S4 E2 The Oncology Journal Club: Chrono-Oncology, Genomic Therapy Matching + iCCA

In this episode of The Oncology Journal Club, the team weigh promising trial signals against the level of evidence needed to change clinical practice. From perioperative cholangiocarcinoma to molecular matching and chrono-oncology, the focus stays on a key question: what meaningfully improves outcomes for patients?

What’s covered

•  NeoGOLP trial in high-risk resectable iCCA: improved event-free survival; overall survival still immature 
•  MoST programme: molecular matching and survival associations when therapies align with biomarkers 
•  Genomic therapy matching in clinical decision-making 
•  Chrono-oncology: does treatment timing influence outcomes? 
•  CHOPIN phase II uveal melanoma trial: combination therapy signals and feasibility 
•  ASCO living guideline updates across lung, gastro-oesophageal and thyroid cancers 

The Oncology Journal Club Podcast hosted by Professor Craig Underhill, Dr Kate Clarke and Professor Chris Jackson, and proudly produced by The Oncology Network

Visit oncologynetwork.com.au for Show Notes, to send us Voice Notes and more information. 

Transcript

Welcome And Global Check-In

Rachael Babin 0:00

Hello and welcome to the Oncology Journal Club Podcast, where Oncology Papers meet real world practice. I'm your producer Rachel Babin, and joining me again among Professor Craig Underhill, Dr. Kate Clarke, and Professor Christopher Jackson. Together they dive into the research shaping cancer care. The important, the intriguing, and the sometimes controversial. This podcast is proudly produced by the Oncology Network. Head over to OncologyNetwork.com.au for the show notes with links to all of the papers discussed today. Okay, over to you, Craig.

Craig Underhill 0:34

G'day, g'day, g'day. Welcome everybody to uh series four, episode two of the Oncology Journal Club or OGC. It's a great pleasure to have Dr. Kate Clark here in the land of long light cloud. How are you, Kate?

Kate Clarke 0:50

Wonderful. And there's no clouds today. Absolutely stunning morning in uh Tefanganui Athara, Wellington, Artherwa, New Zealand.

Craig Underhill 0:56

Wonderful. Take a photo out the window. Professor Christopher Jackson, how are you?

Christopher Jackson 1:02

Pretty good. So I've just been at the Common Sense Oncology annual meeting, which is in Montreal. And people who've been talking about Common Sense Oncology previously, but this is a group that's been around for three or four years now, uh, and it's really about trying to refocus oncology on patient outcomes that matter. Things like uh improving quality of life uh and ensuring good trial design and good trial interpretation uh and good trial communications. It's a really good group, uh, and that's in Montreal. Also got uh hang out in Kingston last week with Chris Booth, who's the um author of the challenge paper, and do grand rounds at Kingston Hostel and Queens University. So it's been uh just under a week here now. It's been great. Wow, is Kingston in Quebec as well? So Kingston's in Ontario. I quite like Montreal. I don't know if we've got any Montreal listeners. If they do send us a message uh in the comments, guys.

Craig Underhill 1:48

Yeah, so listeners, we've been very dedicated crew bringing you this episode because we have Rachel, our producer, uh sitting in Spain, near Alicante. We've got Kate in Wellington, or what was the Mari name for that, Kate?

Kate Clarke 2:03

Tefanganua Tada, the large water of Tada.

NeoGulp Trial In Cholangiocarcinoma

Craig Underhill 2:06

Be careful how you say that. Uh and I'm in Bonagilla, outside Oberudonga, and um Chris is in Monreal, so we're all in four different time zones. I'm in my Qantas pajamas uh because it's 5 a.m. We've got a great episode coming up, so let's get straight into it. Chris, I think you might do your long paper first.

Christopher Jackson 2:27

Yeah, so uh paper just out in the New England Journal of Medicine is uh paper called the Neo Gulp Trial, G O L P. This is a phase two, three open label multi-centre RCT from 11 hospitals in China and receptable high-risk intrahepatic cholangiocarcinoma. Now, people in GI cancers are increasingly used to perioperative chemotherapy, of course, or preoperative chemotherapy uh in borderline receptable and also upfront receptable. It's already the standard of care in gastric cancer, of course. And this should extend it to cholangiocarcinoma, which of course has got very high rates of one and two year recurrence. Uh, this study used neoadjuvant gem cytobine with oxaliplatin, lembetinib, and torapalomab, which is a PD1 inhibitor, the three cycles, so um day one, day eight, uh, every two nine days for three cycles followed by surgery or front surgery, uh, with both groups then getting adjuvant capsidabine, which I think is defensible in that condition. The primary point was event-free survival, and secondary points included overall survival and safety. So the trial, headline of the trial is that the trial is positive for event-free survival. So event-free survival was defined as people not getting to surgery because of progression uh or recurrence. And the median EEFS was 18 months with neo-advent therapy versus 8.7 months with surgery alone. And at 24 months, that's 37% versus 25%. Now, OS is promising but immature. 24 month overall survival was 79%, favoring the neoadjuvent group compared to 61%. Just bearing in mind the very first study in gastric cancer added 13%, and flotters adding about 20-25%. So it's in that same ballpark of benefit for that group. Uh, but that didn't cross the pre-specified significance boundary. So whilst the P was less than 0.05, uh, they specified the P as much smaller than that because they did some hierarchical testing. So at this stage, it's not an OS positive trial, but there's a real biological signal here. Uh response rate was 55%, and pathological response is 19%, and pathological CR 5%. So it's not just noise, the regime's clearly doing something. There's a couple of things I took away from this trial for starters. I think the authors deserve credit uh here. It's a hard disease in which to run trials. It's relatively uncommon. The eligible population's narrow, uh, and perioperative bittery trials are quite difficult to complete. Uh they're focused on a high-risk population, which is exactly where you want to have these intensification strategies. Uh, also the surgical safety data are quite reassuring, given the inclusion of a VegFTKI. Surgery was performed in 97% of patients in the neo-urgent arm and 99% of patients in the control. And the complication rates that were reported weren't high with neourgivent therapy. So pretty important when you're packing in a drug that might cause uh dehiscence or leaks. And so that is good to have that safety signal. But there are some limitations. Just coming back off the common sense oncology uh meeting, of course, this is an the end point for starters. Let's talk about the endpoint. Event-free survival. This is a curative intent population. So event-free survival is a surrogate. Uh, we haven't necessarily validated event-free survival as a surrogate for overall survival. So, whilst OES is promising, I think we have to wait for more data. And I think the standard we need to hold periopitive studies to is overall survival. Um, there are issues, of course, with effectively lead time bias based if you're adding new advent therapy to one uh arm and not to the other. So you could just be delaying recurrence. It's important to be certain that OES matures. The other thing is I didn't actually have access to the detailed post-protocol therapy. So you had PD1 therapy in the periobitive arm, but uh I wasn't clear if you had it in the situation, but it's had a recurrence, uh, although the level population for that would be relatively low. It is buried in the supplementary appendices, but I could get access to those, unfortunately, due to the restrictions of my access to the journal. Um the other thing is this toxicity, there is it's not it's not a trivial regime. Um quad therapy for um billy cancers in the periopital setting has to be taken seriously. Adverse events were 97%. That's of all adverse events, that means they're recording toxicities at least, grade three or higher and around a quarter, uh, which is probably acceptable if it's going to improve your cure rate, but we do have to understand the trade-offs there. So the final thing is we don't really see the quality of life data here either at the moment, which is essential in metastatic disease studies, and we have to think about longer-term toxicities with PD1 agents as well. So, on the whole, I think it's a very strong signal-generating study. The regime fairly improves tumour control and delays recurrence, and it appears certainly feasible, which is not a given in the setting. Um, but I think I'd stop short of saying it's a new standard today until we've got overall survival, which is published. But if overall survival does mature and we get uh information about the long-term toxicities and some quality of life data, then we'll be in that position to start saying this is something that we should be looking at. So well conducted, important EFS positive trial with promising but immature survival data, and this will be one for sure. Uh, I'm going to be watching closely for that data to mature.

Kate Clarke 7:20

Yeah, interesting. I obviously I have a biased population in my clinic, but I'm seeing younger and younger and younger people with biliary cancers. The signal is not as strong as rectal cancer because it's not as common. We've new surgeon who's come from the States, he's blown away by our rates of biliary cancer compared with what he's used to in the east of the USA. So I'm I'm always holding out hope for this truly awful disease that we will get more things that are useful and useful in a curative setting. It's really, really exciting. Did they say what dose of Linvatina? But I just couldn't find that when I'm flicking through the redacted bits I'm allowed to see.

MOST Program And Topograph Evidence Tiers

Craig Underhill 7:53

Yeah, no, you've got me case. No, you've got me. Yeah, interesting, CJ, that you selected this. We are seeing more billary cancers, and as Kate said, there does seem to be a trend towards some younger presentations. I think immunotherapy will have an impact in some subpopulations down the track, but we're waiting on some data on various trials in that. Interesting paper. I have got one to tell you about. This is right across tumour titles. This is from paper from JAMA Oncology, First Order, Franklin. There's been quite a bit of publicity about this study that's come out of the MOST group, the Australian Molecular Screening and Therapeutic Programme. So this was looking at the clinical utility of matching therapies to genomic biomarkers based on varying levels of evidence. They took patients that were recruited to the MOST program. So these are patients with advanced or refractory solid tumours and adequate ECOG score. These patients in this program were recruited from June 2016 to December 2021, follow-up to July 2022. The study's just been published. So they looked at using a framework called the Topograph Therapy Orient Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals Knowledge Base, which the authors have previously published on. And it gives four tiers. So tumours are analysed with the next generation sequencing, there's a molecular tumor board. The tumors are assigned that one of those four levels according to the results of the NGS. Then if there is a match therapy recommended and available, could be on a clinical trial, could be drug that's available, then patients proceed to treatment accordingly. And in this cohort of 3,383 patients from around Australia, and there was a number of uh regional sites participating, which was great. So enabled access to these treatments, remembering that the tumour that's shipped to be analyzed in the laboratory for the NGS rather than the patients having to travel. So many regional patients elected to participate. Of the 3,383, 37% had a clinically active biomarker or T1 to 3A. Among the patients with the T1 to 3A biomarker receiving treatment, they had a longer median overall survival than those with an unmatched therapy, and that was 21 months versus 12 months with a hazard ratio of 0.6. So almost a doubling of survival if a patient's tumour had a biomarker that could be matched to a treatment. Patients receiving therapy matched to investigational evidence on Ts 3.4B, there was an associated survival benefit. It was 14.5 months versus 12.8 months with an hazard ratio 1.04. So this co-wort study of patients with advanced solar tumours with matching therapies to genomic biomarkers has substantially improved survival when there was supportive evidence from prospective clinical trials. So there's a number of editorial issues that immediately sprung to mind, and that's the importance of enabling access to this testing for patients with advanced tumours. And uh the MOST program has been exceptionally good. And its subsequent spin-off program called Prospect, they've been exceptionally good at providing widespread access to this testing uh around Australia. And then if patients have an appropriate biomarker, they uh can receive treatment or go on to a match to a clinical trial. Joe's this study reiterates the importance of making this testing available and the clinical trials available to as many people as possible using decentralized um methodology. So there's been quite a bit of publicity about it. You can read a bit more about it on Oncology News Australia as as well. Some in the mainstream media covered this this paper as well. So kudos to Franklin and David Thomas and his team at the most program for doing the study uh and publishing it.

Kate Clarke 12:20

The editorial that I read, I think, was quite clear that uh you can't use precision oncology as a fishing expedition. You have to use it with a sober look at the evidence that when you're interpreting things. And so if evidence exists that in people with cancers with this mutation, then that is useful. But just throwing a drug on a fishing expedition doesn't seem to help, even though it feels like it should. So I think that was that was quite useful. So it's it's matching sensible evidence from precision oncology with sensible evidence in the existing literature provides sensible outcomes rather than let's just give everybody a go at something.

Craig Underhill 12:58

You mean so the very approach that the this program was taking? Yeah. I missed the editorial, Kate.

Kate Clarke 13:05

So there's one in there's one in MedPage, and I think uh Vivek Subia comments on the study in drama oncology as well, and it is complimentary about the fact that they were sober about their approach to the molecular targets.

Christopher Jackson 13:17

Fantastic. Well, we'll find when you've got sober Aussie investigators, isn't it?

Craig Underhill 13:22

Had to get up very early in the morning for that. Well, I was I was worried when we set up this programme, Chris, that you're at a conference in Montreal and that you'd be sober during the recording, but it's only only 4 p.m.

Christopher Jackson 13:34

What I really like about this one, Craig, for starters, it's quite a big patient population, which is great. Oftentimes these studies are a lot smaller than 3,000 patients, so it's good to see that large number. I also really like how they've tiered the evidence as well. You know, one, two, and three, eight, for example, they're matching it to the quality of the evidence, which is good. Uh, and clearly labeling labelling 3B and 4 is investigational, I think, is also quite helpful too. I mean, that these targets aren't all the same. You know, BRAF inhibitors and melanoma are spectacular, BRAF monotherapy and colorectal cancer is terrible. So, you know, the primary tissue of origin still does seem to matter, I think. So I don't think you can just say it's targeted therapy at the target, doesn't always necessarily mean it will work and the driver mutations different in different cancers, the way in which they uh work. Is it activation, constitutional activation, is it uh overexpression, is it what is it, you know, the the actual driver there? And also, you know, I think we have to be careful about saying that the intervention improved overall survival. I think we can say that the uh intervention was associated with overall survival because we don't want to conflate correlation and causation, because of course, as we know, 100% of people who conflate correlation and causation die. Sure. Thanks, Chris.

Craig Underhill 14:43

So we'll put a link to the topograph database, so therapy-oriented precision oncology guidelines for recommending anti-cancer pharmaceuticals. So it's a curated database that um you can put in the tumor mutation and actually alerts you to some uh evidence uh in this field. So that's a joint venture between the Omicco programme, Garvin University New South Wales, University of Sydney, and the NHNemacy Clinical Trial Centre. So that's a useful resource as well.

Rachael Babin 15:12

Before we get back to the papers, if there's a study you think we should be covering on the Oncology Journal Club podcast, feel free to send it our way. You can join the Oncology Network. Remember, registration is free, and leave us a voice note on the OJC page. That's at Oncology Network.com.au. Or come and chat with us on our socials. And physicians, please don't forget that you can claim CME points for listening to the show. All right, back to the journal club.

Uveal Melanoma Liver Perfusion Plus IO

Christopher Jackson 15:42

Cool. Chris,

Craig Underhill 15:44

do you have some quick bites for us?

Christopher Jackson 15:47

We've been chatting on our melanoma chat group over the last uh week or two about the less common subtypes of melanoma, the uh mucosals uh and the odd UVL that you get along the way. And that's led us all just to start chatting about the different ways in which we approach these diseases and with limitations of the current evidence bases. That meant that when this study was published in the Lance Oncology, it uh excuse the pun, caught my eye because this is a study on UVL melanoma. So I'm obviously in fine form today with the dead jokes, guys. And this is the Chopin study, which is a randomized phase two study in a metastatic UVL melanoma, looking at whether combining percutaneous hepatic perfusion using melphalin, essentially uh high-dose livericted chemotherapy with or without uh epilumimab could improve outcomes. So this is a randomized phase two. Everyone gets continuous hepatic perfusion with melphalin, and then the intervention is with or without epinevo. Uh, the epinevo dose is epi1, nivo three every three weeks times four cycles with no maintenance. So uv is obviously a disease which is very different to cutaneous. It has a low tumour mutational burden burden, it's relatively immunologically cold, uh, and historically checkpoint inhibitors have been much less effective. So they're trying to hot up the tumour using lividrected therapy and then layer it with uh immune therapy. And UVL melanoma has a distinct predilectation for the liver as the solitary site of disease. So, what did they find? Well, this is a trial with a positive signal. Uh the combination of hepatic perfusion with ipping and nevo improve response rates, PFS, and importantly, uh OES was improved compared with perfusion alone. Uh, so unlike a lot of UVL melanoma studies, there's actually an OS signal here, which is what makes it interesting. And this does mechanistically fit the hypothesis of liver directed therapy leading to antigen release, which could improve T cell activation, which might actually help the checkpoint inhibitors to work better. Unsurprisingly, um, there was a higher rate of adverse events, but the authors say toxicity was manageable with known new signals. But the key thing here for the study is the context, and this is where it gets important. So historically, a venevo has got response rates in the order of 10 to 20% uh for UVL melanome, which is quite low. And median OES is about 12 to 18 months, depending on the series. So this increases the response rates by more than you see with abinevo on its own. So it's not just testing is a benivo active in this disease, it is does seem to somehow be synergistic rather than just additive, even though you don't have the epinevo alone arm, which will be the synergy test. And then, of course, this group didn't have to bentafusp. So for those who treat melanoma, you will know that I struggle to say this word, uh to bentafusp is the benchmarks, but that requires HLA uh two uh semicolon O1 positivity, which about half the patients, but the other half don't have that. So it's not everyone. So at least half the patients would not have been eligible to receive Tibentafusp, which would have left um them with IO or liver directed therapies as the only deliberate ones you can do. Uh so it does show that you can take a disease that doesn't respond well to IO and make it more responsive by combining it with lividirected therapy, but it's a small phase two, single center comparison is hepatic perfusion alone, not to bendifusp. So it could only be uh extrapolated so far to the non-HLA 201 pollutative patients. And it's uncertain uh how generalizable this is, and it's certainly a complex and resource-intensive procedure. We certainly don't do hepatic perfusion with Malphalan and our center for this uh particular indication. Uh, but I think it's uh it's uh it's good interesting signal and good to see them doing randomised trials. People often say you can't do randomised trials in rare disease subtypes. These guys are clearly proving that wrong. Uh so again, good on the authors for doing that. And that's why I picked this trial.

Kate Clarke 19:36

It's been tried at other immune cold-ish tumors. Like if you can prod this particular bear, why aren't we prodding other bears?

Christopher Jackson 19:42

I've not seen melphalan infuse livers before, to be honest with you, Kate. That was a new one uh to me. Um but I guess people are trying to do that a bit. I mean, you've got Bok Bell, colorectal cancer. You have the Regonivo study as well, which is trying to switch off to T regs. And I guess it's part of the theory, at least, why giving oxaloplatin with immune therapy does increase antigen exposure. So something along the lines of that. And of course, we'd have this very magical and mysterious property which everyone has seen lots of cases of, but no one's ever actually uh written up a case series called the EBScopal effect, where radiotherapy is used in combination with IO to actually improve the immune response uh rates as well, which is something we talk about a lot in our meetings.

Kate Clarke 20:26

So, what I'm saying is if this one works in this disease type, shouldn't we use this mechanism in other disease types? Yeah, rather than Yeah. Yeah, I think one of those specific things about why um the UN use Malphalan is the agent or liver-directed therapy is more case. Liver-directed therapies, yeah. Because my proposal is that we all know that the liver itself is part of the problem here because it is immune cold. And so when cancer has found a home in liver, it's protected from immunotherapy, you know, is the theory. The reason why a Tesovev works in liver cancer is mostly you are at least in part reversing that. But now we've got a a something that works, at least in UVL or appears to work in UV or melanoma, that's very hard to say. Why not try that in other liver-predominant cancers that are otherwise immune resistant? Use this technique again and see if it's helpful.

Christopher Jackson 21:14

Yeah, it's a good point, isn't it? I mean, I was wondering about whether or not it was the infusion of the chemotherapy into the liver which was also having an effect on local T cells, and that might modify the response. There was some data uh that Ashani presented at PDSO. I'm not sure if you uh can remember that with me, help me through this data, but if I recall correctly, it was people who had melanoma and had a melanoma liver metastis resected, still had lower rates to IO than in people who had non-liver-based metastatic sites. And so they're thinking about being something very specific about once the tumor is gone to the liver, there's an immunologic uh interaction which happens in someone with a much better understanding of immunotherapy and uh immunology than me could probably help us out with that mechanism. But that was the data recall that she presented. Do you have a similar recollection, or am I imagining that?

Kate Clarke 21:59

I Don't recall that, but that feels like a negative abscopal effect, doesn't it? It feels like the the cancer's almost training the immune system by using the liver as a as a training ground to say, hey, chill out, you can't see me. Fascinating. I think we are increasingly finding out that we don't know what we don't know. What we don't know.

Craig Underhill 22:18

So sometimes there's new innovations to raise as many questions as answers. Chris, do we have any other quick bites for us today?

Rectal Cancer Dual Immunotherapy Signals

Christopher Jackson 22:24

Yeah, I've got one more. It's a rectal cancer study, which is called the Neoteric Study. So this is a neoteric study, a randomized phase two study published in JCO and locally advanced rectal cancer, specifically again, microsatellite stable PMMR disease. This is the type of rectal cancer that we see the most of. And this is important. So immunotherapy has historically had very limited activity in this group, and it's the growing uh area. And again, as Kate, you say already, oftentimes, this is the left side and particularly the rectal side, which is growing in our indigenous uh population, particular rectal location. All patients received standard long course chemoradiotherapy and then were randomized to receive either atesalism ab alone or atesalismab plus tyrogolomab, uh, which is a digit inhibitor, and digit is another immune checkpoint thingy, uh, which has been tested a bit in melanoma, uh, so far so negative, uh, but Tigit's another um immune checkpoint that people have been interested in uh looking at. Question here is can we improve response rates in microsatellite stable rectal cancer by adding dual immune therapy after chemaradiotherapy? The primary in point was pathologic complete response, which is obviously looking at the uh the signal rather than actually trying to define a standard of care. Uh and the combination arm had a PEF CR rate of 36% compared to 22% with the Tsilismad alone, which on the face of it looks encouraging, particularly when you compare it to historical PCR rates of around 15 to 25% with chemo reds alone. And there are also signals of improved downstaging and early separation of EFS curves, although obviously data is still immature. But there are some pretty important limitations. And the first is endpoint. Let's just dive straight into that. A PCR-driven study. While PCR is attractive, it is not validated. It is not validated for overall survival in the setting, and we don't have a true control arm. Both groups received immunotherapy, so we don't know actually how much it's coming from a Tizo or how this compares to chemorad alone. And the third, it's a small phase two study with immature survival data and no quality of life outcomes reported so far. The other key thing, of course, is where does it fit in the context of modern rectal cancer trials. Now we've talked about rectal cancer trials a bit on the podcast in the last year or two because there's been a lot happening in rectal cancer uh studies. We had the Oprah study, which was total neodrent therapy with long-course chemoradiation followed by fluoroprominine oxaliplatin, which shows meaningful organ preservation. Pradege 23, which was around fulferoinox, followed by chemo radiotherapy, followed by surgery, followed by a bit more chemotherapy, improving disease-free and metastasis-free survival. And you've got the prospect study, prospect study, which went the other way, which was shown in selective patients, we can omit radiotherapy without compromising the outcomes uh there at all. So the field's moving in multiple different directions, intensification, de-escalation, uh, and organ preservation. And so where neoteric sits, it's a little bit awkward as to where it's sitting at the moment. It says we might be able to improve complete response rates further. We might be able to push organ preservation rates out even further, but it's not combined with the current standard of care, which is chemotherapy and the TNT population. But we might be able to explore it in earlier stages, like T2E naught, for example, where we we don't have the answers for what to do for those T2 patients you'd like to organ preserve. So this is a signal finding study that shows biological activity, and that is important, um, but it doesn't yet tell us whether patients live longer, live better, or avoid surgery more often. And it's not well positioned currently in the current landscape. So it's gonna need to be combined uh with one of the other strategies that's currently in play, or find a different niche. So a slightly earlier part there. So I think that's gonna excite trialists, this one, and drug developers rather than clinicians of the clinic, at least for now. But it's cool to see microsatellite stable PMMR rectal cancer, having some therapy thrown at it. Also, just a very naughty comment, but uh terra golly bab has done very well in phase one, too, and not done very well in phase three across the board. I do not know why. I'm not clever enough to figure that out, but there's been an awful lot of early signals that have gone away in phase three, esophageal cancer, lung cancer, liver cancer. So, you know, I'd be curious to see what happened in a in a bigger, well-controlled, well-consented trial, what would happen, you know. I think I'd be curious actually to know what the team thinks. If you were offered a trial with Neovagent Toro Golumab, knowing the biases that I'm coming with from all of those negative phase threes, what trial would you design and how would you consent your patients to? It doesn't seem to be a signal of danger, but many signals of of no effect.

Craig Underhill 26:50

It's a good question, but it sounds like this is a very complicated field now. So, how are we going to sort out, Chris? Is it through randomized clinical trials comparing these different approaches?

Christopher Jackson 27:00

Of course, I think it needs to go an RCT with chemotherapy now. So that's what'll happen now, won't it? Would be chemotherapy with that dual combination, which I think you can justify doing another phase two looking at the combination with chemotherapy to look for safety signals and then do a randomization between the two. Okay, when we went back to the old days, um, you know, when you and me were both training, uh we had uh all those phase two to phase three studies which showed that when you went from phase two to phase three, your response rates dropped off by about 10% and your OES dropped a bit as well, and most of that is disease burden. Us people in phase twos have got lower disease burden than those in phase threes. Uh, the phase two study patients are usually younger as well. They're usually uh less cumber, but it is less competing, morbidity there as well to drive a signal. Um, but that's why we do phase threes is for the maximum generalizability. And so the phase twos are always signal finders. Uh and I do get worried these days that we are just uh changing practice more and more off phase twos, which are hyperselective patients, which don't take those factors of generalizability into account. And so it's always important, I think, for us to still do the phase three was good numbers. The point of bringing this one forward is that you've had a uh tumour which is immune cold up until now. There isn't that much in the way of signal of IO and uh GI cancer outside of PMMR. Uh and it's cool to see that there's another way other than just VGF, but maybe targeting uh the immune cold tumors another pathway there. So I thought that was interesting. Uh and I think having read that study, if I was offered a digit PD1 study, given that we've got nothing in that space at the moment, I'd certainly give it a second look for sure.

Kate Clarke 28:21

I obviously we all do teach juniors, and I find teaching rectal cancer today is like teaching uh stage three lung cancer ten years ago. So you can pretty much justify any strategy you want depending on your desired outcome and uh the patient's desired uh choices. So it is increasingly complex to understand to teach the quote unquote correct way to manage a a uh locally advanced rectal cancer.

New Guidelines And Chrono-Oncology Timing

Craig Underhill 28:46

Kate, that sounded like a segue into my quick bites. So we've got three ASCII guidelines to mention. People can click on the links and read in a bit more detail. I encourage any trainees listening to have a look at these guidelines. I think they're a pretty good way of seeing an evidence-based summary of why we currently do what we do in these various cancers. So there's one out therapy for stage four non-small cell lung cancer without driver alterations. This is ESCO Living Guidelines. This is uh version 3.0 for 2026, so that's been updated. There is a new ASCO update as well for advanced gastrosophageal cancer with immunotherapy and targeted therapy being added. Also, interestingly, who'd have thought that the 2026 ESCO guideline update on managing thyroid cancer? So, again, 10 years ago, medical oncologists probably weren't much involved in treating thyroid cancer. Increasingly, they are as we recognise the different subtypes. There's the common well-differentiated thyroid cancer, which is treated with radio iodine, but then can become refractory, medolatry thyroid cancer and anaplastic thyroid cancer. And there's quite a number of active treatments, again, often directed by the biomarker subtypes of those tumours. Again, I found it interesting to have a look through this guideline. Any trainees listening, I would encourage you to have a look at that because it gives you a state of the art of where we're up to in treating the various subtypes. And we do like a good guideline on the OJC. Then the last one I want to mention is the chrono oncology study. Again, this received quite a little lot of publicity in the medical media, including there's a good article on Oncology News, but also in the mainstream media. This is a nature medicine paper in lung cancer. Tony Mock in Hong Kong was the corresponding author. This was a randomised phase three study assessing the time of day of delivering immunotherapy. So patients were randomized to receive chemoimmunotherapy either in the morning or the afternoon. And with a median follow-up of 28.7 months, the progression-free survival was 11 months in the early time of day group and 5.7 months in the late time of day group with a hazard ratio of 0.4. So a halving in the risk of progression, median overall survival 28 versus 16 months. Again, hazard ratio of 0.42, a reduction in the risk of early death. And interestingly, they did some translational studies looking at some biomarkers. And over the first four cycles, the morning circulating CD8 T cells increased in the early time of day group, and was a declined in the late time of day group. And there was a higher ratio of activated CD38 HLADR positive versus exhausted TIM3 plus PD1 plus C D8 T cells in the early time of day group. So there was some biological explanation potentially for why giving the immunotherapy in the morning is bad in the afternoon. So interestingly, I know that some people are now designing some prospective studies in other tumours. The AGITG group in Australia is looking at a uh study called circadian, which is early versus late delivery of immunotherapy in people with gastrointestinal tumours. Oh sorry, is it gastrointestinal tumours, Chris, or just colon? I can't remember. But anyway, there's more prospective studies potentially to come. But interestingly, in looking at the feasibility of those studies, turns out that a lot of centres have already switched. And so on the basis of this one randomized study in lung cancer, there are units around in Australia who are now switching to have all the immunotherapy patients receiving immunotherapy in the mornings uh rather than the afternoon, which is interesting.

Kate Clarke 32:45

So what time did they define it as, Craig? What was the time they used as a cut point?

Craig Underhill 32:49

I think it was eleven. Oh, I think it was one o'clock in the afternoon. The afternoon patients started after one and the morning patients were before that.

Christopher Jackson 32:56

So the Chinese study at 3. 3 p.m.

Kate Clarke 32:58

Three o'clock, which is actually quite late. Because once you start hanging that, that means the nurses aren't leaving until six or seven. So I think there's the potential for a lot of confounds in that. The other thing I'd like to see is analysis by biological sex. There is a a significant difference in the circadian rhythms between women and men. We already know that when you look at many immunotherapy studies that the outcomes are different by sex. So I if you throw in something that's as biological as our circadian rhythms and ignore the fact that women are not just men without penises, you knew I had to get a genital in there at some point. I think we could end up throwing the baby out for bath water and uh disadvantaging a group of people. I could be completely wrong.

Craig Underhill 33:34

But there was multivariant analysis, and I presume gender, not sex, was uh one of the variants. That could be today's quote, was it? Women are not just men without a penis, or so the other way, men are just women with a penis.

Kate Clarke 33:47

Yeah, that's better, I think.

Christopher Jackson 33:48

Yeah. Yeah, look, I when I first saw the data around time of day as well, coming from a rural and remote centre, you know, the patients who have their chemo in the afternoons or the trip in the afternoons are different. Because the people from coming out of town, they're further distances, you might need to see them the same day because a bit worried about their wellness to proceed with therapy, for example, as you see them in the morning clinic rather than seeing them a week before and scheduling them, you know. So there's there's inherent uh reasons why some people in the afternoon are supposed to in the morning as well. So I don't necessarily think you should always just take it at face value. So I think that's why randomised trials are again to be celebrated because they are testing that. So of course there's a biological plausibility argument for why uh it would be different, but biological plausibility is not sufficient to make you change your minds about. We just have to be very cautious about the confounders there.

Craig Underhill 34:30

I was surprised to s to hear that people had already switched practice whole as bolus across tumour types. But, you know, this is a low-cost intervention, and maybe if there's further data proving this approach, then maybe we do need a redesign of how we deliver systemic treatments and with a focus on delivering the immunotherapy component in the mornings. I think we may well need to do that. But I think we do need a bit more evidence before we just have a blanket change in practice. 100%. And then there's the um AGIG circadian study coming up, which is a time of day study as well, which I think will be important. Were you asleep when I was talking about that before and last year?

Christopher Jackson 35:09

Did you know? The colorectal melanoma. I gave it the name.

Craig Underhill 35:13

I gave you the name, it was circadian. Did you say the name circadian? Is it in all GI cancers crystals? I think it's just for colorectals, isn't it?

Kate Clarke 35:20

I think it's all DMMR. Yeah, I think it's all DMMR GI cancers, isn't it?

Tools Page Voice Notes And Closing

Craig Underhill 35:24

I think that is right, Kay. Yeah. Just point out we've got a couple of new features, uh, including on our website a tools page. So that topograph database of match biomarkers and treatments would be an appropriate tool that we list on the tool page. So as we mentioned, various things like the SMO relative benefit scale, things like that that we mentioned in the podcast, we'll list on that page so people can find those resources. And we're also feature in our voice notes. So, you know, technology is lost to me. Rachel's going to explain what to do. Rachael, tell us about these voice note things.

Rachael Babin 36:01

Okay, so you go to the show notes and you will see a WhatsApp icon. You click on that and it will open WhatsApp. So if you're doing on your phone and you've got the app, it will open it in the air. It will also open it in the browser if you're on the computer. And then you can hold down the green button and send us a voice note, and then we can include your comment or question or indeed paper recommendation in the next episode.

Craig Underhill 36:27

Fantastic. And so, yeah, you can tell us like what a lot of rubbish that interpretation of that paper was, or well done, guys, or whatever want to do.

Christopher Jackson 36:36

That's excellent. Uh and I've just got here the circadian concept synopsis, a randomized phase control of monitoring morning versus after administration with new checkpoint now it is in DNMA, MSO high, unresectable or metastatic. No, I'm not frozen. That was just a dramatic effect. Gastrointestinal cancers.

Craig Underhill 36:54

Right. Thank you, Chris. We got the end. So thanks very much. I've been getting some nice feedback from people running too. And I just want a big shout out to Victoria, who is a breast cancer nurse who is helping to look after my wife at the moment. Thanks, Victoria, for all your doing and thanks for your feedback on the show. Thank you, Kate, Chris, and Rachel, for today's episode, and we'll see you all in a few weeks. Matewa.

Rachael Babin 37:27

Kiara and goodbye. Always a pleasure. Thanks, Craig. That's it for this episode of the Oncology Journal Club podcast, where Oncology Papers meet real world practice. If you'd like to explore the papers we discussed today, head to oncology network.com.au and visit the Oncology Journal Club tab, where you'll find show notes, links to the research, and a growing collection of OJC resources. Don't forget to join the Oncology Network, it's free. You can send us voice notes and chat with us on social media. And physicians, you can also claim CME points for listening to this show. This podcast was proudly produced by the Oncology Network. Until next time, thanks for listening.