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S3E8 The Oncology Journal Club Podcast: ESMO 2025 Special Part 1

• The Oncology Network • Season 3 • Episode 9

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Welcome to The Oncology Journal Club Podcast Series 3
Hosted by Professor Craig Underhill, Dr Kate Clarke & Professor Christopher Jackson | Proudly produced by The Oncology Network

Are you ready for some ESMO Bingo? Yes—it’s that time of year again!

Join our expert hosts Professor Craig Underhill, Dr. Kate Clarke and Professor Christopher Jackson for the usual OJC antics. 

This is Part 1 of our ESMO Special, where the team cover ovarian, breast, melanoma and GI. Expect the usual nuanced analysis and a few naughty jokes along the way.

To learn more about The Oncology Network, subscribe to our free weekly Newsletter and listen to other fantastic podcasts, visit our website: www.oncologynetwork.com.au. You'll also find the Show Notes on the website with links to the abstracts, bios of our hosts and a downloadable Bingo Card😂

SPEAKER_03:

Welcome back to the Oncology Journal Club Podcast, brought to you by the Oncology Network. Are you ready for some Esmo Bingo? Yes, it's that time of year again. I'm your producer Rachel Gavin and I'm once again joined by our Journal Club Dream Team, Professor Craig Underhill, Dr. Kate Clark, and Professor Christopher Jackson. This is part one of our Esmo special where the team cover ovarian, breast, melanoma, and GI cancers. Expect the usual nuanced analysis and a few naughty jokes along the way. For more information about the Oncology Network, including links to the abstracts discussed, head over to oncologynetwork.com.au. Thanks for tuning in. Let's get started.

SPEAKER_02:

G'day, g'day, g'day, or should I say Gutentag, Gutentag, Gutentag. Welcome to the OJC post-ESMO Berlin 2025. G'day, Dr. Clark, how are you?

SPEAKER_05:

Uh G'day, great. Very well, thank you. Feeling a whole lot better now that the wind has settled.

SPEAKER_02:

Any more sausage jokes to be expected? Seeing talking about Berlin and Bratwurst?

SPEAKER_05:

Oh, look, you've left that door wide open. So you know, you know how much I love a sausage. Um, and there is something obvious I could say. But those of you who know and listen to us podcast will know the two words that I want to say next, but I'm being too well behaved. So, Professor Jackson, how are you this afternoon?

SPEAKER_00:

Uh Kilda, we had some really good uh listener feedback from the last episode, actually, Kate. Um, so yeah, I think keep up the good work, really. Um see if you can slip in a sausage during the course of the uh discussion today.

SPEAKER_05:

Seeing as we're referencing I'd rather a sausage than radiation. There you go. Yeah.

SPEAKER_02:

Oh dear. Um leave that park that's quite funny watching Craig blush on a podcast.

SPEAKER_05:

We need to put that online somehow.

SPEAKER_02:

All right, so let's get into it. So it was a pretty big Esmo. Um, Kate, are you happy to go first? Because I think it was sort of breast moment in the sunshine. There was probably more hype about the breast abstracts and other tumor types of this meeting.

SPEAKER_05:

Yeah, I'm gonna step sideways briefly and talk about one ovarian um uh abstract. But I look I I think increasingly ESMO is the place to be. It's a very long way for us poor Alteroans to go, but um, you know, it that is does seem to be where a lot of the hard-hitting data is coming. So the first I want to speak about is uh keynote B96, which is presented by Nicoletta Colombo. This is a trial in women who have ovarian cancer, who are no longer responding to platinum. So, those of you who look after these women, this is a dire situation. And although we have some systemic therapies, we're not expecting a lot out of many of them. So the addition of Pembrolizmab to Pachytax or plus and minus Bebicismab is what we're looking at. Uh so the difference being the Pembrolizmab, the overall survival was improved statistically significantly in those women with PDL1 of CPS of greater than one, from 14 months to 18.2 months, so 4.2 months delta, and a trend in the overall population from 14 months to 17.7 months, but didn't quite meet their pre-specified statistical criteria. I don't have in front of me, because I only have an abstract, uh, the proportions of PDL1 positivity in platinum resistant ovarium cancer. So I think that's something that we all want to look at. So interestingly, first time that anybody has been able to prove a role for IO in uh immunoncology, sorry, in um in ovarium ligands. So this is this is um interesting. So keynote B96, the only uh gyney thing I'm gonna talk about today.

SPEAKER_02:

So Kate, it's the second time because we talked about it on the last increasingly infamous podcast about NEVO and IP combination in advanced ovarian and endometrial clear cell carcinoma study that Oliver Klein left led um with the clear cell carcinoma showing there's a phase two study, but showing really um quite impressive activity in those rare subtypes.

SPEAKER_05:

In a rare subtype. Apologies, yes. In my head, I'm thinking about the the stock standard ovarian non-clear cell ovarian, so epithelial ovarian. So yes, yes, you're right. So in that clear cell, yes, there was a and that's exciting because that's a not easy-to-treat cancer at all. This is in quote unquote stock and stock standard uh ovarian cancers that are no longer responding to platinum. So that that's interesting. Small delta, but definitely statistically significant.

SPEAKER_02:

So that's grunt. Two studies showing one, of course, a phase two and probably won't be able to do a phase three. Um and interestingly, in Australia, the PBS is approved, PBAC is approved to list on the PBS the combination of IP NEVO in rare cancers. So a tumour agnostic indication, so that's pretty exciting. And so I think it'll be difficult in that rare subtype to do a face-fest study. But there's two studies now showing some activity in ovarian cancer.

SPEAKER_05:

So And that that IP NEVO, the PBS, that's where is the cutoff of rare tumors? What do you call a rare tumour?

SPEAKER_02:

Uh well it's actually tumour agnostic, so the the they think that the role will be mostly in those rare tumors, but basically it's an indication for where clinicians and patients feel that that would be an option in their best interest.

SPEAKER_00:

So is that carp large now, Craig?

SPEAKER_02:

Yeah, pretty much.

SPEAKER_00:

There must be some kind of massive cost sharing deal which has gone on with that. I mean, the otherwise the cost implications of that are huge. I mean, a P uh for four doses at one milligram per kilogram, something like$32,000, something like that. Um, if it's a full dose, you're looking at more light at, you know, what's$120,000 uh New Zealand. So it's a lot of money for that for unproven benefit.

SPEAKER_02:

So it's a very long wording to the listing, but it's basically covering advanced or metastatic cancers where there's evidence to support efficacy and a positive benefit to risk balance, and they're estimating it with about 5,000 patients annually. And they've also removed the once-in-a-lifetime limitation for those medicines as well. So patients have say if they've had checkpoint inhibitor in the adjuvant setting and then subsequently relapse, they can be rechallenged, um, which in the past was difficult to do. So anyway, we let's um we can talk about that on our next regular episode, maybe. Because it it is an interesting area. Um but I just thought I'd throw that in as well. So you know, for those rare cancers now, there is a there is a pathway to access the checkpoint inhibitors if they've if it's got the balances in probability of benefits there.

SPEAKER_05:

Sadly, only in very far west New Zealand. Um uh look and we'll get it, we'll get it. Motorboat.

SPEAKER_02:

Hang on, hang on. What? Far West New Zealand.

SPEAKER_05:

Far West New Zealand. We're going to motorboat through the breasts now. So we've got uh adjuvant CDK46. So two big trials, um, long-term outcome, not really long-term in ER-positive breast cancer, but this is where we are. So Monarch E, just to remind people, two years of 150 milligrams BD of a Bema cyclib alongside people's hormones, a higher risk population than the other trial we'll talk about, um, no node negative women, for example, then Natalie, which were uh five-year outcomes from ribocyclub given adjuvantly at a dose reduction compared with the metastatic setting, uh, a lower risk population. Very similar outcomes. Monarch E, seven-year follow-up, an OS delta of one and a bit percent, and that did reach statistical significance. Natalie, a five-year overall survival difference of 1.6%, but hasn't met statistical significance yet. Hazard ratios for all of the other things are the same, about 3.7. Number needed to treat.

SPEAKER_02:

That's why I'm playing the Bing. I'm playing post-ESMO bingo. I've got a bingo card. And so um you just m met one of the perimeters.

SPEAKER_05:

So the number needed to treat for several hundred thousand dollars worth of treatment per person is in the eighties, in the eight zeros. So yeah, we'll get a pinevo for everybody before we get adjuvant uh CDK46. So that's that one. Thoughts? Will you be prescribing three years of a bemocyclip for no? Chris is pulling a face. Yeah. I think it's interesting because they're very biomarker driven to a point, but not beyond that. Because you'd think there will be, if there is a benefit, there will be a group. Where's my Bing, right? Uh that is biomarker driven. We just don't have the right biomarker yet. Um then I want to quickly go switch to her two positive breast cancer. So destiny breast 05. So this is comparing trastuzimab Dirux TCAN, uh, compared with trastasimab mtanzine, so the two anti-HER2 monoclonal antibody drug conjugates. Very similar trial to Catherine. So reminding yourself, people who have had neoadjuvant chemotherapy with an anti-HER2 agent, or at least one anti-HER2 agent who had residual disease at time of surgery, so it's not a PCR, were randomized between trastasm duroxatecan and trastisum mtanzine. Uh, and there is a hazard ratio for disease-free survival of 0.47 in favor of the trastasmum teroxatecan. I'll be very interested to see how long it takes or if they're able to prove an OS, because remember, it took us about seven years to get the OS out of Catherine. So, and the the um the residual patient numbers are getting very, very small indeed as we're improving things. Destiny breast 11.

SPEAKER_00:

Hang on, Kate. Were there any new safety signals?

SPEAKER_05:

Yeah, actually. No, well well, yes and no. So I just I don't know how you guys feel about this, but in a post-neo adjuvant treatment where the overall survivals are in the 85 to 90 percent, how do you feel about 10% of people having interstitial lung disease, two of whom is grade five?

SPEAKER_00:

Yeah, so is this the adjuvant trail? Is this the adjuvant trail, Kate?

SPEAKER_05:

This is adjuvant post-neo adjuvant, yeah.

SPEAKER_00:

Okay, yeah. So I think yeah, when you were talking about long-term disabling toxicity or death in an adjuvant study, you have to have a very high threshold of benefit to warrant that because adjuvant patients, by and large, are cured. And so you are exposing cured patients to potential lifelong disability or death. Just something we'll come back to in the um OE state of melanoma later. But it's a very high threshold, and the drugs are very toxic in that population.

SPEAKER_05:

So, yeah, so grade zero, no tox. Yeah, grade five dead. So only 0.5% of patients is how it was worded. Um that's a worry if you're one of the 0.5%, I imagine. In the conclusion, safety of TDX2 was generally manageable with no new safety signals. Yeah. Right, Destiny Breast 11. So this is look, I this trial pisses me off. Uh, and I know I know I've been uh lauded and told off for swearing, but ridiculously. So this is a neo adjuvant trial. So what they were doing was comparing their standard of care, what they called standard of care was dose dense AC followed by Paclitaxil with trastuzimab and pituzimab. That's what they call their standard of care. Now that involves a 10 to 12 week delay to your anti-HERD2 therapy. So that makes me grumpy. Anyway, so then they compared, they had two arms, one of which they won't tell us what their outcomes were, and that was eight cycles of trastuzimab diroxatecan. And then the second arm, which they've actually published the comparison, is four cycles of trastuzimab teroxatecan with trastuzimab and packlitaxyl, followed by trastuzimablitaxyl and paclitaxil on a reasonable schedule. So they've just sort of made it unbelievably complicated for no other reason than they can. And then there is a small difference in PCR, but not a huge delta. When would it normally we see if you're gonna change things, it's got to be by more than less than 10%. At the moment, we don't have an an i any other useful endpoints. Conveniently, the grade five toxicity rate is the same in both very complicated arms. And because you avoid the anthracycline, your left ventricular dysfunction is lower. But your interestingly, they're claiming their drug-related pneumonitis is the same, but I think that was probably grade. I think if you they haven't graded that, so if you grade it zero to to to five, Paclitaxel will also give you pneumonitis, but not as not as nasty. So I think this trial is is bullshit. Uh is my short answer, because the standard of care is not standard of care, and uh there's other things, and they've they haven't reported their third arm, which they randomized people to. So yeah, bullshit. Right. And I know the breast team will be all upset with me, but I'm sorry. Bullshit. I'm also really nervous about us using increasingly toxic and quote unquote efficacious drugs in the early setting, and that will get approved tomorrow, right, in many jurisdictions, and we don't have an OS and we don't know what the sensible sequence of anti-HER2 therapies are. And for those of us who work in the both the breast and the colon world, we keep learning stuff we didn't know we knew. Neoagevin or perioperative stucks mib doesn't work. Perioptive chemotherapy, metanchrinous uh medicine tectomy probably kills people. Yeah, or at least uh lowers the chance of survival for those that are going to relapse. We don't, yeah, we don't know what we don't know. So that that's that's what that trial's bullshit.

SPEAKER_02:

Katie, you're saying longer follow-up's needed.

SPEAKER_05:

I am showing say longer follow-up is needed. Yeah. Look, I think so. OS will be a secondary endpoint if mentioned at all.

SPEAKER_00:

It should never be a secondary endpoint in the end. No, of course it's not. Um it's the only endpoint that matters in adjuvant studies because also it's a question of sequencing, you know, it's advantageous in advanced disease. So really you're talking about whether you use it earlier or whether you use it later. So OS is the only thing that matters, and then also ensuring that they have adequate access to post-protocol therapy with that as well. So if they didn't receive it adjuvant then they went on and relapsed, they did get it in that advanced disease setting, which is often not the case. And so by artificially withholding access to a later line of therapy, you can inflate your chance of survival, which is again a trick, unfortunately, we see too often.

SPEAKER_05:

Look, I think short of them publishing the full data maybe able to see that, it's impossible to tell because the follow-up for this trial for the data is 2024. So Tuzimab Durax T can in this in the metastatic setting is relatively new all over the world. I don't know when Europe got access to it. So the first women enrolled in this trial may not have had access in the metastatic setting unless it was mandated in the trial. So, you know, you will hear us. I feel like um Craig needs another bingo card, which is stuff that Chris and Kate will wink on about, but one of them is yeah, OS is the only thing that matters in adjuvant trials. Um metastatic setting, OS and quality of life are probably the only things that really matter in adj in trials. And you've got to have a now or later, otherwise you're cheating. Now versus never is not a fair trial. Yeah.

unknown:

Right.

SPEAKER_00:

It's a fair test in metastatic cake, but it's not a fair test in adjuvant.

SPEAKER_05:

Yeah. Um so now we're quickly going to rob into the unpronounceables. So there are two um Yes. Yes.

SPEAKER_02:

Yeah, monoclonal um These are my two new favorite molecules of the moment.

SPEAKER_05:

That's right. So just now I can pronounce Cesatasmabgova T can, but I want to talk about uh datapotamabderux TCAN. There you go, as well. ISMO did a good thing. They put all of the very similar trials together, which I quite like. So LBA20 and LBA21. So uh SNT 03, presented by Javier Cortez, very charming man from Barcelona. And so uh sacetasmabgova tan in women who, for whatever reason, can't have pembrolyzmeb, understanding that we have data to show that sazatasimabgovate can plus pembrolyzmeb is better, quote unquote, than chemotherapy plus pembrolyzmeb. So they took women who either were PDL1 negative or had had pembalismab in the neo-agement setting or had some contraindication and compared sazatosimab govatecan on its own with chemotherapy, dealer's choice. Uh the primary end was PFS, which was higher in the sazatosimabgovatecan arm. We don't OS is immature. The PFS difference is just under two months. Curiously, the median duration of response in responders is longer, 12 by 7.2 months. He will be very disappointed, however, that he was followed shortly thereafter by Rebecca Dent from Singapore, LBA 21. First line, data potamabduxan in triple needle breast cancer women again uh compared uh with uh chemotherapy dealer's choice, same collection of drugs. And they demonstrated that OS was significantly better with about a five-month difference in both OS and parishion-free survival. So um, Rebecca is the winner there. And then I just want to finish very quickly on a happy, a very happy trial that I don't have a problem with. So LBA 12, Fedro Piccatori from Milan, uh presented the five-year follow-up results from the positive trial, which is pregnancy outcome and safety of interrupting therapy for women with endocrine responsive breast cancer. Uh so what they did was they took uh women who were on adjuvant endocrine therapy, and this was mostly embedded within two cohorts, so positive and soft text. And if you pause your endocrine therapy to get pregnant, not only do many women get pregnant, uh the vast 69% of those that wanted to get pregnant or pause their thing and want to get pregnant had a baby, which is exciting. Uh some had more than one. And there is no difference in breast cancer events or in OS. They were only at five years, but that's as good as it's gonna be. So most women uh went back on the endocrine therapy and had no further problems. Kind of makes sense biologically. Pregnancy is where our bodies are designed to be. It's a happy kind of balance in hormones. That's not a mega statement, that just is what it is. Uh, and uh so um, so I I'm excited by that. And I have been telling my women for a while it's safe to pause your endocrine therapy, uh, try and get pregnant, have a baby, then jump back on it when you've when you've finished.

SPEAKER_00:

Now, I reckon that was one of the most important findings from the whole conference, actually, Kate, because that's going to make a really big difference to people who are in that situation. And and obviously younger people with um hormonely sensitive breast cancer are a population of high need, and having kids is really important to a whole lot of people, uh, and understanding that's not going to increase their risk is really meaningful. So big ups to the investigators for doing that uh particular um study, which is going to be really impactful to a lot of people and lead to a lot of happiness, I hope, uh, in time to come.

SPEAKER_05:

Yeah, no, I'm absolutely delighted.

SPEAKER_02:

I agree, Chris. And so the mantra for a long time has been to avoid.

SPEAKER_00:

Yeah, absolutely. Avoid everything. Avoid HRT, avoid yeah, avoid pregnancy, avoid breastfeeding.

SPEAKER_02:

That's right. So this is part of the accumulating evidence. So can we now put that controversy to bed? Do you think that it's answered now, Kay?

SPEAKER_05:

Oh look, I I think I will. Now that's my personal biases as well. You know, like I I like Chris, happy events, pregnancy amongst cancer, it's lovely. Um, but I think we the other part of hormonal manipulation is we spend a lot of time, particularly with low-res women, talking about a therapy or a behavior, if it's avoiding pregnancy. We talk about therapies which have a 1 to 2% survival difference and ruin women's lives. Uh, and women come to me, often as a second or a third opinion, begging for permission to stop. And when they see the absolute difference in the you know, two large cohorts of women, they're like, well, why did no one put it this simply before? You know? And then in terms of pregnancy, we've never actually had any evidence that it increased the chance of women uh doing badly. We just thought it might. And we have ruined lives on the on our on our uh gut instincts that were robbed.

SPEAKER_00:

Yeah, it's been based on the precautionary principle, hasn't it, that you don't want to um expose people to a risk that may worsen their cancer, and the fact that you consider that cancer is the only risk that people should be concerned about. And I understand why people have made that recommendation because it seems to have made sense, but it's great to have the data which demonstrates that it's it's just dogma that we don't need to adhere to.

SPEAKER_02:

Great. And this sort of segues into what was also one of the most publicised abstracts in the meeting. Certainly in Australia got a lot of publicity, and that was the work done by Shireen Loy and team at Peter Mac, published in Nature, showing that uh a cycle of pregnancy, breastfeeding, and breast recovery induced an accumulation of CD8 T cells within uh human normal breast tissue. It doesn't have any immediate clinical implications, but it may explain why there's a protective effect to breastfeeding. You know, these T cells may act as kind of immune modulating cells that can um help stop the development of precancerous lesions into cancers and will open up a whole lot of other lines of research, so uh on this sort of T cell protection.

SPEAKER_00:

So Yeah, I think that's a really interesting finding. I hadn't actually seen that one um at the meeting, Craig, but CD8 tumour infiltration in colorectal cancer was really strongly associated with good outcomes um from the uh French group um who looked at that. And also in melanoma, it seems that CD8 tumour infiltration seems to be more important than PD1 or PDO1 uh scoring, for example. So the presence of this activated cytotoxic T cells within a tumour seems to be strongly prognostic and predictive of response to therapy. So understanding mechanistically how you can induce that uh CDA infiltration in uh normal healthy tissue is great new information to have. Exactly.

SPEAKER_02:

So, Kate, of all those, you bag some of those abstracts, but of all those that you presented, which and let's just forget about costs or listings, but of all those, which do you think is uh is the um practice changing?

SPEAKER_05:

Is it those um uh I think I am going to put my money apart from the positive trial, of course, on datopotan they've got to think of a better name. Datapotamab directocan, dat O DXD, uh the tropian breast O2 trial. The median overall survival for women with metastatic triple negative breast cancer of 23 months is huge. Um metastatic triple negative breast cancer has a survival similar to pancreatic cancer.

SPEAKER_00:

Yeah, but the agent sounds like a large water-dwelling animal.

SPEAKER_05:

Yeah, I guess. I do hope it gets a sexier name somewhere along the line, but that's uh like a flood of the Concord soul.

SPEAKER_02:

And the death in Flight of the Concords, for those who don't know, is um uh comedy show from New Zealand. It's pretty funny.

SPEAKER_05:

It's actually filmed in New York. Um, the Kiwis. That one I went to school with Brett, so yeah.

SPEAKER_02:

Yeah, wow. Um isn't the time. And what about the destiny abstracts, Kate?

SPEAKER_05:

Women who's having who have neoadjuvant anti-HER2 therapies for breast cancer neo-adjuvantly who do not have a pathological complete response still have a very, very, very good outcome. That's what Chris was talking about before. The Catherine trial, which is published some time ago, has now pushed most of us into rather than completing 12 months of antiherature therapy and knowing that most women are going to be fine, pushing all women onto trastasmam mtanzine, which is not not toxic for 14 further cycles, because that's what the trial said. Transtasmav diroxatecan is another step up toxicity-wise and several steps up price-wise. Uh, and we're chasing an absolute delta that is getting smaller and smaller. So, my concern, I know you said I wasn't allowed to, you know, talk about money and things. I think you have to. Money, tox, etc. I'm just, I'm just not there yet. Um, and I do worry about without an OS, what happens to those women that do relapse? You know, have we taken or have we changed the natural history of their cancer? Is it going to not respond to anything else? Have we, you know, what what have we done? I have worries. I will be alone in my worries. Everybody else will be doing it tomorrow. Because that's how breast cancer is.

SPEAKER_02:

Fantastic. Chris, do you want to do some of the I'm I'm just wildly guessing that you might want to cover some of the GI abstracts.

SPEAKER_00:

Yeah, nah. Oh, I'm gonna do some melanoma, Craig, just to mix it up.

SPEAKER_02:

Oh, okay.

SPEAKER_00:

The um the endpoint thing is a good segue into the nine-year overall survival data of NEVO versus IPI and resected stage three melanoma. So just to recap briefly, until now, the only positive survival data we've got in resected stage three melanoma is COMBAD, which was adjuvant, depravib and trimetinib in BREF mutant melanoma, only positive survival data. So the EORTC Pembrolizmab versus placebo study had DFS positive OS not reported. And NEVO versus IP10, which is a study, had DFS but OS not reported. Because immature data and adjunct population doing quite well to get to a median takes a long time. So this is the nine year survival data of NEVO versus IP at 10 megs per kg. So now we had minimum follow-up of 107 months. Nine years. Wow, it's a long time. So that's 2016.

SPEAKER_01:

Trying to do my 12 divide by 12.

SPEAKER_00:

Yeah, nine years. And so this data was first presented in 2016, and many people have been prescribing Nivoluumab in stage three for quite some time. It's only just been funded in New Zealand, an adjuvant PD1 inhibitor in stage two melanoma for receptive disease. I know Australia's been doing it for a lot longer. Uh we know the recurrence free survival had a hazard ratio of 0.76, which for adjuvant's okay. Um, but with PD1 inhibitors, the question's always been adjuvant versus at relapse, given that we can cure 20 to 30% of people at relapse. Distant metastasis 3 survival 0.81 hazard ratio with a confidence interval touching one. But uh here's the kicker. Overall survival, hazard ratio 0.88, confidence interval 0.69 to 1.11. Overall survival not positive. So, yes, a trend towards significance. Bing um numerically superior um OS 69% versus 65%, which is a 4% difference. And melanoma specific survival has a ratio of 0.87 uh again, confidence interval crosses one um and uh and and and not not positive. The post-protocol therapy is important to note as well. So this was done in 2016 where not everyone was getting access to uh PD1 at relapse. Um, but what it's showing is that 37% of people got access to NEVO in the um in one arm and 22% in the other. So it's relatively low, 20 to 30% of people getting access to post-protocol therapy. So you're not getting that contamination still in the post-protocol therapy, but people were still not getting cured. Uh and so I think this actually says that resected stage three disease, you really have to think very hard, uh, and they'd be very high risk before you'd recommend that therapy because 5% of people get long-term disabling toxicities from PD1. So those of us who held back a little bit uh can feel a little bit sanctimonious uh right now about that data. The landscape's changed quite a bit in that time though, and now you've got Nodena, which is six weeks of Ipinevo, and SWOG 1801, which is three cycles of nevligent Pembroke, followed by Pembroke for up to a year afterwards, which both showed improvements in event-free survival uh at a year, quite good jumps, 20 to 30% jumps in um survival for macroscopic disease. Uh, so they've become the standard in Australia for sure, and about to become the standard in New Zealand. So for me, this group of patients who have resected in transit METS or who have the lymph node surprise at central lymph node biopsy for no macroscopic disease, we we don't have data for anything except for TKI to prove overall survival, and the benefit in terms of absolute numbers, clinically meaningful, statistically non-significant, is really quite small and probably about the same as the lifelong disabling toxicity. So some people may say lifelong disabling toxicities are the same, uh, you know, are outweighed by survival. It's possible, but that'd be pretty optimistic. The other study I wanted to mention, which I do think is practice changing, is the Matterhorn study. So Matterhorn is the study of perioperative flot with or without devilimab in receptable gastric cancer. Uh, this is an important study because back when uh I was a trainee, we had surgery versus perioperative ECF, the magic study. Uh then you had uh flot versus ECF and flot came out better. Uh and then you had the study of the ESOPEC study in esophageal, which was cross versus preoperative flot, um, which was, you know, overall pretty similar, to be fair. It was mostly SCF though rather than FLOP. And so this is the flop with or without DiviliMab and the perioptive setting. Now, we did have PASCR data previously from the study showing that PASCR was better with the addition of Devalimab. But PASCR is not a validated endpoint for overall survival in perioptive gastric cancer, so we weren't quite certain if that was necessarily going to translate. But what this does show us is overall survival was improved with a hazard ratio of 0.78. 95% confidence interval did not include one. Event-free survival was as reported. Pass CR correlated with improved outcomes, good hazard ratio. And the better the past response you got, the better your outcome was, but that's prognostic, not predictive. And the incremental survival gain was almost 7%. And bearing in mind that ECF versus surgery is plus 13%. FLOT versus ECF is about another 10%, and there's about another 7% on top of that. So this is a uh a clinically meaningful and statistically significant improvement in overall survival in a curative intent population where Devalumab is not a survival improver in the salvage setting. So drum roll, I think this represents a new standard of care. And the key issue there is going to be the cost of this medicine coming into the clinic. So I think that's an important improvement and and uh and that I think will rightly uh change practice as of now. So get off to socials and describe if you like. Love to hear your views if you have a different take on that. The other big news that came out was in the circulating tumour DNA uh studies. Now there were two really important but quite contrasting studies, and that was the CT DNA study in adjuvant colon cancer and the CT DNA study in adjuvant bladder cancer. I'm going to discuss these together. First of all, I want to congratulate the researchers on this, particularly in the colorectal study, which was led by Professor Jenny T, who's a Kiwi, in case anyone who listened to the show didn't know that, Jenny Kiwi, uh, and uh and Patty Gibbs at Melbourne, obviously, and a lot of the ADU ITG researchers as well, um, familiar names to um many listeners on this podcast. So a really good effort. A thousand people were uh recruited to that study uh over time. So huge effort um to pull that off and a lot of respect to the investigators for their efforts. A thousand patients in dynamic three, and the randomization was standard clinical pathologic adjuvant therapy versus ct DNA guided strategy. If you were CT DNA positive, you would get oxaliplatin-based chemotherapy usually for six months, and if you were CT DNA negative, you would have shorter duration, so three months, or no adjuvant or fluoropriminine alone. The primary input was DFS, uh, and secondary was overall survival. Uh the results showed that the CT DNA guided strategy did not improve disease-free survival, and if anything, the DFS was slightly worse by 2% than the standard of care arm, uh, which did not consider CT DNA as a strategy, and OS was immature. I was at a conference recently where uh CT DNA was um held up by uh one researcher as being a fait accompli. Why do we need to do randomized phase three trials incorporating CT DNA into our decision-making structures? It was obvious uh phase three trials are expensive and unnecessary and we should just get on with it, and doctors who say that's not the case or they're just gatekeeping. So I think the study published two weeks later really knocks that out of the park and shows that actually in this particular situation uh we don't have a good escalation or de-escalation strategy, that the CT DNA is prognostic, but it's not predictive, and therefore it can't change your clinical management. And if you did use it, you would threaten numerically at least uh overall survival. The other uh CTDNA study that was of note uh at ESMO was the adjuvant atizalismab and muscle invasive bladder cancer study by uh Tom Poles and um and colleagues. And what this study did was it was actually smaller than the uh dynamic three study, but uh uh randomized phase three double blind double blind control. Where those who were CT DNA positive after resection of their muscle invasive bladder cancer were randomized two to one to receive a tissillismab or placebo for up to a year. Uh so this was uh an important study which did have an escalation. Of course, this is in the context of prior adjuvant immune therapy studies in bladder cancer, maybe impacting on DFS but not impacting on OS. OS hadn't been proven uh before in bladder cancers for uh immune therapies, and in adjuvant, it remains controversial as to whether any therapy is particularly uh helpful. The primary endpoint in the um vigor 011 study, which was the um CT DNA study, had a hazard ratio of 0.64 for DFS and a hazard ratio of 0.59 for overall survival. So the overall survival with CT DNA guided at Tizolysomab was 32.8 months compared to 21.1 months. So that's a whopping 11-month improvement in overall survival, which was clinically significant, which was statistically significant and clinically meaningful. I don't think anyone would debate an 11-month improvement in overall survival as being uh clinically not meaningful because it is, and that hazard ratio of 0.59 is strong as well. Um, the authors also reported get ready with your Bing Craig, uh toxicity was manageable with grade 3, 4 adverse events of 28% in the uh atisolism arm versus 22% in the placebo arm. So this is the first CT DNA-triggered adjuvant study to show both DFS and OS benefit, and it validates MRD, minimal residual minimal residual disease, as a predictive biomarker and supports immunotherapy escalation for CT DNA uh positive patients. So now the problems are going to be getting your CT DNA done in a timely fashion, uh particularly in a relevant uh turnaround time uh for patients having the right assay to detect minimal residual disease and then getting people onto this uh therapy as well. So I think those studies are practice changing uh their team. I think um D flot, new standard of care. I think adjuvant ethizalismab and CT DNA positive bitter cancer, new standard of care. Uh and I think ct DNA in stage three uh colon cancer prognostic should not guide your therapy at this stage.

SPEAKER_02:

Yeah. So it's interesting to compare and contrast those two studies and the results, because I'm glad you brought up the ingredients. I was going to mention that amongst the genitor urinary tract. But so there you have clearly CT DNA positive patients, you escalate the treatment with an effective treatment, the checkpoint inhibitor, and you see a benefit. The same strategy in the dynamic three didn't work. There's a sort of confusing result in the dynamic three where the de-escalation is probably the same, but we're not entirely comfortable with that. So what are your thoughts?

SPEAKER_00:

Do you think do you think that de-escalation strategy for the negative patients in the stage threes works or Yeah, look, I think the problem is that actually the problem for the dynamic investigators was that the de-escalation versus escalation strategies just aren't that different. Because three months versus six months of uh FPOX is the same. So it's not a real escalation or de-escalation strategy. That's not the f fault of the investigators, it's not the fault of the technology, it's the fact that we don't have a really good de-escalation position uh in colon cancer, which is really different to InVigor, whereby you do have a good escalation, which is PD1 um in that situation, which don't have that in colon. And um and so that's I think the reason probably why it failed, uh, why it didn't reach physical significance and why there was a numerically worse uh OS in the C DNA guided uh arm. Yeah, good.

SPEAKER_05:

I wanted to congratulate the InVigor team for thinking things through radically and taking a risk because it must have been tempting to do another stockstand angevin I.O. versus nothing trial. And this is really helpful. So in that arm that was CT DNA informed, half of patients avoided adjuvant therapy. Yeah. You know, and that and those people did very, very well, you know, that they they you know aren't relapsing. So that that's so much useful information in one trial because it's been logically thought through and planned. And I wanted to congratulate them for doing that and for taking what must have been a complicated risk at the time. Um, yeah, really, really excited about it.

SPEAKER_00:

Yeah, it provides a blueprint print too, doesn't it, where you know you've got a therapy which is a potential marginal benefit in uh the advent setting to try and identify who might actually benefit from it. Um so I think it's it's a great blueprint for others to follow. Uh unfortunately for colon, we just don't have that good thing. But I think if we do get another drug or another biomarker or something like that, it might actually help uh be another stratification factor uh for that uh and it may well get rerun again.

SPEAKER_05:

Yeah, we had a session at NZSO where I was allowed to give a list of things that I'd like off the scientists, and one of them was some more drugs and colon cancer so we could rescue the patients who don't respond to fibrofuel and not settle thin. In the adjuvant setting, we've got other drugs. Uh yes, yeah.

SPEAKER_00:

It seems a long time since we've had a good adjuvant study in colon cancer. What do we got? We've got aspirin and pick three, we've got exercise um and we've got uh oxalyplatin pregnant pores.

SPEAKER_05:

Which is perfectly safe in breast cancer survivors.

SPEAKER_02:

As we as we reflected. Chris, did you have anything else you wanted to?

SPEAKER_00:

No, that were the key four, the big four I wanted to cover off there, Craig. They were the headline winners there.

SPEAKER_02:

Yeah, great. I think the dynamic three was the most controversial, and you know, I think it's gonna lead to quite a lot more discussion, I would say. Well, that's been fantastic. First part. We'll be back next week for part two, because there's such some great information there. So Dankeschön, everybody. Hopefully you to see.

SPEAKER_04:

Bitter bitte schon schön sehr schön. That's all my German used up. Apart from oh, kommst du mit.

SPEAKER_00:

Oh, I've got German swear words. That's all I've got. That sounds that sounds bad, Kate. Did you say that again and explain it?

SPEAKER_05:

Kommst du mit? It means come with me.

SPEAKER_00:

Right. What you really mean, um, join me from the waiting room to the consultation room, because that's a phrase that reduces monologue, right? I can't think of any other circumstances where you would meet your phrase.

SPEAKER_02:

Interesting. You never know with Kate though, do you? She could have picked that up in a German nightclub.

SPEAKER_05:

I did my elective in India with a whole lot of Germans and may have learnt some things. Yeah.

SPEAKER_00:

Oh dear. Well, you're a lifelong learner though, Kate. That's one of the things I love about you.

SPEAKER_02:

Well, on that note, thank you to all the listeners. Um, thank you for all the feedback. I hope you uh enjoyed that episode and we'll be back with part two next week. So thanks, everyone. See you soon. Matewa.

SPEAKER_03:

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 OncologyNetwork.com.au. 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 websites. Your insights help shape the conversation and drive the direction of future episodes. This is Rachel Babin signing off for the Oncology Journal Club Podcast.