. What do you think were some of the top scientific abstracts presented?

Speaker 4:

The first study I'll talk about comes out of Japan. Abstracts presented. The first study I'll talk about comes out of Japan.

Speaker 3:

It was a study that is known as the DEPA study, of course. So that's cetuximab, which has greater benefit than bevacizumab when combined with first-line M falfoxiri in left-sided RasB-Raf wild-type metastatic colorectal cancer. So can you firstly just explain again. We have a general audience. I may not be fully across it, but what's the significance of? This was a study in left-sided metastatic colorectal cancer.

Speaker 4:

That's right. So it wasn't. It started off as a study in colorectal cancer that was right and left-sided initially and it really wanted to ask the question is Bevacizumab better or is an anti-EGFR antibody in this case Cetuximab better when combined with chemotherapy? And they said let's just choose the best chemo, the one that produces the highest response rate, are only going to include really fit patients, and so the regimen they've chosen is a regimen that combines fluorouracil and oxaliplatin and r-inotecan. So everybody got the triplet chemotherapy and so the randomization was between bevacizumab, the VEGF-targeting monoclonal antibody, and cetuximab, the EGFR-targeting monoclonal antibody. So it started off right and left, but as data was emerging it really provided fairly convincing evidence that for the right-sided tumors you're better off starting with vivacizumab. They actually stopped randomization in the right-sided group and continued with left-sided only, and so they presented findings from the left-sided metastatic colorectal cancer cohort. They were all RAS wild types. That's important. They were patients that were considered patients that could benefit from treatment with an EGFR antibody and, as I said, they all got triplet chemotherapy and so they presented the findings.

Speaker 4:

The primary endpoint was depth of response, so that's really a measure of how much smaller the tumors actually get when you add them up in the absence of any progression. So no new lesions, no PD. But you then kind of add up the diameters of the tumor and see how small they get. So that was their primary endpoint. They were hoping to demonstrate that the EGFR antibody, I think, would produce a greater depth of response. There was some data in the lead up to this randomized trial that this was the case and so they presented the findings around depth of response, which they again demonstrated through this. That was one of the primary endpoints. There was a greater depth of response with the EGFR antibody versus bifidazimab. They looked at just overall response rate, standard resist overall response rate, and there was no real difference when you looked at that and disease control rates were not really different R0 resection rate. So a number of patients had such a good response. They go on and have surgery. It was about the same.

Speaker 4:

The duration of response was longer with cetuximab. They looked at progression-free survival, which was better with cetuximab, particularly in the RAS and BRAF wild-type group, and overall survival was trending for better with cetuximab. The median overall survival was 50 months with cetuximab versus 40 months with bevacizumab. So you know we're getting reasonably long survival times now in these studies and when one considers, I think when we started treating metastatic colorectal cancer, not many patients were living sort of longer than 12 months. So we're getting sort of median OSs in the kind of, you know, 40 and 50 month territory, which is an improvement of 40 and 50-month territory, which is an improvement.

Speaker 4:

It was especially longer in those patients with extrahepatic metastatic disease. So there's some interesting subgroup analyses. So I think this study is providing some evidence that would favor the use of the EGFR antibody over bevacizumab in RAS B, rafoal type left-sided cancer, especially if you're looking for kind of maybe a deep, longer response. We can argue whether that particular clinical endpoint is a clinically meaningful one, but there is a suggestion that PFS and overall survival are better. So I think that was interesting and would probably support a clinical decision around using an EGFR antibody for left-sided disease over using Bevacizumab as first line in that Ras-Wild-type, B-Ras-Wild-type group.

Speaker 2:

Yeah. So Craig, I'm going to get Chris and Craig I'm going to get stuck right into a couple of those comments there. Chris, let's start by talking about that primary endpoint of depth of response. What is your view on that endpoint?

Speaker 4:

As I said, I don't usually consider that in my clinical practice. It's not as though I would look at or try to quantify that depth of response in practice. So it's very much an endpoint that I'd consider research related. But there is data that talks to the patients that have a greater depth of response, also being patients that have a better survival. So there may be a true clinical benefit that translates out into that OS benefit.

Speaker 2:

Yeah, but it's an unvalidated surrogate, right? I mean, you've already got OS data for the primary endpoint which shows it's no different for the primary endpoint, than it becomes a bit meaningless, isn't it? So I mean, the pharmaceutical company's done that a couple of times with the depth of response endpoint. I think we should reject it. In terms of the overall interpretation of the study, chris, a couple of things that stand out to me. You know the medieval survival of 50 months, as you say. That's massive. I want it to be better than that. Oh, but it's massive though, right? I mean, what was the other studies of triplet-based but look, as I said, this is Folfox series.

Speaker 4:

So these patients are selected. We're looking at people without any comorbidity, people that are considered fit, well and good enough to receive a triplet chemo, and then on top of that they get a monoclonal antibody. So there's clearly a selection bias that's going to push that OS out in this study and that's understood. But it's consistent across two arms and we still see this difference in PFS OS. I think it's interesting seeing the difference in those with extra hepatic disease. I think that just talks to the disease burden. So we know that liver's often involved. Some evidence that suggests that Bev may be particularly beneficial with liver involvement. But again, when you're looking at trying to get the total burden of disease under control, I think the EGFR antibodies are active and they can provide that kind of disease control that may translate into a survival benefit.

Speaker 2:

I mean that is really interesting, isn't it? So a couple of things. First of all, around the medieval survival, because the seminal study of triplet chemotherapy was the tribe study, a, you know, fulfoxere versus fulferebev, um, and there are mos, was about 30 odd months. It's a long time ago now, you know 10 years ago, but it's 30 months. This is a really big increment, isn't it? Without any different drugs. So, as you say, I think they probably are selecting quite heavily in that group and that's probably appropriate. I mean, would you use Folfoxeri in many incurable patients these days, chris, in incurable patients?

Speaker 4:

no, no, I don't, no, I don't. And yeah, I mean, obviously we've got toxicity concerns. I'm still not entirely convinced that the triplet provides a survival benefit over proper use of sequencing treatments.

Speaker 2:

So that is important, isn't it? And then the other thing there as well does it take us any further forward than the other studies of cetuximab and left-sided colorectal cancer versus bevacizumab and left-sided colorectal cancer, like the CLGB study?

Speaker 4:

Yeah, I think, as you say, there is evidence around the benefit of EGFR antibody used for left-sided RAS epirethral type disease from the start, and so this is really a study that just adds that additional kind of confirmation that left-sided disease is the disease where you need to consider it in first line over abivacizumab, and again we've got a signal here of a potential survival benefit. So it kind of supports what I would say should represent optimal first-line practice. It's consistent with the NCCN guidelines. The use of nidrafarany bodies in first-line is there Now whether you use it with a triplet or a doublet. As I said, in my practice I'd be usually using it with a doublet, not a triplet.

Speaker 3:

Chris, I saw it as kind of practice affirming, because we've already seen, as you mentioned, NCCN guidelines, ESMO guidelines, ESCO guidelines they're all suggesting for the left-sided tumors to use an EGFR inhibitor rather than a VEGF inhibitor. So this kind of fits that narrative, doesn't it? I agree.

Speaker 2:

The other thing about the liver limousine versus the extra hepatic is that extra hepatic is also going to be the peritoneal disease, isn't it? And they're the ones which we think about as going really badly quite quickly. And that gives a degree to me when I look at the degree of comfort of using EGFR in that group, you know, rather than perhaps having it for later lines of therapy. And, Chris, you are Mr K Raz and Mr Siddiqui.

Speaker 4:

Well, Professor K Raz, a professor of some American, Australia Southern Mr, so you'll still think that its role sits in first line, Chris, in all patients, rather than second or third line For cetuximab, I think for left-sided disease yes, for right-sided disease, my standard practice would be to prefer bivacizumab, given the clinical trial data, and I'd be coming in with EGFR antibodies in the second or third line. There was another really interesting study that was looking at bringing EGFR antibody treatment into Firstline, but this is specifically in the BRAF mutant subgroup. This is the Breakwater trial.

Speaker 3:

Firstline combination EC and Polfox 6 improving outcomes in BRAF V600E mutant metastatic colorectal cancer, offering a new standard of care. Big call Big call.

Speaker 4:

Yeah, so we're looking at ECs and caraphanibs, the Tuximab which I think many people are familiar with, the BEACON study, which was a second line study for patients with BRAF mutation positive metastatic colorectal cancer. The BRAF mutation really confers an aggressive type of tumor biology. Usually we're talking about cancers that can be fast-growing, relatively chemorefractory, bad prognosis, unfortunately. So the BEACON study, a second-line study, did demonstrate a survival benefit in using N-carafnib with cetuximab after prior chemotherapy. The BREAKWATER study is looking at bringing that into the first line again for BRAF mutation V600E metastatic colorectal cancer, comparing the combination of chemotherapy with Folfox, which is a kind of a regimen that many people are very, very familiar with, combined with N-carafenibsatuximab, comparing it to standard of care. So standard of care could have actually been Folfoxerine it was for some patients. It could have been capecidabine, naloxalib, platin, folfox and with or without bevacizumab, and the study's primary endpoints were response rate and progression-free survival.

Speaker 4:

So at this meeting we saw the response rate data and the response rate data did favor the arm that included the EC and caraphanibsutuximab. It was an almost 61% response rate versus 40% response with the standard of care chemo. The duration of response was also longer. So if we look at the proportion of patients that have a response that lasts a year or more. It was 22%. So sort of one in five will have a response that lasts a year or more, with the N-carafenibsituximab added in, versus half that 11% with standard of care.

Speaker 4:

There was an interim overall survival analysis that did look quite promising, but it was interim. The alpha was set ridiculously high and what we saw was a 12-month survival of 79% with the encoraphenibs of Tuximab versus 66% with standard of care. So a numerical advantage, but at an interim level, with an alpha set at 0.00001 or whatever. It wasn't statistically significant. So positive for response rate, responses that last longer. And we did see a statement from Amgen. This was a sponsored study by Amgen and they did release a press release following the meeting to say that the second primary endpoint of progression-free survival was met. It was positive, favoring N-carafenibsituximab. I think that data will be presented either at the AACR meeting in April or possibly ASCO ASM in June. So we're waiting for that.

Speaker 3:

So I noticed that I'm going to throw to Chris, but I noticed the FDA actually gave accelerated approval for this combination. I think it'll be a while before we see it in our own jurisdictions and obviously we need that longer follow jurisdictions and obviously we need that longer follow-up. But again, interesting study, chris Jackson.

Speaker 2:

Yeah, look, I'm really excited about the study because, of course you know, beacon was a second and subsequent lines of therapy study, wasn't it? So it was following oral chemo and Brakewater's first line. So do you combine it with chemo or do you just use it on its own? And this really seems to point very, very strongly to the combination, doesn't it it?

Speaker 4:

does it does. Yeah, I mean there are toxicity issues that many people involved in kind of managing patients with colorectal cancer are now quite across. You do get more rash, obviously, with the EGFR antibodies. You get more asthenia, pyrexia with encorafenib, but those toxicities are manageable. But you need to obviously take that into account.

Speaker 2:

Well, so encocetax had quality of life data which was better than chemotherapy and Beacon, right? I mean for a couple of reasons One, because the combo is not chemotherapy and that got marketed as non-chemotherapy. But second of all, they live longer and if you live longer you have better quality of life in general. Eh, but when you're combining two drugs plus chemo which in this study was two drugs or three drugs there's a real question about synergistic or additive toxicities, right? Did you see much of that coming through, chris, in terms of the quality of life stuff or signals that made you, as a clinician, worry about this combo?

Speaker 4:

Yeah, look, as I say, I think it's important to take into account the toxicity and kind of making decisions around whether you're going to prefer to go with an approach that brings in the BRAF, targeting from first line versus second line. But they didn't present quality of life data. I'm sure that's coming, but I didn't see an indication that we were seeing significantly more of the toxicities that we're familiar with. And the other thing is that we're actually quite familiar with using drugs like cetuximab or panetumumab combined with Folfox. It's not a new regimen really. We're doing that already in the treatment of metastatic colorectal cancer first line. The big difference is adding in the apn carafinate, the management of that were you seeing on treatment deaths at all, chris?

Speaker 2:

you know things like deaths on treatment deaths or anything like that no, no, um.

Speaker 4:

And you know that the, the interim overall survival um data does suggest that we're going to probably see a true survival benefit.

Speaker 2:

Yeah, which is exciting, eh. And also there's panetumumab with dabrafenib. Isn't there in C delaciflavinase competitor? Basically, do you see this as a class effect or do you think this is going to be agent-specific?

Speaker 4:

Class effect, I suspect Probably hitting the target, is it? Yeah, that's right. So we certainly see remarkable similarity between panitumumab and cetuximab in terms of anti-tumor effect. We do see differences in toxicities, you know. So you get hypersensitivity reactions with one. You may not get it with the other. So they're not the same drug but in terms of their anti-tumor effect, their efficacy data, remarkably similar and same. With the TKIs. You get some TKIs that will cause more asthenia, pyrexia, others that will cause more rash and diarrhea. So they do differ and I think it's definitely worth shifting from one to the other in a patient that's tolerating one poorly, especially if the efficacy data looks similar.

Speaker 3:

All right, it's good. I'm glad Kristen's excited.

Speaker 2:

I think that one gets a bouquet for aiming for overall survival and PFS data, so it gets a bouquet. The last one gets both a brick bat and a bouquet. Brick bat getting a crappy primary endpoint in the first instance, but a bouquet for actually showing overall survival gains, so a bit of a mix.

Speaker 3:

Fantastic, glad you're both excited about that. It does seem like a potential leap forward, but it's a watch this space for some further data.

Speaker 4:

But while we're on the targeted therapy topic, Chris, do you want to talk about this new pan-RAS inhibitor that was this is remarkable for the fact that it was just a poster, so this didn't make it to any of the oral sessions the main oral session or even the rapid fire oral session. You had to sort of seek this out as a poster, but it got a lot of interest right, Because we're seeing multi-selective RAS. This is a RAS on a tricomplex inhibitor that is showing a significant degree of activity. They looked at patients with pancreatic cancer who had RAS mutations, and pretty much every case of pancreatic cancer will have a RAS mutation. These were specifically G12 mutations, not including G12C. All of the patients had prior chemotherapy, good performance status, and they presented waterfall plots where, you know, it's one of those sort of diagrams where just about every tumour got smaller In terms of actually reaching the degree of shrinkage, to call it a response. The actual response rate was 36%, but impressive water plots. This is the sort of early phase data.

Speaker 4:

There is a phase three second line trial that has started. The sponsor is a company named Revolution Medicines, and so these drugs costly, both in terms of financial costs, I'm sure, but also toxicities. There are significant toxicity issues that need to be considered. There's a lot of grade one, two toxicity, and I know we sometimes tend to underemphasize the importance of grade one, two, but it does have a major impact on quality of life. So things like rash, diarrhea, fatigue, asthenia pretty common. So you'd really want to see survival benefit come through in these phase three studies. But certainly exciting. And when it comes to pancreatic cancer, we need to be doing so much better than second line chemotherapy, so much better than second-line chemotherapy.

Speaker 3:

Chris, we've talked a lot on the podcast about these persistent but low-grade toxicities that you know can have quite a substantial impact on people's quality of life, so there was a lot of press about this paper. So it was in pancreas cancer. They were RAS mutated. Ras mutation is quite high in pancreas cancer. We've had KRAS G12C inhibitors on the market sotiracib in lung cancer and also adagracib in non-small cell lung cancer and colorectal cancer, and this one's even less pronounceable. Can you say it, chris?

Speaker 4:

Daraxonracib, daraxonracib, daraxon.

Speaker 3:

Look, it'll have a better name than that when it finally kind of yeah, but I think because it's an unmet need, isn't it having a RAS mutant that's not specific to the subtype, the 12C or 12D, etc. So I think that's probably why this had quite a bit of attention.

Speaker 4:

Yeah, yeah, they did some interesting research as well, looking at RAS allele frequency in blood samples, and they did see that there was a significant reduction in the RAS mutation allele frequency rate. So there was a sort of a molecular response and those molecular responders had a really good you hear it in a disease control, progression-free survival. So this is definitely biologically active, you know, and hopefully the phase three studies will prove that these medicines provide a survival benefit.

Speaker 2:

Yeah, it's pretty important to you know. Look at them either alone or in combination with chemotherapy in a randomized way, isn't it? You know we've seen that a lot and they promised a lot because it was supposed to be a tag that you far didn't deliver very much. You know Aleprib and the PARP subgroup. You know nice idea, but you know the OES data didn't pan out so well. So you're right, we do need the renawised data there. Chris, really strongly endorse that comment. But, as you say, this is a really high mutation frequency. What? 75% plus of pancreas cancers a really important target. So it is a really huge watch the space, isn't it?

Speaker 4:

It is, it is, it's huge. I think they got a median survival in this study. Again, this is sort of phase one, two data of over 12 months in sort of second line. So I do want to see phase three data, but it certainly looks promising.

Speaker 2:

Yeah, we'll get the first line pretty quick, won't it?

Speaker 3:

Yeah, I expect so. So, Chris, let's switch tack. What about Alaska aspirin? You know, from the sublime to the ridiculous, from the multi thousands of dollars targeted therapy to something like pain, tell us about this study. Now this was, it was adjuvant low dose aspirin in colorectal cancer or alaska yeah, yeah, that's that's what the study is looking at.

Speaker 4:

but but they did something really clever and they basically performed a genomic testing on the cancers. These were all stage 1 to stage 3, some very early stage as well. They included rectal or the rectus was stage 1 to 3, and the colon was stage 2 and 3. And they looked particularly for PIK3CA somatic mutations exon 9, exon 20, and other PIK3CA mutations. So they had a cohort A, which was the exon 9 and 20 group, and the others were a cohort B.

Speaker 4:

But both cohorts benefited significantly from aspirin in terms of reducing the risk of colorectal cancer recurrence the hazard ratio was 0.49 and reducing or improving disease-free survival at three years from 81% to 88%. So that's a significant proportion, or reduction of 40% if you do the math. It's actually quite a significant improvement, and that's through giving aspirin at a dose of 160 milligrams for three years. So I looked at the data. This is proper prospective randomized control data. It stems from a group based at Karolinska in Sweden. The patients were recruited across the Scandinavian countries. You know reasonable numbers over 300 patients in each cohort.

Speaker 4:

Interestingly, it only made it into the mini oral sessions. They're like sort of the tantalizing tidbits rather than the real deal make it into the oral. But I looked at that and I thought gee, you know, I think we've got something here and we should start looking at PIK3CA for our patients with resected stage 2 and stage 3 colon cancer and rectal cancer and it's a three-year program. I mean there were the recognized risks of aspirin but the risks were quite low within this cohort the bleeding risk, obviously, and a significant difference in the disease-free survival and colorectal cancer recurrence risk. So I kind of saw this as potentially practice changing. But I don't think any of us are routinely checking for PIK3CA somatic mutations currently.

Speaker 3:

You read my mind. Is that not something that's routinely done now, especially in the early stages? Should we be testing people?

Speaker 4:

Well, that's what the data from the Alaska study indicates, that we should be testing and we should be discussing aspirin use in patients that have PIK3CA mutations. You know this study was really based on a number of studies that looked at the benefit of aspirin in this group, but these were mainly retrospective or population-based cohort studies. But they have suggested a benefit in the patients with PIK3CA mutation, somatic mutation, positive colorectal cancer. This is a prospective randomized controlled trial showing a benefit. I just looked at it and I thought if aspirin was a really expensive molecular target or tyrosine kinase inhibitor, this would be a plenary at ASCO.

Speaker 3:

So, Chris Jackson, can I ask you are you going to start testing all your patients now for mutations?

Speaker 2:

Yeah, look, I think the thing is that the PI3 kinase mutation testing is not funded, craig, and the paper's not even been published yet, so we would have had to ourselves to talk about funding and reimbursement, I think. And also we've got data from ASCOLT. It must be the AGI-TG ASCOLT tissue sub-study which must be due or overdue, at least.

Speaker 4:

It's overdue, it's coming, I can tell you, and PIK3CA is definitely something that's been tested and it's like there'll be. You know, effectively it'll be a retrospective, ad hoc analysis, looking back at the experience and the outcomes and dividing by PIK3CA status. So that'd be very interesting, I think.

Speaker 2:

And if that's confirmatory, then we're there right. I mean, I must confess I did send this study straight on to my pathologist when it was announced and said, you know, coming to a path lab near you and asked him to edit. You know, and with colorectal we're getting close to lung in terms of the relevant actionable mutations, in terms of mismatch repair, microsatellite stability, you know, raf-ras, pik3 kinase now as well, and HER2 expression also. You know, once you get up to six, seven, eight immunohistochemical stains you're looking at, really it's almost getting cheaper to an NGS if the NGS can get down to the thousand dollar mark. So I think we're going to get there very, very soon.

Speaker 4:

I agree. I agree. I think we're getting to a point where any cancer that's considered advanced, at least including locally advanced, will probably be tested more comprehensively when it comes to genomic mutations, because I think it's going to have a bearing on our treatment recommendation. So fantastic.

Speaker 2:

And the ASCOT study. The only other problem in the ASCOT study was people who were on aspirin and omeprazole PPI were excluded and we found we were recruiting for that study that half or more of our patients were actually on omeprazole results. We couldn't put them in and so we took the approach while that study was ongoing just to give everyone who had another indication, such as hypertension or cardiovascular disease, aspirin or high cardiovascular risk until Ascult came out as negative.

Speaker 3:

Fantastic, we're running out of time. We can't finish the podcast without talking about immunotherapy, even in the BI settings.

Speaker 4:

In colorectal cancer there were two big kind of immunotherapy presentations. One was the Checkmate AHW study, which was a study that looked at patients with deficient mismatch repair metastatic colorectal cancer. They could come into it after previous chemo. They could come into it first line. So it was a mixture of stages in terms of their cancer treatment or had good performance status. So there were three arms in the study. It was a 2-2-1 randomization. The first arm was NEVO alone, the second arm was ipinevo and the third arm was a standard of care chemo arm. So what we saw at the ASCO GI meeting this year was the comparison of NEVO alone versus ipinevo. So we already know that immune therapy is better than chemotherapy for metastatic colorectal cancer with deficiency and mismatch repair or microsatellite instability. We already know that. So this is now saying which is the best immune therapy? Is combination IO better than just PD-1 targeting immune therapy? And the answer is combination is better.

Speaker 4:

The progression-free survival hazard ratio was 0.62. The response rate was higher. Yes, there were more adverse events, mainly endocrine events, things like adrenal insufficiency. You do see more of that with IPI. But there was definitely a benefit. This was IPI-NEVO, where the IPI is given just four times every three weeks. One milligram per kilogram was the dose and then after that you continued maintenance, nevo, but there was a PFS benefit with a combination. So that was interesting.

Speaker 4:

And the other immune therapy study that was interesting was a study known as RESECT-C, which was a study that came out of interesting. And the other immune therapy study that was interesting was a study known as RESECT-C, which was a study that came out of Denmark, and this looked at giving patients with early stage colon cancer again deficient miscarriage repair just one cycle of pembrolizumab and it kind of showed us what other studies have shown us in this setting, that you do get significant response. You get a high rate of pathological CR. This is just with one dose. It was a 44% PAT-CR rate and a 57% major path response, higher actually for those cancers that were considered to be stage one, stage two clinically. It's always a bit difficult to stage cancers like this clinically, but it was 61%, patsy R, if it was stage one or two cancer. So you know this is tantalizing. You know maybe we'll be moving towards using just immune therapy and avoiding surgery, but we're not quite there yet. It's just really exciting, I think.

Speaker 2:

Which is a small population, isn't it? But a really important one to discover, which is why, you know, everyone these days is getting MMR or MSI testing as standard right.

Speaker 4:

Correct it's yeah, you don't even have to ask for it now it's going to happen.

Speaker 2:

I think, chris. I think 8HW is a really important study because everyone has been using immune monotherapy versus chemotherapy. We knew that and 8HW was three arm but that only reported two of them, which I never quite understood. So we didn't actually know if combination IO was better than monotherapy. Right, and this really does suggest, or does suggest to me, what's your opinion. Do you think it does confirm, to your satisfaction, that combination IO is better than monotherapy in this group?

Speaker 4:

No, it does Look. I think we're going to see that this group of patients are going to have clinical outcome improvements that start to mirror what we see with melanoma, where we're already seeing incredibly durable responses with relatively short courses of IO. So this is a really immune therapy responsive group and in the melanoma world we know that combination IO is more likely to give you a durable complete response. Ie always reluctant to use the word cure, but cure is, I think, what we're seeing in melanoma and I think there are going to be some patients that have deficient mismatch repair, metastatic colorectal cancer that are going to have responses that last for many years, and you're more likely to get that with the combination. Again, it's about patient selection, because you will get more toxicity and we need a bit more data.

Speaker 2:

Anything on subgroups like liver-only group, for example? Because liver's an immunosuppressive phenotype, isn't it so? Was that a factor at all?

Speaker 4:

Every group, I think, benefited from the combination. Yeah, Every group.

Speaker 2:

Well, that is really important to have combination versus monotherapy, as a largely settled on PIS at least, if not on OIS.

Speaker 3:

Yep, all righty. Fantastic discussion, gents. Well done. Sounds like it was a great meeting, chris, even though there was not great representation from this part of the world, but some exciting data.

Speaker 4:

I spent some great time with Michael Jamison from New Zealand as he presented SPAR, and it was really I mean, this is where the meetings the face-to-face meetings become really useful, because we met up with a researcher from Tata Memorial in Mumbai who would basically just he was a lead investigator on a trial that did exactly what SPAR did, and this was a study that looked at combining chemo radiotherapy with a statin for patients with rectal cancer operable rectal cancer. We met with this fellow and we're looking at potentially combining data sets, and I think a lot of good things will come from it. So, and it was just great spending time with Michael. He had a poster there, a really interesting poster that does suggest that statins may provide a benefit, but we need more research, obviously.

Speaker 3:

So wonderful, all right. Thank you both for a great discussion. Thanks, chris, for taking the time to come on the podcast. Thanks, chris Jackson, and hopefully we'll see each other face-to-face soon. Thanks again, rachel. Look forward to some feedback from our listeners on today's episode. And you may also want to sign up for the Oncology News Australia newsletters. We'll put the link and people can sign up for some regular oncology news. All right?

Speaker 2:

Well, happy birthday to you too, craig, thank you. I know that listeners can only hear you, not see you, but I'd just like to assure everyone he doesn't look a day over 70.

Speaker 3:

Ah, dear Touche, All right, see you later.

Speaker 1:

Thank you 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 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.